79 results on '"Yana G Najjar"'
Search Results
2. 888 Identification of tumor-intrinsic drivers of immune exclusion in acral melanoma
- Author
-
Riyue Bao, Hassane Zarour, Yana G Najjar, Diwakar Davar, Cindy Sander, Jason J Luke, John M Kirkwood, Ryan C Augustin, Aofei Li, Marion Joy, Maureen Lyons, Katelyn Smith, Brian Isett, Sarah Brodeur, Mary Pham, and Peter C Lucas more...
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
- Full Text
- View/download PDF
Catalog
3. 43 Harnessing the power of glycoproteomics: a cutting-edge approach for predicting treatment efficacy in metastatic melanoma with immune checkpoint inhibitors
- Author
-
Joseph Markowitz, Yana G Najjar, Michael P Brown, Dennie Frederick, Genevieve M Boland, Klaus Lindpaintner, Gege Xu, Rachel Rice, Daniel Serie, Lisa M Ebert, Alan Mitchell, Xin Cong, Gonzalo Tapia-Rico, Chad Pickering, Paul Aiyetan, Ranjan Bhadra, Chirag Dhar, and Flavio Schwarz more...
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
- Full Text
- View/download PDF
4. Identification of tumor-intrinsic drivers of immune exclusion in acral melanoma
- Author
-
Riyue Bao, Yana G Najjar, Diwakar Davar, Cindy Sander, John M Kirkwood, Jason John Luke, Sarah Newman, Hassane M Zarour, Peter Lucas, Ryan C Augustin, Aofei Li, Marion Joy, Maureen Lyons, Mary P Pham, Katelyn Smith, and Brian Isett more...
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Acral melanoma (AM) has distinct characteristics as compared with cutaneous melanoma and exhibits poor response to immune checkpoint inhibitors (ICIs). Tumor-intrinsic mechanisms of immune exclusion have been identified in many cancers but less studied in AM. We characterized clinically annotated tumors from patients diagnosed with AM at our institution in correlation with ICI response using whole transcriptome RNAseq, whole exome sequencing, CD8 immunohistochemistry, and multispectral immunofluorescence imaging. A defined interferon-γ-associated T cell-inflamed gene signature was used to categorize tumors into non-T cell-inflamed and T cell-inflamed phenotypes. In combination with AM tumors from two published studies, we systematically assessed the immune landscape of AM and detected differential gene expression and pathway activation in a non-T cell-inflamed tumor microenvironment (TME). Two single-cell(sc) RNAseq AM cohorts and 11 bulk RNAseq cohorts of various tumor types were used for independent validation on pathways associated with lack of ICI response. In total, 892 specimens were included in this study. 72.5% of AM tumors showed low expression of the T cell-inflamed gene signature, with 23.9% of total tumors categorized as the non-T cell-inflamed phenotype. Patients of low CD3+CD8+PD1+ intratumoral T cell density showed poor prognosis. We identified 11 oncogenic pathways significantly upregulated in non-T cell-inflamed relative to T cell-inflamed TME shared across all three acral cohorts (MYC, HGF, MITF, VEGF, EGFR, SP1, ERBB2, TFEB, SREBF1, SOX2, and CCND1). scRNAseq analysis revealed that tumor cell-expressing pathway scores were significantly higher in low versus high T cell-infiltrated AM tumors. We further demonstrated that the 11 pathways were enriched in ICI non-responders compared with responders across cancers, including AM, cutaneous melanoma, triple-negative breast cancer, and non-small cell lung cancer. Pathway activation was associated with low expression of interferon stimulated genes, suggesting suppression of antigen presentation. Across the 11 pathways, fatty acid synthase and CXCL8 were unifying downstream target molecules suggesting potential nodes for therapeutic intervention. A unique set of pathways is associated with immune exclusion and ICI resistance in AM. These data may inform immunotherapy combinations for immediate clinical translation. more...
- Published
- 2023
- Full Text
- View/download PDF
5. Search for effective treatments in patients with advanced refractory melanoma continues: can novel intratumoral therapies deliver?
- Author
-
Yana G Najjar
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Most patients with advanced melanoma ultimately fail immune checkpoint inhibitor (ICI) therapy because of primary or acquired resistance. There remains a critical unmet need for new therapies that function via alternative immune activation mechanisms to safely trigger an antitumor immune response in patients with ICI-refractory disease. This commentary discusses the recent failures and hope for novel intratumoral therapies under development in the advanced refractory melanoma setting, outlining key mechanistic differences that may be critical to yielding success in this difficult-to-treat population. more...
- Published
- 2021
- Full Text
- View/download PDF
6. Ipilimumab plus nivolumab for patients with metastatic uveal melanoma: a multicenter, retrospective study
- Author
-
Arun Singh, Richard Carvajal, Yana G Najjar, Igor Puzanov, Marc Ernstoff, Shailender Bhatia, Katy Tsai, Fei Ding, Zeynep Eroglu, Douglas Johnson, Pauline Funchain, Sunandana Chandra, Ryan Sullivan, Roma Bhatia, Kristina Navrazhina, Kelly Abbate, Barbara Durden, Song Park, Akansha Chowdhary, Jonathan Kennedy, Pankit Vachhani, Joseph Drabick, Tan Xu, Jessica Yang, Daniel Manson, John M Kirkwood, Justine Cohen, and Alexander Shoushtari more...
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background Uveal melanoma (UM) is the most common intraocular malignancy in adults. In contrast to cutaneous melanoma (CM), there is no standard therapy, and the efficacy and safety of dual checkpoint blockade with nivolumab and ipilimumab is not well defined.Methods We conducted a retrospective analysis of patients with metastatic UM (mUM) who received treatment with ipilimumab plus nivolumab across 14 academic medical centers. Toxicity was graded using National Cancer Institute Common Terminology Criteria for Adverse Events V.5.0. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier methodology.Results 89 eligible patients were identified. 45% had received prior therapy, which included liver directed therapy (29%), immunotherapy (21%), targeted therapy (10%) and radiation (16%). Patients received a median 3 cycles of ipilimumab plus nivolumab. The median follow-up time was 9.2 months. Overall response rate was 11.6%. One patient achieved complete response (1%), 9 patients had partial response (10%), 21 patients had stable disease (24%) and 55 patients had progressive disease (62%). Median OS from treatment initiation was 15 months and median PFS was 2.7 months. Overall, 82 (92%) of patients discontinued treatment, 34 due to toxicity and 27 due to progressive disease. Common immune-related adverse events were colitis/diarrhea (32%), fatigue (23%), rash (21%) and transaminitis (21%).Conclusions Dual checkpoint inhibition yielded higher response rates than previous reports of single-agent immunotherapy in patients with mUM, but the efficacy is lower than in metastatic CM. The median OS of 15 months suggests that the rate of clinical benefit may be larger than the modest response rate. more...
- Published
- 2020
- Full Text
- View/download PDF
7. Adjuvant therapy versus watch-and-wait post surgery for stage III melanoma: a multicountry retrospective chart review
- Author
-
Peter Mohr, Felix Kiecker, Virtudes Soriano, Olivier Dereure, Karmele Mujika, Philippe Saiag, Jochen Utikal, Rama Koneru, Caroline Robert, Florencia Cuadros, Matias Chacón, Rodrigo U Villarroel, Yana G Najjar, Lisa Kottschade, Eva M Couselo, Roy Koruth, Annie Guérin, Rebecca Burne, Raluca Ionescu-Ittu, Maurice Perrinjaquet, and Jonathan S Zager more...
- Subjects
adjuvant therapy ,interferon ,melanoma ,metastatic melanoma ,nodal disease ,stage III melanoma ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Aim: To describe treatment patterns among patients with stage III melanoma who underwent surgical excision in years 2011–2016, and assess outcomes among patients who subsequently received systemic adjuvant therapy versus watch-and-wait. Methods: Chart review of 380 patients from 17 melanoma centers in North America, South America and Europe. Results: Of 129 (34%) patients treated with adjuvant therapy, 85% received interferon α-2b and 56% discontinued treatment (mostly due to adverse events). Relapse-free survival was significantly longer for patients treated with adjuvant therapy versus watch-and-wait (hazard ratio = 0.63; p < 0.05). There was considerable heterogeneity in adjuvant treatment schedules and doses. Similar results were found in patients who received interferon-based adjuvant therapy. Conclusion: Adjuvant therapies with better safety/efficacy profiles will improve clinical outcomes in patients with stage III melanoma. more...
- Published
- 2019
- Full Text
- View/download PDF
8. Supplementary Tables 1 and 6-8 from Obesity Is Associated with Altered Tumor Metabolism in Metastatic Melanoma
- Author
-
Jennifer L. McQuade, Yana G. Najjar, Greg M. Delgoffe, Michael A. Davies, Weiyi Peng, James S. Wilmott, Jianhua Zhang, Andrew Futreal, Han Liang, Ralph J. DeBerardinis, John M. Kirkwood, Jennifer A. Wargo, Dirk Schadendorf, Alexander J. Lazar, Michael T. Tetzlaff, Richard A. Scolyer, Georgina V. Long, Jeffrey E. Gershenwald, Nadim Ajami, Patrick Hwu, Jeffrey E. Lee, John F. Thompson, Khalida M. Wani, Jian Wang, Grant M. Fischer, Renato Guerrieri, Y.N. Vashisht Gopal, Scott E. Woodman, Nagireddy Putluri, Chantale Bernatchez, Julie M. Simon, Jared Malke, Elizabeth M. Burton, Vancheswaran Gopalakrishnan, M.A. Wadud Khan, Lauren E. Haydu, Theodore Nowicki, Courtney W. Hudgens, Carrie R. Daniel, Alexander M. Menzies, Christine N. Spencer, Yan Zang, Camelia Quek, Tuba N. Gide, Aditya K. Mishra, Xiaogang Wu, Jun Li, Mingchu Xu, Ryan C. Augustin, Dayana B. Rivadeneira, Ashley V. Menk, and Andrew W. Hahn more...
- Abstract
Supplementary Table 1: Baseline characteristics for patients included in the integrated gene set enrichment analysis (Figure 2-3) by cohort; Supplementary Table 6: The most frequent somatic alterations (alts) in patients with regionally metastatic melanoma by body mass index from The Cancer Genome Atlas cohort; Supplemental Table 7: Integrated gene set enrichment analysis for pathways associated with fatty acid metabolism by body mass index; Supplemental Table 8: Gene expression of selected genes of interest involved in fatty acid metabolism. more...
- Published
- 2023
- Full Text
- View/download PDF
9. Supplementary Figure S1 from Obesity Is Associated with Altered Tumor Metabolism in Metastatic Melanoma
- Author
-
Jennifer L. McQuade, Yana G. Najjar, Greg M. Delgoffe, Michael A. Davies, Weiyi Peng, James S. Wilmott, Jianhua Zhang, Andrew Futreal, Han Liang, Ralph J. DeBerardinis, John M. Kirkwood, Jennifer A. Wargo, Dirk Schadendorf, Alexander J. Lazar, Michael T. Tetzlaff, Richard A. Scolyer, Georgina V. Long, Jeffrey E. Gershenwald, Nadim Ajami, Patrick Hwu, Jeffrey E. Lee, John F. Thompson, Khalida M. Wani, Jian Wang, Grant M. Fischer, Renato Guerrieri, Y.N. Vashisht Gopal, Scott E. Woodman, Nagireddy Putluri, Chantale Bernatchez, Julie M. Simon, Jared Malke, Elizabeth M. Burton, Vancheswaran Gopalakrishnan, M.A. Wadud Khan, Lauren E. Haydu, Theodore Nowicki, Courtney W. Hudgens, Carrie R. Daniel, Alexander M. Menzies, Christine N. Spencer, Yan Zang, Camelia Quek, Tuba N. Gide, Aditya K. Mishra, Xiaogang Wu, Jun Li, Mingchu Xu, Ryan C. Augustin, Dayana B. Rivadeneira, Ashley V. Menk, and Andrew W. Hahn more...
- Abstract
Integrated gene set enrichment analysis by body mass index (BMI) with correction for S phase. This figure presents a dotplot of genes differentially up- or downregulated in OW/OB patients versus NL BMI patients. Red indicates upregulation in OW/OB verse NL. The far left column is all patients, and then, an analysis controlling for sex, cohort, and tissue site is shown in the 3 columns to the right. more...
- Published
- 2023
- Full Text
- View/download PDF
10. Supplementary Table 3 from Obesity Is Associated with Altered Tumor Metabolism in Metastatic Melanoma
- Author
-
Jennifer L. McQuade, Yana G. Najjar, Greg M. Delgoffe, Michael A. Davies, Weiyi Peng, James S. Wilmott, Jianhua Zhang, Andrew Futreal, Han Liang, Ralph J. DeBerardinis, John M. Kirkwood, Jennifer A. Wargo, Dirk Schadendorf, Alexander J. Lazar, Michael T. Tetzlaff, Richard A. Scolyer, Georgina V. Long, Jeffrey E. Gershenwald, Nadim Ajami, Patrick Hwu, Jeffrey E. Lee, John F. Thompson, Khalida M. Wani, Jian Wang, Grant M. Fischer, Renato Guerrieri, Y.N. Vashisht Gopal, Scott E. Woodman, Nagireddy Putluri, Chantale Bernatchez, Julie M. Simon, Jared Malke, Elizabeth M. Burton, Vancheswaran Gopalakrishnan, M.A. Wadud Khan, Lauren E. Haydu, Theodore Nowicki, Courtney W. Hudgens, Carrie R. Daniel, Alexander M. Menzies, Christine N. Spencer, Yan Zang, Camelia Quek, Tuba N. Gide, Aditya K. Mishra, Xiaogang Wu, Jun Li, Mingchu Xu, Ryan C. Augustin, Dayana B. Rivadeneira, Ashley V. Menk, and Andrew W. Hahn more...
- Abstract
Differential gene expression analysis for each subgroup.
- Published
- 2023
- Full Text
- View/download PDF
11. Data from Obesity Is Associated with Altered Tumor Metabolism in Metastatic Melanoma
- Author
-
Jennifer L. McQuade, Yana G. Najjar, Greg M. Delgoffe, Michael A. Davies, Weiyi Peng, James S. Wilmott, Jianhua Zhang, Andrew Futreal, Han Liang, Ralph J. DeBerardinis, John M. Kirkwood, Jennifer A. Wargo, Dirk Schadendorf, Alexander J. Lazar, Michael T. Tetzlaff, Richard A. Scolyer, Georgina V. Long, Jeffrey E. Gershenwald, Nadim Ajami, Patrick Hwu, Jeffrey E. Lee, John F. Thompson, Khalida M. Wani, Jian Wang, Grant M. Fischer, Renato Guerrieri, Y.N. Vashisht Gopal, Scott E. Woodman, Nagireddy Putluri, Chantale Bernatchez, Julie M. Simon, Jared Malke, Elizabeth M. Burton, Vancheswaran Gopalakrishnan, M.A. Wadud Khan, Lauren E. Haydu, Theodore Nowicki, Courtney W. Hudgens, Carrie R. Daniel, Alexander M. Menzies, Christine N. Spencer, Yan Zang, Camelia Quek, Tuba N. Gide, Aditya K. Mishra, Xiaogang Wu, Jun Li, Mingchu Xu, Ryan C. Augustin, Dayana B. Rivadeneira, Ashley V. Menk, and Andrew W. Hahn more...
- Abstract
Purpose:Overweight/obese (OW/OB) patients with metastatic melanoma unexpectedly have improved outcomes with immune checkpoint inhibitors (ICI) and BRAF-targeted therapies. The mechanism(s) underlying this association remain unclear, thus we assessed the integrated molecular, metabolic, and immune profile of tumors, as well as gut microbiome features, for associations with patient body mass index (BMI).Experimental Design:Associations between BMI [normal (NL < 25) or OW/OB (BMI ≥ 25)] and tumor or microbiome characteristics were examined in specimens from 782 patients with metastatic melanoma across 7 cohorts. DNA associations were evaluated in The Cancer Genome Atlas cohort. RNA sequencing from 4 cohorts (n = 357) was batch corrected and gene set enrichment analysis (GSEA) by BMI category was performed. Metabolic profiling was conducted in a subset of patients (x = 36) by LC/MS, and in flow-sorted melanoma tumor cells (x = 37) and patient-derived melanoma cell lines (x = 17) using the Seahorse XF assay. Gut microbiome features were examined in an independent cohort (n = 371).Results:DNA mutations and copy number variations were not associated with BMI. GSEA demonstrated that tumors from OW/OB patients were metabolically quiescent, with downregulation of oxidative phosphorylation and multiple other metabolic pathways. Direct metabolite analysis and functional metabolic profiling confirmed decreased central carbon metabolism in OW/OB metastatic melanoma tumors and patient-derived cell lines. The overall structure, diversity, and taxonomy of the fecal microbiome did not differ by BMI.Conclusions:These findings suggest that the host metabolic phenotype influences melanoma metabolism and provide insight into the improved outcomes observed in OW/OB patients with metastatic melanoma treated with ICIs and targeted therapies.See related commentary by Smalley, p. 5 more...
- Published
- 2023
- Full Text
- View/download PDF
12. Supplementary Table 2 from Obesity Is Associated with Altered Tumor Metabolism in Metastatic Melanoma
- Author
-
Jennifer L. McQuade, Yana G. Najjar, Greg M. Delgoffe, Michael A. Davies, Weiyi Peng, James S. Wilmott, Jianhua Zhang, Andrew Futreal, Han Liang, Ralph J. DeBerardinis, John M. Kirkwood, Jennifer A. Wargo, Dirk Schadendorf, Alexander J. Lazar, Michael T. Tetzlaff, Richard A. Scolyer, Georgina V. Long, Jeffrey E. Gershenwald, Nadim Ajami, Patrick Hwu, Jeffrey E. Lee, John F. Thompson, Khalida M. Wani, Jian Wang, Grant M. Fischer, Renato Guerrieri, Y.N. Vashisht Gopal, Scott E. Woodman, Nagireddy Putluri, Chantale Bernatchez, Julie M. Simon, Jared Malke, Elizabeth M. Burton, Vancheswaran Gopalakrishnan, M.A. Wadud Khan, Lauren E. Haydu, Theodore Nowicki, Courtney W. Hudgens, Carrie R. Daniel, Alexander M. Menzies, Christine N. Spencer, Yan Zang, Camelia Quek, Tuba N. Gide, Aditya K. Mishra, Xiaogang Wu, Jun Li, Mingchu Xu, Ryan C. Augustin, Dayana B. Rivadeneira, Ashley V. Menk, and Andrew W. Hahn more...
- Abstract
Differential gene expression analysis for covariates controlled.
- Published
- 2023
- Full Text
- View/download PDF
13. Supplementary Table 4 from Obesity Is Associated with Altered Tumor Metabolism in Metastatic Melanoma
- Author
-
Jennifer L. McQuade, Yana G. Najjar, Greg M. Delgoffe, Michael A. Davies, Weiyi Peng, James S. Wilmott, Jianhua Zhang, Andrew Futreal, Han Liang, Ralph J. DeBerardinis, John M. Kirkwood, Jennifer A. Wargo, Dirk Schadendorf, Alexander J. Lazar, Michael T. Tetzlaff, Richard A. Scolyer, Georgina V. Long, Jeffrey E. Gershenwald, Nadim Ajami, Patrick Hwu, Jeffrey E. Lee, John F. Thompson, Khalida M. Wani, Jian Wang, Grant M. Fischer, Renato Guerrieri, Y.N. Vashisht Gopal, Scott E. Woodman, Nagireddy Putluri, Chantale Bernatchez, Julie M. Simon, Jared Malke, Elizabeth M. Burton, Vancheswaran Gopalakrishnan, M.A. Wadud Khan, Lauren E. Haydu, Theodore Nowicki, Courtney W. Hudgens, Carrie R. Daniel, Alexander M. Menzies, Christine N. Spencer, Yan Zang, Camelia Quek, Tuba N. Gide, Aditya K. Mishra, Xiaogang Wu, Jun Li, Mingchu Xu, Ryan C. Augustin, Dayana B. Rivadeneira, Ashley V. Menk, and Andrew W. Hahn more...
- Abstract
Body mass index values by patient ID for all RNASeq cohorts.
- Published
- 2023
- Full Text
- View/download PDF
14. A retrospective analysis of the impact of the COVID-19 pandemic on staging at presentation of patients with invasive melanoma
- Author
-
Saba S, Shaikh, Xi, Yang, Dylan D, Fortman, Hong, Wang, Diwakar, Davar, Jason J, Luke, Hassane, Zarour, John M, Kirkwood, and Yana G, Najjar
- Subjects
Skin Neoplasms ,Brain Neoplasms ,COVID-19 ,Humans ,Dermatology ,Melanoma ,Pandemics ,Neoplasm Staging ,Retrospective Studies - Published
- 2022
- Full Text
- View/download PDF
15. Supplementary Figure S2 from Neoadjuvant Pembrolizumab and High-Dose IFNα-2b in Resectable Regionally Advanced Melanoma
- Author
-
Ahmad A. Tarhini, John M. Kirkwood, Hassane M. Zarour, Amy Rose, Cindy Sander, Matthew P. Holtzman, James F. Pingpank, Christian Laing, Zeni Alfonso, Jennifer Tsau, Anil Pahuja, Ghanashyam Sarikonda, Beiru Chen, Ju Young Kim, Jehovana O. Bender, IlaSri B. Summit, Jennifer Bordeaux, Joseph J. Skitzki, Igor Puzanov, Marc S. Ernstoff, Lisa H. Butterfield, Rogerio I. Neves, Joseph J. Drabick, Arivarasan Karunamurthy, Diwakar Davar, Yan Zang, Yan Lin, Huang Lin, Dustin McCurry, and Yana G. Najjar more...
- Abstract
Treatment significantly affects the circulating immune compartment.
- Published
- 2023
- Full Text
- View/download PDF
16. Supplementary figure legend 1 from Neoadjuvant Pembrolizumab and High-Dose IFNα-2b in Resectable Regionally Advanced Melanoma
- Author
-
Ahmad A. Tarhini, John M. Kirkwood, Hassane M. Zarour, Amy Rose, Cindy Sander, Matthew P. Holtzman, James F. Pingpank, Christian Laing, Zeni Alfonso, Jennifer Tsau, Anil Pahuja, Ghanashyam Sarikonda, Beiru Chen, Ju Young Kim, Jehovana O. Bender, IlaSri B. Summit, Jennifer Bordeaux, Joseph J. Skitzki, Igor Puzanov, Marc S. Ernstoff, Lisa H. Butterfield, Rogerio I. Neves, Joseph J. Drabick, Arivarasan Karunamurthy, Diwakar Davar, Yan Zang, Yan Lin, Huang Lin, Dustin McCurry, and Yana G. Najjar more...
- Abstract
Representative gating strategy illustrating (A) CD4 and CD8 T cell identification (B) expression of ICOS on CD4 positive T cells (C) expression of PD-1 and Ki-67 within PD-1 positive cells and (D) expression of CD38/HLA-DR, PD-1 and KI-67 within CD8+ PD-1+ T cells is shown. more...
- Published
- 2023
- Full Text
- View/download PDF
17. Supplementary figure legend 2 from Neoadjuvant Pembrolizumab and High-Dose IFNα-2b in Resectable Regionally Advanced Melanoma
- Author
-
Ahmad A. Tarhini, John M. Kirkwood, Hassane M. Zarour, Amy Rose, Cindy Sander, Matthew P. Holtzman, James F. Pingpank, Christian Laing, Zeni Alfonso, Jennifer Tsau, Anil Pahuja, Ghanashyam Sarikonda, Beiru Chen, Ju Young Kim, Jehovana O. Bender, IlaSri B. Summit, Jennifer Bordeaux, Joseph J. Skitzki, Igor Puzanov, Marc S. Ernstoff, Lisa H. Butterfield, Rogerio I. Neves, Joseph J. Drabick, Arivarasan Karunamurthy, Diwakar Davar, Yan Zang, Yan Lin, Huang Lin, Dustin McCurry, and Yana G. Najjar more...
- Abstract
Treatment significantly affects the circulating immune compartment.
- Published
- 2023
- Full Text
- View/download PDF
18. Data from Neoadjuvant Pembrolizumab and High-Dose IFNα-2b in Resectable Regionally Advanced Melanoma
- Author
-
Ahmad A. Tarhini, John M. Kirkwood, Hassane M. Zarour, Amy Rose, Cindy Sander, Matthew P. Holtzman, James F. Pingpank, Christian Laing, Zeni Alfonso, Jennifer Tsau, Anil Pahuja, Ghanashyam Sarikonda, Beiru Chen, Ju Young Kim, Jehovana O. Bender, IlaSri B. Summit, Jennifer Bordeaux, Joseph J. Skitzki, Igor Puzanov, Marc S. Ernstoff, Lisa H. Butterfield, Rogerio I. Neves, Joseph J. Drabick, Arivarasan Karunamurthy, Diwakar Davar, Yan Zang, Yan Lin, Huang Lin, Dustin McCurry, and Yana G. Najjar more...
- Abstract
Purpose:Neoadjuvant immunotherapy may improve the clinical outcome of regionally advanced operable melanoma and allows for rapid clinical and pathologic assessment of response. We examined neoadjuvant pembrolizumab and high-dose IFNα-2b (HDI) therapy in patients with resectable advanced melanoma.Patients and Methods:Patients with resectable stage III/IV melanoma were treated with concurrent pembrolizumab 200 mg i.v. every 3 weeks and HDI 20 MU/m2/day i.v., 5 days per week for 4 weeks, then 10 MU/m2/day subcutaneously 3 days per week for 2 weeks. Definitive surgery followed, as did adjuvant combination immunotherapy, completing a year of treatment. Primary endpoint was safety of the combination. Secondary endpoints included overall response rate (ORR), pathologic complete response (pCR), recurrence-free survival (RFS), and overall survival (OS). Blood samples for correlative studies were collected throughout. Tumor tissue was assessed by IHC and flow cytometry at baseline and at surgery.Results:A total of 31 patients were enrolled, and 30 were evaluable. At data cutoff (October 2, 2019), median follow-up for OS was 37.87 months (range, 33.2–43.47). Median OS and RFS were not reached. Radiographic ORR was 73.3% [95% confidence interval (CI): 55.5–85.8], with a 43% (95% CI: 27.3–60.1) pCR rate. None of the patients with a pCR have had a recurrence. HDI and pembrolizumab were discontinued in 73% and 43% of patients, respectively. Correlative analyses suggested that intratumoral PD-1/PD-L1 interaction and HLA-DR expression are associated with pCR (P = 0.002 and P = 0.008, respectively).Conclusions:Neoadjuvant concurrent HDI and pembrolizumab demonstrated promising clinical activity despite high rates of treatment discontinuation. pCR is a prognostic indicator.See related commentary by Menzies et al., p. 4133 more...
- Published
- 2023
- Full Text
- View/download PDF
19. Obesity is associated with altered tumor metabolism in metastatic melanoma
- Author
-
Andrew W. Hahn, Ashley V. Menk, Dayana B. Rivadeneira, Ryan C. Augustin, Mingchu Xu, Jun Li, Xiaogang Wu, Aditya K. Mishra, Tuba N. Gide, Camelia Quek, Yan Zang, Christine N. Spencer, Alexander M. Menzies, Carrie R. Daniel, Courtney W. Hudgens, Theodore Nowicki, Lauren E. Haydu, M.A. Wadud Khan, Vancheswaran Gopalakrishnan, Elizabeth M. Burton, Jared Malke, Julie M. Simon, Chantale Bernatchez, Nagireddy Putluri, Scott E. Woodman, Y.N. Vashisht Gopal, Renato Guerrieri, Grant M. Fischer, Jian Wang, Khalida M. Wani, John F. Thompson, Jeffrey E. Lee, Patrick Hwu, Nadim Ajami, Jeffrey E. Gershenwald, Georgina V. Long, Richard A. Scolyer, Michael T. Tetzlaff, Alexander J. Lazar, Dirk Schadendorf, Jennifer A. Wargo, John M. Kirkwood, Ralph J. DeBerardinis, Han Liang, Andrew Futreal, Jianhua Zhang, James S. Wilmott, Weiyi Peng, Michael A. Davies, Greg M. Delgoffe, Yana G. Najjar, and Jennifer L. McQuade more...
- Subjects
Cancer Research ,Oncology ,Humans ,Neoplasms, Second Primary ,Obesity ,Overweight ,Melanoma ,Article - Abstract
Purpose: Overweight/obese (OW/OB) patients with metastatic melanoma unexpectedly have improved outcomes with immune checkpoint inhibitors (ICI) and BRAF-targeted therapies. The mechanism(s) underlying this association remain unclear, thus we assessed the integrated molecular, metabolic, and immune profile of tumors, as well as gut microbiome features, for associations with patient body mass index (BMI). Experimental Design: Associations between BMI [normal (NL < 25) or OW/OB (BMI ≥ 25)] and tumor or microbiome characteristics were examined in specimens from 782 patients with metastatic melanoma across 7 cohorts. DNA associations were evaluated in The Cancer Genome Atlas cohort. RNA sequencing from 4 cohorts (n = 357) was batch corrected and gene set enrichment analysis (GSEA) by BMI category was performed. Metabolic profiling was conducted in a subset of patients (x = 36) by LC/MS, and in flow-sorted melanoma tumor cells (x = 37) and patient-derived melanoma cell lines (x = 17) using the Seahorse XF assay. Gut microbiome features were examined in an independent cohort (n = 371). Results: DNA mutations and copy number variations were not associated with BMI. GSEA demonstrated that tumors from OW/OB patients were metabolically quiescent, with downregulation of oxidative phosphorylation and multiple other metabolic pathways. Direct metabolite analysis and functional metabolic profiling confirmed decreased central carbon metabolism in OW/OB metastatic melanoma tumors and patient-derived cell lines. The overall structure, diversity, and taxonomy of the fecal microbiome did not differ by BMI. Conclusions: These findings suggest that the host metabolic phenotype influences melanoma metabolism and provide insight into the improved outcomes observed in OW/OB patients with metastatic melanoma treated with ICIs and targeted therapies. See related commentary by Smalley, p. 5 more...
- Published
- 2023
20. Hereditary Cancer Syndromes-A Broader Clinical Spectrum Than Previously Understood?
- Author
-
Susrutha Puthanmadhom Narayanan and Yana G. Najjar
- Subjects
Cancer Research ,Oncology ,Neoplastic Syndromes, Hereditary ,Humans ,Genetic Predisposition to Disease ,Genetic Testing ,Colorectal Neoplasms, Hereditary Nonpolyposis - Published
- 2022
21. Abstract CT109: First-in-class first-in-human phase 1 trial and translational study of the mono(ADP-ribose) polymerase-7 (PARP7) inhibitor RBN-2397 in patients with selected advanced solid tumors
- Author
-
Timothy A. Yap, Andres Cervantes, Gerald S. Falchook, Manish R. Patel, Dejan Juric, Saiama N. Waqar, Erin L. Schenk, Geoffrey Shapiro, Valentina Boni, Cesar A. Perez, Barbara Burtness, Yana G. Najjar, Fabricio Racca, Katerin Rojas, Kristy Kuplast-Barr, Kristen McEachern, Manoj Samant, Viviana Bozón, Sudha Parasuraman, and Melissa Johnson more...
- Subjects
Cancer Research ,Oncology - Abstract
Background: PARP7 is a stress-induced monoART that suppresses the cellular type I interferon (IFN) response following cytosolic nucleic acid sensing. RBN-2397 is a first-in-class PARP7 inhibitor that induces IFN and an adaptive immune response. The tumor-intrinsic immunomodulatory mechanism of RBN-2397 and preliminary antitumor activity in patients (pts) was demonstrated during dose escalation (Falchook, ASCO 2021; Kuplast-Barr, AACR 2022). Methods: Pts with solid tumors were treated with RBN-2397 at the RP2D of 200 mg BID in 3 expansion cohorts: squamous cell carcinoma of the lung (SCCL), head and neck squamous cell carcinoma (HNSCC), and hormone receptor-positive breast cancer (HR+ BC). Objectives of the expansion phase included safety, pharmacokinetics, pharmacodynamics, and antitumor activity. Results: As of 2 July 2022, 31 pts have been treated: SCCL (n=13), HNSCC (n=10), and HR+ BC (n=8). RBN-2397-related AEs (all grades >10%) included dysgeusia (42%, n=13), nausea (26%, n=8), fatigue (23%, n=7), with Grade 3 events of nausea and pleural infection (each n=1) and ALT/AST increase (n=2), and no Grade 4 events. No significant chronic toxicities were observed. The disease control rate in response-evaluable pts was 44% in SCCL (stable disease [SD] in 4/9 pts), 71% in HNSCC (RECIST partial response [PR] for 12+ months in 1/7; SD in 4/7), and 29% in HR+ BC (SD in 2/7). Biomarker analyses confirmed PARP7 mRNA expression in all baseline biopsies, with H-scores higher in tumor cells than in stromal cells (n=26, H-score range 66-256, P Conclusions: RBN-2397 was well tolerated at biologically active drug exposures, with preliminary antitumor activity observed. Paired tumor biopsy translational studies demonstrated the immunomodulatory mechanism of RBN-2397 and support the ongoing trial of RBN-2397 in combination with pembrolizumab (NCT05127590). Citation Format: Timothy A. Yap, Andres Cervantes, Gerald S. Falchook, Manish R. Patel, Dejan Juric, Saiama N. Waqar, Erin L. Schenk, Geoffrey Shapiro, Valentina Boni, Cesar A. Perez, Barbara Burtness, Yana G. Najjar, Fabricio Racca, Katerin Rojas, Kristy Kuplast-Barr, Kristen McEachern, Manoj Samant, Viviana Bozón, Sudha Parasuraman, Melissa Johnson. First-in-class first-in-human phase 1 trial and translational study of the mono(ADP-ribose) polymerase-7 (PARP7) inhibitor RBN-2397 in patients with selected advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT109. more...
- Published
- 2023
- Full Text
- View/download PDF
22. Neoadjuvant Pembrolizumab and High-Dose IFNα-2b in Resectable Regionally Advanced Melanoma
- Author
-
Jennifer Bordeaux, Dustin McCurry, Arivarasan Karunamurthy, Lisa H. Butterfield, Rogerio I. Neves, Anil Pahuja, Matthew P. Holtzman, Beiru Chen, Jehovana Orozco Bender, Ahmad A. Tarhini, Yan Zang, Ju Young Kim, John M. Kirkwood, Yan Lin, Cindy Sander, Joseph J. Skitzki, IlaSri B. Summit, Marc S. Ernstoff, Christian Laing, Joseph J. Drabick, Yana G. Najjar, Huang Lin, Jennifer Tsau, Ghanashyam Sarikonda, Igor Puzanov, Hassane M. Zarour, Zeni Alfonso, Amy Rose, James F. Pingpank, and Diwakar Davar more...
- Subjects
Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Skin Neoplasms ,medicine.medical_treatment ,Oncology and Carcinogenesis ,Antineoplastic Agents ,Pembrolizumab ,Interferon alpha-2 ,Antibodies, Monoclonal, Humanized ,Antibodies ,Drug Therapy ,Clinical Research ,Internal medicine ,Monoclonal ,80 and over ,medicine ,Clinical endpoint ,Humans ,Oncology & Carcinogenesis ,Stage (cooking) ,Melanoma ,Humanized ,Neoplasm Staging ,Aged ,Cancer ,Aged, 80 and over ,business.industry ,Evaluation of treatments and therapeutic interventions ,Immunotherapy ,Middle Aged ,medicine.disease ,Neoadjuvant Therapy ,Confidence interval ,Discontinuation ,6.1 Pharmaceuticals ,Combination ,Drug Therapy, Combination ,Female ,Immunization ,business ,Adjuvant - Abstract
Purpose:Neoadjuvant immunotherapy may improve the clinical outcome of regionally advanced operable melanoma and allows for rapid clinical and pathologic assessment of response. We examined neoadjuvant pembrolizumab and high-dose IFNα-2b (HDI) therapy in patients with resectable advanced melanoma.Patients and Methods:Patients with resectable stage III/IV melanoma were treated with concurrent pembrolizumab 200 mg i.v. every 3 weeks and HDI 20 MU/m2/day i.v., 5 days per week for 4 weeks, then 10 MU/m2/day subcutaneously 3 days per week for 2 weeks. Definitive surgery followed, as did adjuvant combination immunotherapy, completing a year of treatment. Primary endpoint was safety of the combination. Secondary endpoints included overall response rate (ORR), pathologic complete response (pCR), recurrence-free survival (RFS), and overall survival (OS). Blood samples for correlative studies were collected throughout. Tumor tissue was assessed by IHC and flow cytometry at baseline and at surgery.Results:A total of 31 patients were enrolled, and 30 were evaluable. At data cutoff (October 2, 2019), median follow-up for OS was 37.87 months (range, 33.2–43.47). Median OS and RFS were not reached. Radiographic ORR was 73.3% [95% confidence interval (CI): 55.5–85.8], with a 43% (95% CI: 27.3–60.1) pCR rate. None of the patients with a pCR have had a recurrence. HDI and pembrolizumab were discontinued in 73% and 43% of patients, respectively. Correlative analyses suggested that intratumoral PD-1/PD-L1 interaction and HLA-DR expression are associated with pCR (P = 0.002 and P = 0.008, respectively).Conclusions:Neoadjuvant concurrent HDI and pembrolizumab demonstrated promising clinical activity despite high rates of treatment discontinuation. pCR is a prognostic indicator.See related commentary by Menzies et al., p. 4133 more...
- Published
- 2021
- Full Text
- View/download PDF
23. Fecal microbiota transplant overcomes resistance to anti–PD-1 therapy in melanoma patients
- Author
-
Richelle DeBlasio, Marie Vétizou, Jonathan H. Badger, Giorgio Trinchieri, Stephanie Prescott, Hassane M. Zarour, Miriam R. Fernandes, John A. McCulloch, Bochra Zidi, Richard R. Rodrigues, Amir A. Borhani, Yana G. Najjar, Amy Rose, John M. Kirkwood, Shuowen Zhang, Hong Wang, Carmine Menna, Quanquan Ding, Scarlett J. Ernst, Amiran K. Dzutsev, Alicia M. Cole, Joe Marc Chauvin, Robert M. Morrison, Ornella Pagliano, Diwakar Davar, Andrey Morgun, Ascharya K. Balaji, Raquel Galvão Figueredo Costa, Howard M. Dubner, Ivan Vujkovic-Cvijin, Yasmine Belkaid, and Marc Schwartz more...
- Subjects
Skin Neoplasms ,T cell ,Programmed Cell Death 1 Receptor ,Drug resistance ,CD8-Positive T-Lymphocytes ,Gut flora ,Antibodies, Monoclonal, Humanized ,Lymphocyte Activation ,Antineoplastic Agents, Immunological ,Lymphocytes, Tumor-Infiltrating ,Tumor Microenvironment ,medicine ,Humans ,Myeloid Cells ,Melanoma ,Tumor microenvironment ,Multidisciplinary ,biology ,business.industry ,Interleukin-8 ,Gastrointestinal Microbiome ,Cancer ,Fecal Microbiota Transplantation ,medicine.disease ,biology.organism_classification ,medicine.anatomical_structure ,Drug Resistance, Neoplasm ,Immunology ,business ,CD8 - Abstract
New fecal microbiota for cancer patients The composition of the gut microbiome influences the response of cancer patients to immunotherapies. Baruch et al. and Davar et al. report first-in-human clinical trials to test whether fecal microbiota transplantation (FMT) can affect how metastatic melanoma patients respond to anti–PD-1 immunotherapy (see the Perspective by Woelk and Snyder). Both studies observed evidence of clinical benefit in a subset of treated patients. This included increased abundance of taxa previously shown to be associated with response to anti–PD-1, increased CD8 + T cell activation, and decreased frequency of interleukin-8–expressing myeloid cells, which are involved in immunosuppression. These studies provide proof-of-concept evidence for the ability of FMT to affect immunotherapy response in cancer patients. Science , this issue p. 602 , p. 595 ; see also p. 573 more...
- Published
- 2021
- Full Text
- View/download PDF
24. 523 Preliminary clinical experience with XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in patients with advanced solid tumors
- Author
-
Catherine Fleener, Raphael Clynes, Ezra E.W. Cohen, Bartosz Chmielowski, Shubham Pant, Ying Ding, Joaquina Baranda, Barbara Hickingbottom, Rom Leidner, Yana G. Najjar, Adil Daud, Lei Bao, Roger B. Cohen, Siwen Hu-Lieskovan, Anthony F. Shields, Alain C. Mita, John A. Thompson, Elaine Shum, Sowmya Chollate, Matthew J. Reilley, Mark N. Stein, R. Donald Harvey, and Jolene Shorr more...
- Subjects
Pharmacology ,Oncology ,Cancer Research ,medicine.medical_specialty ,Myeloid ,business.industry ,Melanoma ,Immunology ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Rash ,Prostate cancer ,medicine.anatomical_structure ,Renal cell carcinoma ,Internal medicine ,Pharmacodynamics ,medicine ,Molecular Medicine ,Immunology and Allergy ,medicine.symptom ,Ovarian cancer ,Adverse effect ,business ,RC254-282 - Abstract
BackgroundXmAb20717 is a humanized bispecific monoclonal antibody that simultaneously targets PD-1 and CTLA-4. We report updated data on patients treated at the recommended expansion dose from an ongoing, multicenter, Phase 1, dose-escalation and -expansion study of intravenous XmAb20717 in patients with selected advanced solid tumors that progressed after treatment with all standard therapies or with no standard therapeutic options.MethodsA maximum tolerated dose was not reached in dose escalation. XmAb20717 10 mg/kg every 2 weeks (Q2W) was selected as the expansion dose, based on consistent T-cell proliferation in peripheral blood indicative of dual PD-1/CTLA-4 checkpoint blockade, and response to treatment (RECIST[1.1]).1 Parallel expansion cohorts included ~20 patients each with melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), castration-resistant prostate cancer (CRPC), and a basket of tumor types without an FDA-approved checkpoint inhibitor (CI). Patients treated with 10 mg/kg in dose escalation were pooled with expansion cohorts for analysis of clinical activity and safety.ResultsAs of 9 June 2021, 110 patients, ranging in age from 39 to 89 years and 66.4% male, were treated, and 5 were continuing treatment. Patients had received a median of 4 prior systemic treatment regimens, including CI therapy for 64.5%. The objective response rate was 13.0% (10/77 patients evaluable for efficacy), including 1 complete response (melanoma [confirmed]) and 9 partial responses (confirmed: 1 melanoma, 2 RCC, 2 CRPC, 1 ovarian cancer; unconfirmed: 1 melanoma, 2 NSCLC). The CRPC responders (2/7 with RECIST-measurable disease) had confirmed PSA decreases ≥ 50% from baseline (to 0.02 and 0.3 ng/mL); neither had progression on bone scans. All responders had prior CI exposure, except those with CRPC. Robust CD4 and CD8 T-cell activation was seen. Low baseline tumoral expression of myeloid recruitment genes, including IL-8, was associated with clinical benefit. Grade ≥ 3 immunotherapy-related adverse events in ≥ 3 patients included rash (16.4%), transaminase elevations (9.1%), hyperglycemia (4.5%), acute kidney injury (3.6%), amylase and lipase increased (2.7%), and lipase increased (2.7%).ConclusionsPreliminary data indicate 10 mg/kg XmAb20717 Q2W was associated with complete and partial responses in multiple tumor types and was generally well-tolerated in these heavily pretreated patients with advanced cancer. Changes in T-cell populations in the periphery and tumor are consistent with robust dual checkpoint blockade. These findings support further development of XmAb20717 in advanced solid tumors, including metastatic prostate cancer.Trial RegistrationNCT03517488ReferencesShum E, Daud A, Reilley M, et al. Preliminary safety, pharmacokinetics/pharmacodynamics, and antitumor activity of XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in patients with advanced solid tumors. JITC 2020;8(3):A247-8.Ethics ApprovalThe study was approved by each institution’s IRB. more...
- Published
- 2021
25. Immune-Related Adverse Events in PD-1 Treated Melanoma and Impact Upon Anti-Tumor Efficacy: A Real World Analysis
- Author
-
Melissa L. Bastacky, Hong Wang, Dylan Fortman, Zahra Rahman, Gerard P. Mascara, Timothy Brenner, Yana G. Najjar, Jason J. Luke, John M. Kirkwood, Hassane M. Zarour, and Diwakar Davar
- Subjects
Antitumor activity ,Cancer Research ,business.industry ,Melanoma ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,autoimmune ,medicine.disease ,metastatic ,immune related adverse events ,Immune system ,Oncology ,irAE ,PD-1 ,Cancer research ,melanoma ,Medicine ,CTLA-4 ,immunotherapy ,business ,Adverse effect ,RC254-282 ,Original Research - Abstract
BackgroundAnti-PD-1 immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of melanoma by producing durable long-term responses in a subset of patients. ICI-treated patients develop unique toxicities - immune related adverse events (irAEs) – that arise from unrestrained immune activation. The link between irAE development and clinical outcome in melanoma and other cancers is inconsistent; and little data exists on the occurrence of multiple irAEs. We sought to characterize development of single and multiple irAEs, and association of irAE(s) development with clinical variables and impact upon outcomes in advanced melanoma patients treated with anti-PD-1 ICIs.MethodsWe conducted a retrospective study of 190 patients with metastatic melanoma treated with single-agent anti-PD-1 ICI therapy between June 2014 and August 2020 at a large integrated network cancer center identified through retrospective review of pharmacy records. irAEs were graded based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.Results190 patients were evaluated of whom 114 patients (60.0%) experienced ≥1 irAE, including 30 (15.8%) with grade 3/4 irAEs. The occurrence of any irAE was strongly associated with the development of investigator-assessed response to anti-PD-1 therapy (p < 0.0001); whether evaluated by current (p=0.0082) or best (p=0.0001) response. In patients with ≥2 irAEs, distinct patterns were observed. Median progression-free survival (PFS) and overall survival (OS) were greater in those with any irAE compared to those without (PFS, 28 monthsvs. 5 months, p < 0.0001; OS, not reachedvs. 9 months, p < 0.0001). Development of ≥2 irAEs had a trend towards improved PFS and OS compared to those who developed a single irAE, although this did not reach statistical significance (p=0.2555, PFS; p=0.0583, OS). Obesity but not age or gender was distinctly associated with irAE development.ConclusionsIn this study, we demonstrated that irAE occurrence was significantly associated with response to anti-PD-1 therapy and improved PFS/OS. Those who developed multiple irAEs had a trend towards improved PFS and OS compared to those who developed only a single irAE. Increased BMI but neither age nor gender were associated with irAE development. Distinct patterns of irAEs observed suggest shared etiopathogenetic mechanisms. more...
- Published
- 2021
26. An updated analysis of 4 randomized ECOG trials of high‐dose interferon in the adjuvant treatment of melanoma
- Author
-
Maneka Puligandla, Yana G. Najjar, Sandra J. Lee, and John M. Kirkwood
- Subjects
Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Population ,Antineoplastic Agents ,Interferon alpha-2 ,Article ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Interferon ,Internal medicine ,medicine ,Adjuvant therapy ,Overall survival ,Humans ,Stage iib ,030212 general & internal medicine ,education ,Melanoma ,Aged ,Proportional Hazards Models ,Randomized Controlled Trials as Topic ,Aged, 80 and over ,education.field_of_study ,business.industry ,Interferon-alpha ,Evidence-based medicine ,Middle Aged ,Prognosis ,medicine.disease ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Female ,business ,Adjuvant ,Follow-Up Studies ,medicine.drug - Abstract
Background The pivotal E1684, E1690, E1694, and E2696 trials of adjuvant high-dose interferon-α (HDI) enrolled nearly 2000 patients, and established HDI as the standard of care in adjuvant therapy for patients with resected high-risk melanoma. Herein, the authors present an updated analysis of these 4 trials. Methods Survival and disease status were updated in September 2016. These data represent a median follow-up of 17.9 years for the E1684 trial, 12.2 years for the E1690 trial, 16.0 years for the E1694 trial, and 16.5 years for the E2696 trial. Results The current analysis confirmed the benefit to recurrence-free survival (RFS) of HDI in the E1684 trial at a median follow-up of 17.9 years. The RFS benefit in the E1694 trial remained evident at a median follow-up of 16 years. Furthermore, the results of the current study confirmed the RFS benefit of adjuvant HDI compared with observation in a pooled analysis of the E1684 and E1690 trials. No overall survival benefit was apparent in this pooled analysis. Updated results for the E1690 and E2696 trials did not differ from those previously reported. In addition, to the authors' knowledge, the current study is the first to report a significant difference in melanoma-specific survival (MSS) between patients treated with HDI compared with the ganglioside GM2/keyhole limpet hemocyanin (GMK) vaccine in the E1694 trial. Conclusions In patients with resected high-risk melanoma, adjuvant HDI demonstrated improved RFS in the E1684 and E1694 trials, and improved MSS in a pooled analysis of HDI in the E1694 trial. To the authors' knowledge, these findings represent the most mature level of evidence for the benefit of HDI with respect to RFS and MSS. HDI is the only approved adjuvant treatment for which there are data available in patients with resected stage IIB/IIC melanoma, and remains a reasonable treatment option in this population. more...
- Published
- 2019
- Full Text
- View/download PDF
27. Perspectives in immunotherapy: meeting report from the 'Immunotherapy Bridge' (December 4th-5th, 2019, Naples, Italy)
- Author
-
Paul Nathan, Michael Dougan, Chrystal M. Paulos, Silvia C. Formenti, Katie M. Campbell, Paolo A. Ascierto, Alessandro Morabito, Yana G. Najjar, Lisa H. Butterfield, John M. Timmerman, Filip Janku, Akash Patnaik, Samir N. Khleif, Leisha A. Emens, Bruno Daniele, Bradley I. Reinfeld, Heath D. Skinner, Tomas Kirchhoff, Igor Puzanov, and Kunle Odunsi more...
- Subjects
0301 basic medicine ,medicine.medical_specialty ,medicine.medical_treatment ,Immune checkpoint inhibitors ,Immunology ,lcsh:Medicine ,Disease ,Meeting Report ,Medical Oncology ,Clinical success ,Medical and Health Sciences ,General Biochemistry, Genetics and Molecular Biology ,Vaccine Related ,03 medical and health sciences ,0302 clinical medicine ,Cancer immunotherapy ,Biomarkers, Tumor ,medicine ,Humans ,Combination therapy ,Intensive care medicine ,Melanoma ,Cancer ,Tumor ,business.industry ,lcsh:R ,General Medicine ,Immunotherapy ,Immune checkpoint ,Clinical trial ,030104 developmental biology ,Good Health and Well Being ,Italy ,Tumor microenvironment ,030220 oncology & carcinogenesis ,Immunization ,business ,Vaccine ,Biomarkers ,Checkpoint inhibitors - Abstract
Over the last few years, numerous clinical trials and real-world experience have provided a large amount of evidence demonstrating the potential for long-term survival with immunotherapy agents across various malignancies, beginning with melanoma and extending to other tumours. The clinical success of immune checkpoint blockade has encouraged increasing development of other immunotherapies. It has been estimated that there are over 3000 immuno-oncology trials ongoing, targeting hundreds of disease and immune pathways. Evolving topics on cancer immunotherapy, including the state of the art of immunotherapy across various malignancies, were the focus of discussions at the Immunotherapy Bridge meeting (4–5 December, 2019, Naples, Italy), and are summarised in this report. more...
- Published
- 2021
28. Phase II study of nivolumab (nivo) with relatlimab (rela) in patients (pts) with first-line advanced melanoma: Early on-treatment major pathologic response on biopsy
- Author
-
Lilit Karapetyan, Arivarasan Karunamurthy, Anthony Cillo, Anjali Rohatgi, Ryan Campbell Massa, William E. Gooding, Yana G. Najjar, Diwakar Davar, Jason J. Luke, Tullia C. Bruno, Dario Vignali, and John M. Kirkwood more...
- Subjects
Cancer Research ,Oncology - Abstract
9514 Background: A phase II study of nivo and rela was designed to evaluate the antitumor activity and mechanism of this combination and components for first-line treatment of pts with advanced melanoma. Pts received lead-in treatment with 1 cycle of nivo (480mg IV q4wk), rela (160mg IV q4wk), or nivo-rela followed by combination therapy. We assessed the effect of each lead-in treatment on immune-related pathological response (irPR) at 4-wk biopsy to develop early biomarkers of antitumor response. Methods: Core biopsy of an index lesion was performed at baseline and after 4 wk on-treatment. Immune characteristics of pathological response were assessed on H&E sections, including presence of tumor-infiltrating lymphocytes (TIL), neovascularization, proliferative fibrosis, plasma cells, and lymphoid aggregates. irPR score was calculated as described by Stein JE et al Ann Oncol 2019, from 0 (no irPR features) to 3 (major pathologic response on biopsy [MPRbx], ≤10% residual viable tumor). We assessed the association between irPR and radiological response (RECIST v1.1) at 4-wk evaluations. Results: The current cohort includes 22 pts, median age = 67, male = 13. Pts were randomized to nivo = 7, rela = 7, and nivo-rela = 8 lead-in groups. Two pts had no irPR evaluation due to early progression and unscorable tumor. Among 20 evaluable pts, proliferative fibrosis, neovascularization, plasma cells, brisk TIL, and lymphoid aggregates were identified in 50%, 35%, 26.3%, 25%, and 5% of cases, respectively. Lead-in nivo (n = 2/6), rela (n = 0/6), and nivo-rela (n = 3/8) resulted in irPR = 3 in 25% of pts. Radiological response was identified as partial response (PR) = 1/22 (4.5%), stable disease (SD) = 12/22 (54.5%), and progressive disease (PD) = 9/22 (41%). Among pts with PD, 44% received rela-, 33% nivo-, and 22% nivo-rela- lead-in. Pts with irPR score = 3 had radiological PR = 1, SD = 3, and PD = 1 at 4wks. No association was found between MPRbx and radiological response at 4 wks. Conclusions: Four-wk MPRbx may serve as an early biomarker of treatment response in advanced melanoma. Lead-in treatment resulted in MPRbx of 25% and was greatest with nivo-rela lead-in. Correlations between 4 wk MPRbx and later radiological responses, survival and other endpoints will be made at completion of trial accrual. Clinical trial information: NCT03743766. [Table: see text] more...
- Published
- 2022
- Full Text
- View/download PDF
29. 435 A phase II trial of nivolumab plus axitinib in patients with anti-PD1 refractory advanced melanoma
- Author
-
Yana G. Najjar, Diwakar Davar, Xi Yang, Saba Shaikh, Greg M. Delgoffe, Yan Zang, Amy Rose, John M. Kirkwood, Hassane M. Zarour, Hong Wang, Jason J. Luke, and Cindy Sander
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Tumor microenvironment ,business.industry ,Angiogenesis ,Tumor-infiltrating lymphocytes ,medicine.medical_treatment ,Melanoma ,Cancer ,Immunotherapy ,medicine.disease ,Axitinib ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Nivolumab ,business ,medicine.drug - Abstract
Background Immunotherapy has changed the treatment landscape for melanoma, although many patients (pts) do not respond to treatment. While there are likely multiple mechanisms of resistance at play, one key mechanism is the generation of an immunosuppressive and metabolically harsh tumor microenvironment (TME).1 This is likely the result of an altered angiogenic pattern along with dysregulated metabolism of the tumor itself, which leads to hypoxia.2 CD8+ tumor infiltrating lymphocytes (TIL) isolated from tumors with high oxidative metabolism have an exhausted phenotype and decreased functionality (decreased IFN-У and TNF-α production).3 Thus, TIL may be blunted due to failure to meet their metabolic needs. Vascular endothelial growth factor (VEGF) is a critical mediator of angiogenesis and is overexpressed in many solid tumors, including melanoma. Axitinib has high inhibitory activity for VEGF receptors1, 2, and 3. In a preclinical B16 melanoma model, we found that anti-PD1 plus axitinib provided an improved and durable response compared to monotherapy with either agent. We hypothesize that by modulating angiogenesis, axitinib will reduce intra-tumoral hypoxia and resultant T cell dysfunction, which will re-sensitize melanoma to anti-PD1 therapy. Methods This is an investigator-initiated, phase II trial of nivolumab plus axitinib for pts with unresectable stage III or IV melanoma who have progressed on prior anti-PD1 therapy with or without concomitant anti-CTLA4. Prior treatment with BRAF/MEK inhibitors is permitted. Pts with brain metastases are permitted if they are asymptomatic and have stable disease 2 weeks after CNS-directed treatment. Pts will receive nivolumab 480 mg IV every 4 weeks and axitinib PO 5 mg twice daily for up to two years or until progression or unacceptable toxicity. Timing of biopsies is reported in figure 1, with an optional biopsy at progression. Pts will receive an oral dose of pimonidazole 0.5 mg/m2 before each biopsy to permit in vivo evaluation of intra-tumoral hypoxia. Primary endpoint: overall response rate (ORR). Secondary endpoints: safety, progression-free survival, overall survival, and correlative analyses (evaluation of hypoxia in the TME, TIL function, immune phenotype, and tumor cell metabolism). Statistical analysis includes Simon’s minimax two-stage design. The null hypothesis is that the true ORR is 10%, tested against a one-sided alternative of 25% or higher. N=31 patients with a type I error rate of 0.08 and power 0.81 when the true response rate is 0.25. Results N/A Conclusions N/A Trial Registration NCT04493203 Ethics Approval The study was approved by the University of Pittsburgh Institutional Review Board, approval number HCC 20-101. References Romero IL, Mukherjee A, Kenny HA, Litchfield LM, Lengyel E. Molecular pathways: trafficking of metabolic resources in the tumor microenvironment. Clin Cancer Res 2015;21(4):680–6. doi: 10.1158/1078-0432.CCR-14-2198. PubMed PMID: 25691772. Justus CR, Sanderlin EJ, Yang LV. Molecular connections between cancer cell metabolism and the tumor microenvironment. Int J Mol Sci 2015;16(5):11055–86. doi: 10.3390/ijms160511055. PubMed PMID: 25988385. Najjar YG, Menk AV, Sander C, Rao U, Karunamurthy A, Bhatia R, et al. Tumor cell oxidative metabolism as a barrier to PD-1 blockade immunotherapy in melanoma. JCI insight. 2019;4(5). Epub 2019/02/06. doi: 10.1172/jci.insight.124989. PubMed PMID: 30721155; PubMed Central PMCID: PMCPMC6483505. more...
- Published
- 2020
- Full Text
- View/download PDF
30. 407 Preliminary safety, pharmacokinetics/pharmacodynamics, and antitumor activity of XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in patients with advanced solid tumors
- Author
-
Rom Leidner, Ezra E.W. Cohen, Elaine Shum, Shubham Pant, Siwen Hu-Lieskovan, Yana G. Najjar, Raphael Clynes, Jolene Shorr, Alain C. Mita, R. Donald Harvey, Sowmya Chollate, Ying Ding, Adil Daud, Matthew J. Reilley, Anthony F. Shields, John A. Thompson, Mark N. Stein, Joaquina Baranda, Roger B. Cohen, Hector Avina, Barbara Hickingbottom, Bartosz Chmielowski, and Catherine Fleener more...
- Subjects
0301 basic medicine ,medicine.medical_specialty ,business.industry ,Melanoma ,Area under the curve ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,lcsh:RC254-282 ,Gastroenterology ,03 medical and health sciences ,Prostate cancer ,030104 developmental biology ,0302 clinical medicine ,Tolerability ,Pharmacokinetics ,Renal cell carcinoma ,030220 oncology & carcinogenesis ,Internal medicine ,Pharmacodynamics ,medicine ,Adverse effect ,business - Abstract
Background XmAb20717 is a humanized bispecific monoclonal antibody that simultaneously targets PD-1 and CTLA-4. We report preliminary data from an ongoing, multicenter, Phase 1 study investigating the safety/tolerability, pharmacokinetics/pharmacodynamics, and clinical activity (RECIST 1.1) of XmAb20717 in patients with selected advanced solid tumors. Methods A 3+3 dose-escalation design was used to establish a maximum tolerated (MTD)/recommended dose for evaluation in parallel expansion cohorts, including melanoma, renal cell carcinoma, non-small cell lung cancer (NSCLC), prostate cancer, and a basket of tumor types without an FDA-approved checkpoint inhibitor (CI; n≤20 each). XmAb20717 was administered as an infusion on Days 1 and 15 of each 28-day cycle. Results As of 08Jul2020, 109 patients had been treated (table 1), and 30 were continuing treatment. In escalation, 6 dose levels (0.15–10.0 mg/kg) were evaluated (n=34); an MTD was not established. Expansion cohorts were initiated at 10 mg/kg (n=72), and a 15 mg/kg escalation cohort was added (n=3). T-cell proliferation was noted in peripheral blood at doses as low as 3 mg/kg and was highest at 10 mg/kg. At this dose, consistent proliferation of CD8+ and CD4+ T cells was observed, indicative of dual PD-1 and CTLA-4 checkpoint blockade (figure 1). Paired pre- and post-dosing biopsies showed increased intratumoral T-cell infiltration and IFN-response signatures following treatment. Grade 3/4 treatment-related adverse events (TRAEs) reported for ≥3 patients included rash (13%), transaminase elevations (7%), lipase increased (4% [2% with amylase increased]), and acute kidney injury (3%), all considered immune-related. There were 2 Grade 5 TRAEs: immune-mediated pancreatitis (in the presence of pancreatic metastases) and immune-mediated myocarditis (Grade 4) that contributed to respiratory failure. A complete response was reported as the best overall response for 1 patient (melanoma); partial responses were reported for 5 patients (2 melanoma, 2 NSCLC, 1 ovarian). The objective response rate was 13% overall and 21% at 10 mg/kg (6/46 and 6/29 evaluable patients, respectively). All responders had prior CI exposure. Responses were observed only at 10 mg/kg and, within the 10 mg/kg group, appeared to correlate with higher peak serum concentration and area under the curve. Conclusions XmAb20717 induced T-cell proliferation in peripheral blood consistent with dual-checkpoint blockade. Preliminary data indicate XmAb20717 was generally well-tolerated and associated with evidence of antitumor activity in CI-pretreated patients with various types of advanced solid tumors. Trial Registration NCT03517488 Ethics Approval The study was approved by each institution’s IRB. more...
- Published
- 2020
- Full Text
- View/download PDF
31. 75 Generalizability of potential biomarkers of response to CTLA-4 and PD-1 blockade therapy in cancer
- Author
-
Cara Haymaker, Randy F. Sweis, Uqba Khan, Christine N. Spencer, Sara Valpione, Vesteinn Thorsson, Yana G. Najjar, Anne Monette, Valentin Barsan, Erik Wennerberg, Sarah Entwistle, Steven Vensko, Alexandria P. Cogdill, Dante S. Bortone, Danny Wells, Roberta Zappasodi, Wungki Park, Houssein Abdul Sater, Vinita Popat, Nicholas Tschernia, Praveen K. Bommareddy, Maria Libera Ascierto, Nils Petter Rudqvist, Benjamin G. Vincent, and Heather M. McGee more...
- Subjects
CTLA-4 ,Potential biomarkers ,Cancer genome ,Cox proportional hazards regression ,Pd 1 blockade ,In patient ,Gene signature ,Biology ,Molecular biology ,T-Cell Receptor Repertoire - Abstract
Background Multiple genomics-based biomarkers of response to immune checkpoint inhibition have been reported or proposed, including tumor mutation/neoantigen frequency, PD-L1 expression, T cell receptor repertoire clonality, interferon gene signature expression, HLA expression, and others.1 Although genomics associations of response have been reported, the primary studies have used a variety of data generation and processing techniques. There is a need for data harmonization and assessment of generalizability of potential biomarkers across multiple datasets. Methods We acquired patient-level RNA sequencing FASTQ data files from 10 data sets reported in seven pan-cancer PD-1 and CTLA-4 immune checkpoint inhibition trials with matched clinical annotations.2–7 We applied a common bioinformatics workflow for quality control, mapping to reference (STAR), generating gene expression matrices (SALMON), T cell receptor repertoire inference (MiXCR), extraction of immune gene signatures and immune subtypes,8 and differential gene expression analysis (DESeq2). We analyzed i) immunogenomics features proposed as biomarkers, and ii) gene expression signatures built from each trial for association with overall survival across the set of trials using univariable Cox proportional hazards regression. In all, we assessed 9 total immunogenomics features/signatures. P-values were adjusted for multiple testing using the Benjamini-Hochberg method. Results Of the 9 immunogenomics features assessed, cytolytic activity score and expression of the Follicular Dendritic Cell Secreted Protein gene (FDCSP) were associated with survival in two of seven studies, respectively (adjusted p Conclusions No proposed biomarkers were highly generalizable across studies. We expect that integrated modeling incorporating multiple immunogenomics features will be required to build a robust and generalizable biomarker for ICI response. Further work is needed to analyze determinants of response and clinical benefit. Acknowledgements We would like to thank SITC for funding for this work as part of the Sparkathon TimIOS collaborative project. References Zappasodi R, Wolchok JD, Merghoub T. Strategies for Predicting Response to Checkpoint Inhibitors. Curr Hematol Malig Rep 2018;13(5):383–95. Liu D, Schilling B, Liu D, Sucker A, Livingstone E, Jerby-Arnon L, Zimmer L, Gutzmer R, Satzger I, Loquai C, Grabbe S, Vokes N, Margolis CA, Conway J, He MX, Elmarakeby H, Dietlein F, Miao D, Tracy A, Gogas H, Goldinger SM, Utikal J, Blank CU, Rauschenberg R, von Bubnoff D, Krackhardt A, Weide B, Haferkamp S, Kiecker F, Izar B, Garraway L, Regev A, Flaherty K, Paschen A, Van Allen EM, Schadendorf D. Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma. Nat Med 2019;25(12):1916–27. Gide TN, Quek C, Menzies AM, Tasker AT, Shang P, Holst J, Madore J, Lim SY, Velickovic R, Wongchenko M, Yan Y, Lo S, Carlino MS, Guminski A, Saw RPM, Pang A, McGuire HM, Palendira U, Thompson JF, Rizos H, Silva IPD, Batten M, Scolyer RA, Long GV, Wilmott JS. distinct immune cell populations define response to anti-pd-1 monotherapy and Anti-PD-1/Anti-CTLA-4 Combined Therapy. Cancer Cell 2019;35(2):238–55 e6. Cloughesy TF, Mochizuki AY, Orpilla JR, Hugo W, Lee AH, Davidson TB, Wang AC, Ellingson BM, Rytlewski JA, Sanders CM, Kawaguchi ES, Du L, Li G, Yong WH, Gaffey SC, Cohen AL, Mellinghoff IK, Lee EQ, Reardon DA, O’Brien BJ, Butowski NA, Nghiemphu PL, Clarke JL, Arrillaga-Romany IC, Colman H, Kaley TJ, de Groot JF, Liau LM, Wen PY, Prins RM. Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat Med. 2019;25(3):477–86. Riaz N, Havel JJ, Makarov V, Desrichard A, Urba WJ, Sims JS, Hodi FS, Martin-Algarra S, Mandal R, Sharfman WH, Bhatia S, Hwu WJ, Gajewski TF, Slingluff CL, Jr., Chowell D, Kendall SM, Chang H, Shah R, Kuo F, Morris LGT, Sidhom JW, Schneck JP, Horak CE, Weinhold N, Chan TA. Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell 2017;171(4):934–49 e16. Hugo W, Zaretsky JM, Sun L, Song C, Moreno BH, Hu-Lieskovan S, Berent-Maoz B, Pang J, Chmielowski B, Cherry G, Seja E, Lomeli S, Kong X, Kelley MC, Sosman JA, Johnson DB, Ribas A, Lo RS. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 2016;165(1):35–44. Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O’Donnell PH, Balmanoukian A, Loriot Y, Srinivas S, Retz MM, Grivas P, Joseph RW, Galsky MD, Fleming MT, Petrylak DP, Perez-Gracia JL, Burris HA, Castellano D, Canil C, Bellmunt J, Bajorin D, Nickles D, Bourgon R, Frampton GM, Cui N, Mariathasan S, Abidoye O, Fine GD, Dreicer R. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909–20. Thorsson V, Gibbs DL, Brown SD, Wolf D, Bortone DS, Ou Yang TH, Porta-Pardo E, Gao GF, Plaisier CL, Eddy JA, Ziv E, Culhane AC, Paull EO, Sivakumar IKA, Gentles AJ, Malhotra R, Farshidfar F, Colaprico A, Parker JS, Mose LE, Vo NS, Liu J, Liu Y, Rader J, Dhankani V, Reynolds SM, Bowlby R, Califano A, Cherniack AD, Anastassiou D, Bedognetti D, Mokrab Y, Newman AM, Rao A, Chen K, Krasnitz A, Hu H, Malta TM, Noushmehr H, Pedamallu CS, Bullman S, Ojesina AI, Lamb A, Zhou W, Shen H, Choueiri TK, Weinstein JN, Guinney J, Saltz J, Holt RA, Rabkin CS, Cancer Genome Atlas Research N, Lazar AJ, Serody JS, Demicco EG, Disis ML, Vincent BG, Shmulevich I. The Immune Landscape of Cancer. Immunity 2018;48(4):812–30e14. more...
- Published
- 2020
- Full Text
- View/download PDF
32. Ipilimumab plus nivolumab for patients with metastatic uveal melanoma: a multicenter, retrospective study
- Author
-
Roma Bhatia, Alexander N. Shoushtari, Kristina Navrazhina, Jonathan Kennedy, Katy K. Tsai, Fei Ding, John M. Kirkwood, Pankit Vachhani, Ryan J. Sullivan, Justine V. Cohen, Yana G. Najjar, Akansha Chowdhary, Tan Xu, Douglas B. Johnson, Igor Puzanov, Zeynep Eroglu, Shailender Bhatia, Richard D. Carvajal, Barbara Durden, Kelly Abbate, Pauline Funchain, Jessica Yang, Song Park, Marc S. Ernstoff, Joseph J. Drabick, Sunandana Chandra, Arun D. Singh, and Daniel K. Manson more...
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Immunology ,Ipilimumab ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Immunology and Allergy ,Adverse effect ,RC254-282 ,Pharmacology ,business.industry ,Melanoma ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Common Terminology Criteria for Adverse Events ,Retrospective cohort study ,medicine.disease ,Rash ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Molecular Medicine ,medicine.symptom ,Nivolumab ,business ,Progressive disease ,medicine.drug - Abstract
BackgroundUveal melanoma (UM) is the most common intraocular malignancy in adults. In contrast to cutaneous melanoma (CM), there is no standard therapy, and the efficacy and safety of dual checkpoint blockade with nivolumab and ipilimumab is not well defined.MethodsWe conducted a retrospective analysis of patients with metastatic UM (mUM) who received treatment with ipilimumab plus nivolumab across 14 academic medical centers. Toxicity was graded using National Cancer Institute Common Terminology Criteria for Adverse Events V.5.0. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier methodology.Results89 eligible patients were identified. 45% had received prior therapy, which included liver directed therapy (29%), immunotherapy (21%), targeted therapy (10%) and radiation (16%). Patients received a median 3 cycles of ipilimumab plus nivolumab. The median follow-up time was 9.2 months. Overall response rate was 11.6%. One patient achieved complete response (1%), 9 patients had partial response (10%), 21 patients had stable disease (24%) and 55 patients had progressive disease (62%). Median OS from treatment initiation was 15 months and median PFS was 2.7 months. Overall, 82 (92%) of patients discontinued treatment, 34 due to toxicity and 27 due to progressive disease. Common immune-related adverse events were colitis/diarrhea (32%), fatigue (23%), rash (21%) and transaminitis (21%).ConclusionsDual checkpoint inhibition yielded higher response rates than previous reports of single-agent immunotherapy in patients with mUM, but the efficacy is lower than in metastatic CM. The median OS of 15 months suggests that the rate of clinical benefit may be larger than the modest response rate. more...
- Published
- 2020
33. P854 Construction of the immune landscape of durable response to checkpoint blockade therapy by integrating publicly available datasets
- Author
-
Daniel K. Wells, Erik Wennerberg, Benjamin G. Vincent, Christine N. Spencer, Heather M. McGee, Yana G. Najjar, Nils Rudqvist, Randy F. Sweis, Anne Monette, Houssein Abdul Sater, Uqba Khan, Maria Libera Ascierto, Cara Haymaker, Nicholas Tschernia, Praveen K. Bommareddy, Roberta Zappasodi, Vinita Popat, Sara Valpione, Alexandria P. Cogdill, Valentin Barsan, Vesteinn Thorsson, and Wungki Park more...
- Subjects
Clinical trial ,Immune system ,Cancer immunotherapy ,medicine.medical_treatment ,Systems biology ,medicine ,Cancer ,Computational biology ,Immunotherapy ,Biology ,medicine.disease ,Immune checkpoint ,Blockade - Abstract
Background Immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, long-term benefits are only achieved in a small fraction of patients. Understanding the mechanisms underlying ICB activity is key to improving the efficacy of immunotherapy. A major limitation to uncovering these mechanisms is the limited number of responders within each ICB trial. Integrating data from multiple studies of ICB would help overcome this issue and more reliably define the immune landscape of durable responses. Towards this goal, we formed the TimIOs consortium, comprising researchers from the Society for Immunotherapy of Cancer Sparkathon TimIOs Initiative, the Parker Institute of Cancer Immunotherapy, the University of North Carolina-Chapel Hill, and the Institute for Systems Biology. Together, we aim to improve the understanding of the molecular mechanisms associated with defined outcomes to ICB, by building on our joint and multifaceted expertise in the field of immuno-oncology. To determine the feasibility and relevance of our approach, we have assembled a compendium of publicly available gene expression datasets from clinical trials of ICB. We plan to analyze this data using a previously reported pipeline that successfully determined main cancer immune-subtypes associated with survival across multiple cancer types in TCGA.1 Methods RNA sequencing data from 1092 patients were uniformly reprocessed harmonized, and annotated with predefined clinical parameters. We defined a comprehensive set of immunogenomics features, including immune gene expression signatures associated with treatment outcome,1,2 estimates of immune cell proportions, metabolic profiles, and T and B cell receptor repertoire, and scored all compendium samples for these features. Elastic net regression models with parameter optimization done via Monte Carlo cross-validation and leave-one-out cross-validation were used to analyze the capacity of an integrated immunogenomics model to predict durable clinical benefit following ICB treatment. Results Our preliminary analyses confirmed an association between the expression of an IFN-gamma signature in tumor (1) and better outcomes of ICB, highlighting the feasibility of our approach. Conclusions In line with analysis of pan-cancer TCGA datasets using this strategy (1), we expect to identify analogous immune subtypes characterizing baseline tumors from patients responding to ICB. Furthermore, we expect to find that these immune subtypes will have different importance in the model predicting response and survival. Results of this study will be incorporated into the Cancer Research Institute iAtlas Portal, to facilitate interactive exploration and hypothesis testing. References Thorsson V, Gibbs DL, Brown SD, Wolf D, Bortone DS, Yang T-H O, Porta-Pardo E. Gao GF, Plaisier CL, Eddy JA, et al. The Immune Landscape of Cancer. Immunity 2018; 48(4): 812–830.e14. https://doi.org/10.1016/j.immuni.2018.03.023. Auslander N, Zhang G, Lee JS, Frederick DT, Miao B, Moll T, Tian T, Wei Z, Madan S, Sullivan RJ, et al. Robust Prediction of Response to Immune Checkpoint Blockade Therapy in Metastatic Melanoma. Nat. Med 2018; 24(10): 1545. https://doi.org/10.1038/s41591-018-0157-9. more...
- Published
- 2020
- Full Text
- View/download PDF
34. Novel agents in renal carcinoma: a reality check
- Author
-
Yana G. Najjar and Brian I. Rini
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The discovery of the molecular mechanisms underlying development of renal cell carcinoma have allowed for the development of novel targeted therapy for treatment of this disease. Recently, multiple agents have become approved by regulatory authorities for the treatment of advanced renal cell carcinoma, including sunitinib, sorafenib, bevacizumab (with interferon alpha), pazopanib, temsirolimus and everolimus. While these therapies have generated excitement and have clearly altered the treatment paradigm, multiple limitations have been elucidated over time. These include but are not limited to the fact that treatment is not associated with complete responses, a significant number of patients are primarily refractory to treatment, and clinical trials mostly include clear cell histology. Furthermore, the role of these therapies in the treatment of brain metastases remains unclear and therapies can have considerable toxicities. RECIST criteria (Response Evaluation Criteria In Solid Tumors) can be inadequate for the assessment of these modalities’ treatment efficacy, and biomarkers predictive of individual patient benefit have been elusive. This review summarizes the major clinical data and discusses these limitations. more...
- Published
- 2012
- Full Text
- View/download PDF
35. Abstract LB062: Efficacy of Responder-derived Fecal Microbiota Transplant (R-FMT) and Pembrolizumab in Anti-PD-1 Refractory Patients with Advanced Melanoma
- Author
-
Hassane M. Zarour, Richelle DeBlasio, Marc Schwartz, Stephanie Prescott, Ivan Vujkovic-Cvijin, Amy Rose, Marie Vétizou, Scarlett J. Ernst, Jonathan H. Badger, Howard M. Dubner, Hong Wang, Yasmine Belkaid, John M. Kirkwood, Ascharya K. Balaji, Amiran Dzutsev, Diwakar Davar, Yana G. Najjar, Quanquan Ding, Raquel Galvão Figueredo Costa, Joe-Marc Chauvin, Shuowen Zhang, Carmine Menna, Amir A. Borhani, Giorgio Trinchieri, John A. McCulloch, Bochra Zidi, Richard R. Rodrigues, Ornella Pagliano, Miriam R. Fernandes, Andrey Morgun, Robert M. Morrison, and Alicia M. Cole more...
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Melanoma ,Phases of clinical research ,Cancer ,Pembrolizumab ,Immunotherapy ,medicine.disease ,Internal medicine ,medicine ,Microbiome ,business ,CD8 ,Progressive disease - Abstract
Background: Monoclonal antibodies (mAb) targeting the programmed cell death protein 1 (PD-1) receptor provide durable long-term benefit in a subset of patients (pts) with advanced melanoma with response rates of 35-42% and 4-year progression-free survival (PFS) rate of 27%. Separately, the composition of the gut microbiota has been shown to correlate with anti-PD-1 efficacy in human cancer pts with melanoma, renal cell cancer and non-small cell lung cancer (NSCLC) although the precise organisms differ considerably across various studies. In preclinical models, responder-derived fecal microbiome and microbiome consortia produce anti-tumor responses. The effect of microbiome modulation in pts with anti-PD-1 refractory melanoma has not been evaluated. Methods: To evaluate whether primary resistance to anti-PD-1 immunotherapy could be overcome by intestinal microbiome modulation, we designed and conducted a phase II study (NCT03341143). We enrolled pts with primary refractory metastatic melanoma with best response of short-term stable disease (≤6 months) or progressive disease (PD) to prior anti-PD-1 based immunotherapy. Pts received single-administration of responder-derived fecal microbiota transplantation (R-FMT) together with pembrolizumab. Candidate donors were pts with advanced melanoma treated with anti-PD-1 immunotherapy with durable partial or complete response (PR, CR). Pembrolizumab was continued till intolerable toxicity or disease progression. Safety and clinical activity (based on RECIST v1.1) were main objectives; while progression-free survival (PFS) was a key secondary endpoint. Results: As of December 1, 2020, 16 pts with primary refractory melanoma were enrolled, of whom 15 were evaluable. LDH was elevated in 14/15 pts; and the median number of prior therapies was 2. Recipient pts were seromatched to receive a single R-FMT from one of eight candidate donors (5 CR; 3 PR; median PFS 58 months, range 43-70). R-FMT was administered via colonoscopy after bowel preparation with no use of antibiotics. Pembrolizumab was administered IV per label. R-FMT/pembrolizumab was well-tolerated, with no unusual toxicity signals. R-FMT induced rapid and durable microbiota perturbation in most pts; while 6 of 15 evaluable pts had evidence of clinical benefit. Response to R-FMT/pembrolizumab was associated with an increased abundance of taxa previously shown to be associated with response to anti-PD-1, increased CD8+ T cell activation, and decreased frequency of IL-8 expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. Conclusions: In pts with anti-PD-1 primary refractory melanoma, R-FMT/pembrolizumab changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti-PD-1 immunotherapy. Response was associated with CD8 T cell induction and reduction of IL-8 expressing myeloid cells. Citation Format: Diwakar Davar, Amiran Dzutsev, John A. McCulloch, Richard R. Rodrigues, Joe-Marc Chauvin, Robert M. Morrison, Richelle N. Deblasio, Carmine Menna, Quanquan Ding, Ornella Pagliano, Bochra Zidi, Shuowen Zhang, Jonathan H. Badger, Marie Vetizou, Alicia M. Cole, Miriam R. Fernandes, Stephanie Prescott, Raquel G. Costa, Ascharya K. Balaji, Andrey Morgun, Ivan Vujkovic-Cvijin, Hong Wang, Amir A. Borhani, Marc B. Schwartz, Howard M. Dubner, Scarlett J. Ernst, Amy Rose, Yana G. Najjar, Yasmine Belkaid, John M. Kirkwood, Giorgio Trinchieri, Hassane M. Zarour. Efficacy of Responder-derived Fecal Microbiota Transplant (R-FMT) and Pembrolizumab in Anti-PD-1 Refractory Patients with Advanced Melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB062. more...
- Published
- 2021
- Full Text
- View/download PDF
36. Thick melanoma is associated with low melanoma knowledge and low perceived health competence, but not delays in care
- Author
-
John M. Kirkwood, Stephanie R. Jackson Cullison, Laura K. Ferris, Neil A. Houston, Matthew P. Holtzman, Galen E. Switzer, Rebecca Liu, Nalyn Siripong, Diwakar Davar, Sophia Zhang, Keely Marshall, and Yana G. Najjar more...
- Subjects
Male ,medicine.medical_specialty ,Health Knowledge, Attitudes, Practice ,Skin Neoplasms ,Time Factors ,MEDLINE ,Dermatology ,Thick melanoma ,Perceived health ,Risk Factors ,Medicine ,Humans ,Competence (human resources) ,Melanoma ,Early Detection of Cancer ,Aged ,Neoplasm Staging ,Skin ,business.industry ,Age Factors ,Middle Aged ,Patient Acceptance of Health Care ,medicine.disease ,Family medicine ,Self-Examination ,Female ,business - Published
- 2019
37. Tumor cell oxidative metabolism as a barrier to PD-1 blockade immunotherapy in melanoma
- Author
-
Shuyan Zhai, Roma Bhatia, Cindy Sander, Arivarasan Karunamurthy, Uma Rao, John M. Kirkwood, Ashley V. Menk, Greg M. Delgoffe, and Yana G. Najjar
- Subjects
Adult ,Male ,medicine.medical_treatment ,T cell ,T-Lymphocytes ,Programmed Cell Death 1 Receptor ,Melanoma, Experimental ,Lymphocyte Activation ,Mice ,Immune system ,Cancer immunotherapy ,Cell Line, Tumor ,medicine ,Tumor Microenvironment ,Animals ,Humans ,Prospective Studies ,Hypoxia ,Melanoma ,Aged ,Aged, 80 and over ,Mice, Knockout ,Tumor microenvironment ,Glucose Transporter Type 1 ,Electron Transport Complex I ,Tumor hypoxia ,business.industry ,General Medicine ,Immunotherapy ,Hypoxia (medical) ,Middle Aged ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,Oxidative Stress ,medicine.anatomical_structure ,Glucose ,Cancer research ,Female ,medicine.symptom ,business ,Glycolysis ,Research Article - Abstract
The tumor microenvironment presents physical, immunologic, and metabolic barriers to durable immunotherapy responses. We have recently described roles for both T cell metabolic insufficiency as well as tumor hypoxia as inhibitory mechanisms that prevent T cell activity in murine tumors, but whether intratumoral T cell activity or response to immunotherapy varies between patients as a function of distinct metabolic profiles in tumor cells remains unclear. Here, we show that metabolic derangement can vary widely in both degree and type in patient-derived cell lines and in ex vivo analysis of patient samples, such that some cells demonstrate solely deregulated oxidative or glycolytic metabolism. Further, deregulated oxidative, but not glycolytic, metabolism was associated with increased generation of hypoxia upon implantation into immunodeficient animals. Generation of murine single-cell melanoma cell lines that lacked either oxidative or glycolytic metabolism showed that elevated tumor oxygen consumption was associated with increased T cell exhaustion and decreased immune activity. Moreover, melanoma lines lacking oxidative metabolism were solely responsive to anti-PD-1 therapy among those tested. Prospective analysis of patient sample immunotherapy revealed that oxidative, but not glycolytic, metabolism was associated with progression on PD-1 blockade. Our data highlight a role for oxygen as a crucial metabolite required for the tumor-infiltrating T cells to differentiate appropriately upon PD-1 blockade, and suggest that tumor oxidative metabolism may be a target to improve immunotherapeutic response. more...
- Published
- 2019
38. Adjuvant Systemic Therapy for High-Risk Melanoma Patients
- Author
-
John M. Kirkwood, Ryan Massa, Yana G. Najjar, Alexander M.M. Eggermont, Helen Gogas, and Vernon K. Sondak
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Melanoma ,Internal medicine ,medicine ,medicine.disease ,business ,Systemic therapy - Published
- 2019
- Full Text
- View/download PDF
39. Impact of the COVID-19 pandemic on staging at presentation of patients with invasive melanoma
- Author
-
Diwakar Davar, Yana G. Najjar, Hassane M. Zarour, Xi Yang, Hong Wang, John M. Kirkwood, Jason J. Luke, Dylan Fortman, and Saba Shaikh
- Subjects
Cancer Research ,medicine.medical_specialty ,2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Cancer ,medicine.disease ,Viral infection ,Oncology ,Pandemic ,Advanced disease ,medicine ,Invasive Melanoma ,Presentation (obstetrics) ,Intensive care medicine ,business - Abstract
e21579 Background: The COVID-19 pandemic has impacted cancer care beyond the direct implications of viral infection. Delays in presentation and diagnosis may lead to more advanced disease and worse patient outcomes. We evaluated the impact of the pandemic on patients (pts) with melanoma (mel). Methods: A single-institution, retrospective comparison of pts with newly diagnosed invasive mel or metastatic recurrence prior to (pre-cohort, n = 246) and after (post-cohort, n = 246) declaration of the COVID-19 pandemic on March 11, 2020. 492 pts were evaluated between March 1, 2019 and January 12, 2021. Key variables collected included demographics, pathology, stage at diagnosis, surgical management, receipt of adjuvant or systemic therapy, and follow up. Categorical variables were compared using the two-sided Fisher’s exact test, continuous variables were compared using the two-sided Wilcoxon rank sum test, and survival endpoints were evaluated with the Kaplan-Meier method. This study was exempt from review by the IRB. Results: 200 (81.3%) pts presented with early-stage disease and 46 (18.7%) pts presented with metastatic disease in the post-cohort, compared to 209 (85%) and 37 (15%) pts in the pre-cohort, respectively. In the post-cohort there was a significant decrease in stage I pts (28.5% vs 40.7%, p = 0.006), a significant increase in stage III pts (30.5% vs 21.1%, p = 0.023), and a significant increase in pts with metastatic recurrence (7.7% vs 3.3%, p = 0.046) compared to the pre-cohort. There was also a significant increase in pts with brain metastases (BM) in the post-cohort (6.5% vs 1.6%, p = 0.010). For pts with early-stage disease, there was a significant increase in median Breslow depth (2.0 vs 1.4 mm, p = 0.047) and mitotic rate > 1 (78.1% vs 66%, p = 0.008) in the post-cohort. There were trends toward increased ulceration, lymphovascular/perineural invasion, and microsatellite presence. Pts receiving adjuvant therapy in the post-cohort were significantly more likely to receive oral targeted therapy (37.6% vs 27.5%) compared to IV immunotherapy (62.4% vs 72.5%), p = 0.034, perhaps reflecting an attempt to minimize in-person visits. There was not a significant difference between the 2 groups in the type of systemic therapy administered in the metastatic setting. Median progression-free and overall survival were not reached due to a limited number of events in each arm. Conclusions: There was a significant decrease in pts with stage I mel along with a significant increase in pts with stage III mel, metastatic recurrence, and BMs presenting to our institution during the pandemic. Findings are likely related to delays from both the patient (to avoid interaction with the healthcare system - including primary care, dermatology, and oncology) and from the system itself, with some clinics potentially evaluating pts in a limited capacity. These data reaffirm the importance of early detection and evaluation of melanoma. more...
- Published
- 2021
- Full Text
- View/download PDF
40. A phase I trial of pembrolizumab plus vemurafenib and cobimetinib in patients with advanced melanoma
- Author
-
Saba Shaikh, Yan Zang, Diwakar Davar, Hassane M. Zarour, Hong Wang, Yana G. Najjar, John M. Kirkwood, Janel Hanmer, and Yan Lin
- Subjects
Cobimetinib ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Pembrolizumab ,Targeted therapy ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Mutation (genetic algorithm) ,medicine ,In patient ,Vemurafenib ,business ,medicine.drug ,Advanced melanoma - Abstract
e21506 Background: Management of patients (pts) with advanced melanoma includes anti-PD1 with or without anti-CTLA4, and for pts with a BRAF mutation, the additional option of targeted therapy. Preclinical and translational evidence suggest BRAF/MEK inhibitors (i) modulate the tumor microenvironment, providing rationale for combination with immune checkpoint inhibitors. Phase 3 IMspire data reported improved progression-free survival (PFS) with triplet therapy (atezolizumab/vemurafenib/cobimetinib), yielding regulatory approval. However, 79% of pts experienced grade 3/4 adverse events (AE) in the triplet arm. Methods: This is an investigator-initiated, phase I trial of pembrolizumab (pembro) plus vemurafenib (vem) and cobimetinib (cobi) for pts with advanced melanoma in the first line setting. The first 4 pts received vem/pembro. The protocol was subsequently amended, and the next 5 pts received vem/cobi/pembro. Vem/cobi had an escalating dosing regimen. Pembro was 200 mg q3 weeks. Primary endpoints: safety and maximum tolerated dose of vem/cobi when administered with pembro. Secondary endpoints: overall response rate (ORR), PFS, overall survival (OS), and quality of life (QoL). We planned to accrue 30 pts; however, the trial was closed after enrollment of 9 pts due to dose-limiting toxicity (DLT). This study NCT02818023 was approved by the IRB, and all pts provided informed consent. Results: Pts received a median of 6 cycles of triplet therapy. 8 of 9 pts experienced drug-related grade 3/4 AEs, most commonly dermatitis (89%). In the vem/pembro group, DLTs included hepatitis (n = 1), dermatitis (n = 3), and arthralgias (n = 1). In the vem/cobi/pembro group, DLTs included dermatitis (n = 5), QTc prolongation (n = 1), and arthralgias (n = 1). QoL assessments identified a clinically significant decrease in average health utility at 1 year compared to baseline (0.38 v 0.43). Median PFS was 20.7 months and median OS was 23.8 months for vem/pembro, and neither was reached for vem/cobi/pembro. Overall, 4 pts had ongoing responses at the time of data analysis. 2 pts experienced a complete response, 5 had a partial response, 1 had stable disease, and 1 had progressive disease at first restaging. Peripheral blood flow cytometry identified significantly decreased PD1 expression on CD4+ T-cells at 3 and 9 weeks compared to baseline. This did not correspond to clinical response. PD-L1 testing was also performed on 6 paired tumor samples, and no significant association was identified between PD-L1 expression and clinical outcomes. Conclusions: Despite preclinical and translational evidence for tumor immunomodulation with BRAF/MEKi and improved PFS noted in IMspire150, toxicity incurred with the triplet is challenging from a practical standpoint. Our study highlights clinical efficacy of the combination and adds additional toxicity data for triplet therapy, with 8 of 9 pts experiencing at least a grade 3 AE. Clinical trial information: NCT02818023. more...
- Published
- 2021
- Full Text
- View/download PDF
41. Characteristics of the Tumor Microenvironment That Influence Immune Cell Functions: Hypoxia, Oxidative Stress, Metabolic Alterations
- Author
-
Ryan C. Augustin, Greg M. Delgoffe, and Yana G. Najjar
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_treatment ,immunometabolism ,Review ,medicine.disease_cause ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,cellular energetics ,Tumor microenvironment ,Tumor-infiltrating lymphocytes ,business.industry ,Immunosuppression ,Immunotherapy ,Immune dysregulation ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Unfolded protein response ,immunotherapy ,business ,Oxidative stress - Abstract
Simple Summary For decades nearly all cancer patients were treated with cytotoxic chemotherapy, killing any rapidly dividing cell in the body. More recently, researchers have been studying the immune system’s response to cancer and have developed a novel class of drugs that stimulate the body’s own response to tumors. This class of immunotherapy drugs primarily involve T-cells, immune cells that target and destroy cancer cells. While these drugs can lead to remarkable and sustained response, most patients do not respond. Understanding the resistance mechanisms in non-responding tumors is now an active area of investigation. In this review, we explore a host of factors in the tumor microenvironment, the cellular and molecular space within tumor tissue, to identify possible culprits of immunotherapy resistance. Specifically, the downstream effects of low oxygen and metabolic byproducts in the tumor microenvironment have been associated with immune cell dysfunction. Importantly, targeting these pathways may offer promising therapies to improve the response to current immunotherapy. Abstract Immunotherapy (IMT) is now a core component of cancer treatment, however, many patients do not respond to these novel therapies. Investigating the resistance mechanisms behind this differential response is now a critical area of research. Immune-based therapies, particularly immune checkpoint inhibitors (ICI), rely on a robust infiltration of T-cells into the tumor microenvironment (TME) for an effective response. While early efforts relied on quantifying tumor infiltrating lymphocytes (TIL) in the TME, characterizing the functional quality and degree of TIL exhaustion correlates more strongly with ICI response. Even with sufficient TME infiltration, immune cells face a harsh metabolic environment that can significantly impair effector function. These tumor-mediated metabolic perturbations include hypoxia, oxidative stress, and metabolites of cellular energetics. Primarily through HIF-1-dependent processes, hypoxia invokes an immunosuppressive phenotype via altered molecular markers, immune cell trafficking, and angiogenesis. Additionally, oxidative stress can promote lipid peroxidation, ER stress, and Treg dysfunction, all associated with immune dysregulation. Finally, the metabolic byproducts of lipids, amino acids, glucose, and cellular energetics are associated with immunosuppression and ICI resistance. This review will explore these biochemical pathways linked to immune cell dysfunction in the TME and highlight potential adjunctive therapies to be used alongside current IMT. more...
- Published
- 2020
- Full Text
- View/download PDF
42. Metastatic melanoma with sebocyte-like melanocytes and widespread visceral involvement
- Author
-
Viktoryia Kazlouskaya, Li-Wei Chang, Jenna R Bordelon, Marion A. Hughes, Yuri L Bunimovich, Yana G. Najjar, Arivarasan Karunamurthy, and Jonhan Ho
- Subjects
melanocyte ,Metastatic melanoma ,business.industry ,malignant melanoma ,Articles ,Dermatology ,Melanocyte ,clear-cell melanocyte ,sebocyte-like melanoma ,medicine.anatomical_structure ,Oncology ,RL1-803 ,Genetics ,medicine ,Cancer research ,business ,Molecular Biology ,metastatic melanoma - Published
- 2020
- Full Text
- View/download PDF
43. Adjuvant therapy versus watch-and-wait post surgery for stage III melanoma: a multicountry retrospective chart review
- Author
-
Rodrigo U Villarroel, Rama Koneru, Virtudes Soriano, Jonathan S. Zager, Roy Koruth, Olivier Dereure, Maurice Perrinjaquet, Karmele Mujika, Felix Kiecker, Eva Muñoz Couselo, Lisa A. Kottschade, Yana G. Najjar, Peter Mohr, Raluca Ionescu-Ittu, Matias Chacón, Philippe Saiag, Rebecca Burne, Jochen Utikal, Florencia Cuadros, Caroline Robert, and Annie Guerin more...
- Subjects
nodal disease ,medicine.medical_specialty ,medicine.medical_treatment ,Dermatology ,Post surgery ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Chart review ,melanoma ,medicine ,Adjuvant therapy ,Stage III melanoma ,In patient ,030212 general & internal medicine ,Adverse effect ,business.industry ,Melanoma ,adjuvant therapy ,interferon ,medicine.disease ,Oncology ,030220 oncology & carcinogenesis ,stage III melanoma ,business ,Adjuvant ,Research Article ,metastatic melanoma - Abstract
Aim: To describe treatment patterns among patients with stage III melanoma who underwent surgical excision in years 2011–2016, and assess outcomes among patients who subsequently received systemic adjuvant therapy versus watch-and-wait. Methods: Chart review of 380 patients from 17 melanoma centers in North America, South America and Europe. Results: Of 129 (34%) patients treated with adjuvant therapy, 85% received interferon α-2b and 56% discontinued treatment (mostly due to adverse events). Relapse-free survival was significantly longer for patients treated with adjuvant therapy versus watch-and-wait (hazard ratio = 0.63; p < 0.05). There was considerable heterogeneity in adjuvant treatment schedules and doses. Similar results were found in patients who received interferon-based adjuvant therapy. Conclusion: Adjuvant therapies with better safety/efficacy profiles will improve clinical outcomes in patients with stage III melanoma. more...
- Published
- 2019
- Full Text
- View/download PDF
44. A phase I study of neoadjuvant combination immunotherapy in locally/regionally advanced melanoma
- Author
-
Yana G. Najjar, Dustin McCurry, Igor Puzanov, Joseph J. Drabick, Cindy Sander, Matthew P. Holtzman, Diwakar Davar, John M. Kirkwood, Yan Lin, Marc S. Ernstoff, Amy Rose, Joseph J. Skitzki, Huang Lin, James F. Pingpank, Rogerio I. Neves, and Ahmad A. Tarhini more...
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Pembrolizumab ,Phase i study ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Combination immunotherapy ,business ,030215 immunology ,Advanced melanoma - Abstract
9586 Background: A trial of neoadjuvant pembrolizumab (P) in combination with high dose interferon-α (HDI) in high-risk patients (pts) with locoregionally advanced melanoma (mel) has completed enrollment. Methods: Primary endpoint: safety of combination P-HDI. Pts were treated with P x 2 doses followed by definitive surgery, then x1 year. HDI was given concurrently, and both agents were per standard regimen. Tumor and blood samples were obtained at baseline and at surgery (wk 6-8), blood at 6 wks, 3,6,12 months (mos). Results: 30 pts were treated (22 male, 8 female, age 26-83). 16 had cutaneous primary, 3 mucosal, 11 unknown. At enrollment, 16 had recurrent disease, 6 received prior adjuvant therapy with ipilimumab (4) or HDI (2). 16 had AJCC 7 stage IIIB, 9 IIIC, 5 IV. 332 P cycles have been delivered (median 13), 496 doses of HDI induction (median 17), 1329 doses of HDI maintenance (median 44). HDI was dose reduced in 20 pts, discontinued in 27, P discontinued in 8. Radiologic preoperative RR was 77% (95% CI, 59-88) (6 CR, 17 PR). 20% (6) had SD and 1 had PD. All pts underwent definitive surgery. The pathologic complete response (pCR) of 26 pts was 32% (95% CI, 18-51). 6 pts recurred and 3 died. No pt with pCR has recurred. Median f/u time is 17.4 mos, median PFS/OS not reached. Most common grade (Gr) 3 toxicities: hypophosphatemia (10; 33%), fatigue (10; 33%), ↑CPK (6; 20%), ↑lipase (4; 13%). 3 Gr 4 events (↑CPK, hyperglycemia, lymphocyte count decreased). 1 suspected grade 5 event occurred 6 months after completion of therapy. PD-L1 expression at baseline did not correlate with clinical outcomes. In 8 pts with pre and post treatment tumor samples, IHC expression of PD-1, PD-L1, CD11b, CD8, Foxp3 and CD25 increased post-treatment (p < 0.05). Conclusions: Neoadjuvant P-HDI has promising clinical activity, although treatment is limited by HDI toxicity. Treatment increases the immune cell infiltrate, and outcomes do not correlate with baseline expression of PD-L1. Longer follow up and further mechanistic studies are underway. Clinical trial information: NCT02339324. more...
- Published
- 2019
- Full Text
- View/download PDF
45. Association of medication (Med) and antibiotic (Abx) use with response and survival in advanced melanoma (MEL) receiving PD-1 inhibitors
- Author
-
Amit Hemadri, Yana G. Najjar, Cindy Sander, Hassane M. Zarour, John M. Kirkwood, Amy Rose, Yan Lin, Huang Lin, and Diwakar Davar
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Aspirin ,medicine.drug_class ,business.industry ,medicine.medical_treatment ,Antibiotics ,Retrospective cohort study ,Immunotherapy ,computer.file_format ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,ABX test ,business ,computer ,030215 immunology ,Advanced melanoma ,medicine.drug - Abstract
9572 Background: Retrospective studies suggest that various med could dichotomous effects in regards to immunotherapy. These include adverse (antibiotics) and positive (aspirin, beta-blockers) influences. To evaluate potential additive or detrimental effects of various med in patients (pts) receiving PD-1 immunotherapy, we performed a retrospective evaluation of med intake in 172 pts with stage IV cutaneous MEL focusing on aspirin (asp), antacid (ant), antibiotic (abx), bisphosphonate (bisp), metformin (met) and statin (stat) intake. Methods: Pts with stage IV cutaneous MEL who received anti PD-1 therapy at the University of Pittsburgh between 2014-2018 were included in this analysis. PD-1 blockade was continued until progression or intolerable toxicity. Tumor assessment was performed at baseline and every 12 weeks and response classified per RECIST v1.1. Clinical and demographic data were obtained. Med intake was documented based on chart review in all pts. Intake was confirmed by analyzing at least one other note from a non-oncological provider. Descriptive statistics were created for all covariates. Kaplan Meier and Cox proportional hazard regression were performed to assess how categorical variables related to response (ORR), overall survival (OS) and progression free survival (PFS) measured in months (mths). Results: 172 pts with advanced MEL were evaluated. Asp, ant, abx, bisp, met and stat use was documented in 62, 82, 29, 4, 15 and 57 pts respectively. ORR was not significantly related to intake of asp, ant, bisp, met and stat use; although ORR was lower in pts who received abx (p=0.0328). There was no significant difference in PFS and OS in pts who received asp, ant, bisp, met and stat. In patients who received abx compared to those who did not, median PFS (16.6 mths vs. 19.8 mths) and median OS (23.8 mths vs. 35.4) were both lower. Abx use did not interact with other meds. Conclusions: In this retrospective series of advanced MEL pts treated with PD-1 blockade, abx use was adversely associated with response to PD-1 blockade. Abx use was also associated with poorer PFS and OS. Conversely, neither a positive nor negative association with ORR, PFS and/or OS was seen with asp, ant, bisp, met and stat use. These results validate prior studies suggesting that abx use is associated with worse outcomes in pts receiving PD-1 blockade possibly by mediating intestinal dysbiosis. more...
- Published
- 2019
- Full Text
- View/download PDF
46. Association of baseline neutrophil-to-lymphocyte ratio (NLR) with response and survival in advanced melanoma (MEL) receiving PD-1 inhibitors
- Author
-
Amit Hemadri, John M. Kirkwood, Yan Lin, Hassane M. Zarour, Cindy Sander, Amy Rose, Yana G. Najjar, Diwakar Davar, and Huang Lin
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Prognostic factor ,business.industry ,fungi ,Cancer ,Inflammation ,Systemic inflammation ,medicine.disease ,Internal medicine ,medicine ,Biomarker (medicine) ,Neutrophil to lymphocyte ratio ,medicine.symptom ,business ,Advanced melanoma - Abstract
9571 Background: Inflammation is an adverse prognostic factor in cancer. Neutrophil-to-lymphocyte ratio (NLR) is an easily derived biomarker of systemic inflammation. Several studies have demonstrated that elevated NLR is linked with adverse prognosis in patients (pts) receiving immunotherapy including PD-1 inhibitors. To evaluate the prognostic utility of NLR, we performed a retrospective evaluation of NLR and other covariates in stage IV cutaneous MEL. Methods: Stage IV cutaneous MEL pts who received anti PD-1 therapy at the University of Pittsburgh between 2014-2018 were included in this analysis. PD-1 blockade was continued until progression or intolerable toxicity. Tumor assessment was performed at baseline and every 12 weeks and response classified per RECIST v1.1. Clinical and demographic data were obtained. Baseline NLR was defined based on values at the first treatment date. Descriptive statistics were created for all covariates. Kaplan Meier and Cox proportional hazard regression were performed to assess how variables related to response (ORR), overall survival (OS) and progression free survival (PFS) measured in months (mos). Results: 172 pts with advanced MEL were evaluated. Elevated NLR was associated with poorer PFS and OS and ORR at all cutoffs (NLR≥2 to NLR≥5) with NLR≥5 having the greatest discriminative value. ORR steadily declined with increasing NLR: NLR≥1 (ORR 64%), NLR≥2 (ORR 61%), NLR≥3 (ORR 52%), NLR≥4 (ORR 43%), NLR≥5 (ORR 43%). Elevated NLR ( < 5 vs. ≥5) was associated with poorer PFS (median 21.5 mths vs. 5.2 mos; p = 0.00041) and OS (median 35.4 os vs. 10.6 mos; p < 0.0001). In a multivariate model, elevated NLR ( < 5 vs. ≥5) was independently associated with poorer OS/PFS separate from ulceration, performance status and elevated LDH. There was no evidence of an age-related increase or decrease in NLR. Conclusions: Baseline NLR was independently associated with response, PFS and OS in the largest retrospective series of advanced MEL pts treated with PD-1 blockade. NLR independent of other factors predicted poorer PFS and OS at NLR cutoffs (NLR≥3 to NLR≥5), although NLR≥5 segregated pts best. NLR is an inexpensive and easily obtained real-world biomarker that has a high value in predicting outcomes to PD-1 blockade. more...
- Published
- 2019
- Full Text
- View/download PDF
47. Association of baseline body mass index (BMI) with response and survival in patients (Pts) with advanced melanoma (MEL) receiving PD-1 inhibitors
- Author
-
Yana G. Najjar, Amit Hemadri, Diwakar Davar, Cindy Sander, John M. Kirkwood, Yan Lin, Hassane M. Zarour, Huang Lin, and Amy Rose
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,nutritional and metabolic diseases ,medicine.disease ,Tumor response ,Obesity ,Blockade ,T-cell dysfunction ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,In patient ,business ,Body mass index ,030215 immunology ,Advanced melanoma - Abstract
9579 Background: Obesity promotes PD-1–mediated T cell dysfunction but also improves tumor response to PD-1 blockade. Obesity has been linked with positive outcomes in pts treated with PD-1 blockade. To evaluate the prognostic utility of BMI, we performed a retrospective evaluation of BMI and other covariates in 172 pts with stage IV cutaneous MEL. Methods: Pts with stage IV cutaneous MEL who received anti PD-1 therapy at the University of Pittsburgh between 2014-2018 were included in this analysis. PD-1 blockade was continued until progression or intolerable toxicity. Tumor assessment was performed at baseline and every 12 weeks and response classified per RECIST v1.1. Clinical and demographic data were obtained. BMI was defined based on values at the first treatment date and dichotomized into two groups: ≥30 vs. < 30. Fisher exact test was used to evaluate the correlation between BMI group and ORR. Kaplan Meier method and Cox proportional hazard models were performed to analyzed the time-to-event outcomes (OS and PFS). Results: 172 pts with advanced MEL were evaluated. Greater BMI was associated with greater ORR, PFS and OS across various BMI cutoffs (BMI≥28, BMI≥30 and BMI≥35) although this effect was most obvious at BMI≥30. Pts with BMI≥30 achieved higher ORR than those with BMI < 30 (74% vs. 58%, p-value = 0.04). Concordantly, pts with BMI≥30 had improved PFS and OS: median PFS (BMI≥30 21.1 mos vs. BMI < 30 10.7 mos) and median OS (BMI≥30 35.4 mos vs. BMI < 30 22.8 mos). Higher BMI was independently associated with improved OS (p = 0.018) and PFS (p = 0.047) adjusting for age, Breslow thickness and sex. No significant interaction was observed between the effects of BMI and that of age, sex, or Breslow thickness. Conclusions: Increased BMI was associated with greater ORR in addition to previously reported associations with PFS/OS in a large retrospective series of advanced MEL pts treated with PD-1 blockade. This data was independent of other prognostic factors and underscore the “inflammaging” effects of obesity and age in relation to anti PD-1 therapy in advanced cancer. more...
- Published
- 2019
- Full Text
- View/download PDF
48. Melanoma antigen-specific effector T cell cytokine secretion patterns in patients treated with ipilimumab
- Author
-
Yana G. Najjar, Robert Alan VanderWeele, Yan Lin, Fei Ding, Lisa H. Butterfield, and Ahmad A. Tarhini
- Subjects
0301 basic medicine ,Adult ,Male ,Chemokine ,medicine.medical_treatment ,T cell ,T-Lymphocytes ,General Biochemistry, Genetics and Molecular Biology ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Antigens, Neoplasm ,Medicine ,Cluster Analysis ,Humans ,Melanoma ,Aged ,Demography ,Medicine(all) ,Aged, 80 and over ,biology ,business.industry ,Biochemistry, Genetics and Molecular Biology(all) ,Research ,General Medicine ,Middle Aged ,Ipilimumab ,3. Good health ,Interleukin 10 ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,biology.protein ,Myeloid-derived Suppressor Cell ,Cytokines ,Cytokine secretion ,Female ,Neoadjuvant ,business ,CD8 - Abstract
Background In a previously reported study, patients with regionally advanced melanoma were treated with neoadjuvant ipilimumab (ipi) (Tarhini in PLoS ONE 9(2): e87705, 3). Significant changes in circulating myeloid derived suppressor cells (MDSC), regulatory T cells (Treg) and peptide specific type I CD4+ and CD8+ T cells were noted at week 6 that correlated with clinical outcome. Characterization of antigen-specific effector T cell secreted cytokines may shed insights into ipi associated T cell activation and function. Methods Patients were treated with neoadjuvant ipi (10 mg/kg every 3 weeks ×2) administered intravenously before and after surgery. Peripheral blood mononuclear cells (PBMC) that were collected at baseline and week 6 (after ipi) were tested here. Each sample was divided into 5 groups and stimulated with controls or shared melanoma antigen overlapping peptide pools (NY-ESO 1, gp-100, MART-1). Secreted cytokines, chemokines and growth factors were assessed using Luminex. Cytokine expression levels between the 3 antigen groups were compared using the Wilcox rank-sum test. Results Seventeen cytokines were differentially expressed with stimulation by each antigen at baseline (p value more...
- Published
- 2016
49. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one
- Author
-
Andreas Lundqvist, Vincent van Hoef, Xiaonan Zhang, Erik Wennerberg, Julie Lorent, Kristina Witt, Laia Masvidal Sanz, Shuo Liang, Shannon Murray, Ola Larsson, Rolf Kiessling, Yumeng Mao, John-William Sidhom, Catherine A. Bessell, Jonathan Havel, Jonathan Schneck, Timothy A. Chan, Eliot Sachsenmeier, David Woods, Anders Berglund, Rupal Ramakrishnan, Andressa Sodre, Jeffrey Weber, Roberta Zappasodi, Yanyun Li, Jingjing Qi, Philip Wong, Cynthia Sirard, Michael Postow, Walter Newman, Henry Koon, Vamsidhar Velcheti, Margaret K. Callahan, Jedd D. Wolchok, Taha Merghoub, Lawrence G. Lum, Minsig Choi, Archana Thakur, Abhinav Deol, Gregory Dyson, Anthony Shields, Cara Haymaker, Marc Uemura, Ravi Murthy, Marihella James, Daqing Wang, Julie Brevard, Catherine Monaghan, Suzanne Swann, James Geib, Mark Cornfeld, Srinivas Chunduru, Sudhir Agrawal, Cassian Yee, Jennifer Wargo, Sapna P. Patel, Rodabe Amaria, Hussein Tawbi, Isabella Glitza, Scott Woodman, Wen-Jen Hwu, Michael A. Davies, Patrick Hwu, Willem W. Overwijk, Chantale Bernatchez, Adi Diab, Erminia Massarelli, Neil H. Segal, Vincent Ribrag, Ignacio Melero, Tara C. Gangadhar, Walter Urba, Dirk Schadendorf, Robert L. Ferris, Roch Houot, Franck Morschhauser, Theodore Logan, Jason J. Luke, William Sharfman, Fabrice Barlesi, Patrick A. Ott, Laura Mansi, Shivaani Kummar, Gilles Salles, Cecilia Carpio, Roland Meier, Suba Krishnan, Dan McDonald, Matthew Maurer, Xuemin Gu, Jaclyn Neely, Satyendra Suryawanshi, Ronald Levy, Nikhil Khushalani, Jennifer Wu, Jinyu Zhang, Fahmin Basher, Mark Rubinstein, Mark Bucsek, Guanxi Qiao, Cameron MacDonald, Bonnie Hylander, Elizabeth Repasky, Shilpak Chatterjee, Anusara Daenthanasanmak, Paramita Chakraborty, Kyle Toth, Megan Meek, Elizabeth Garrett-Mayer, Michael Nishimura, Chrystal Paulos, Craig Beeson, Xuezhong Yu, Shikhar Mehrotra, Fei Zhao, Kathy Evans, Christine Xiao, Alisha Holtzhausen, Brent A. Hanks, Nicole Scharping, Ashley V. Menk, Rebecca Moreci, Ryan Whetstone, Rebekah Dadey, Simon Watkins, Robert Ferris, Greg M. Delgoffe, Jonathan Peled, Sean Devlin, Anna Staffas, Melissa Lumish, Kori Porosnicu Rodriguez, Katya Ahr, Miguel Perales, Sergio Giralt, Ying Taur, Eric Pamer, Marcel R. M. van den Brink, Robert Jenq, Nicola Annels, Hardev Pandha, Guy Simpson, Hugh Mostafid, Kevin Harrington, Alan Melcher, Mark Grose, Bronwyn Davies, Gough Au, Roberta Karpathy, Darren Shafren, Jacob Ricca, Dmitriy Zamarin, Luciana Batista, Florence Marliot, Angela Vasaturo, Sabrina Carpentier, Cécile Poggionovo, Véronique Frayssinet, Jacques Fieschi, Marc Van den Eynde, Franck Pagès, Jérôme Galon, Fabienne Hermitte, Sean G. Smith, Khue Nguyen, Sruthi Ravindranathan, Bhanu Koppolu, David Zaharoff, Gustavo Schvartsman, Roland Bassett, Jennifer L. McQuade, Lauren E. Haydu, Douglas Kline, Xiufen Chen, Dominick Fosco, Justin Kline, Abigail Overacre, Maria Chikina, Erin Brunazzi, Gulidanna Shayan, William Horne, Jay Kolls, Tullia C. Bruno, Creg Workman, Dario Vignali, Prasad S. Adusumilli, Ephraim A Ansa-Addo, Zihai Li, Andrew Gerry, Joseph P. Sanderson, Karen Howe, Roslin Docta, Qian Gao, Eleanor A. L. Bagg, Nicholas Tribble, Miguel Maroto, Gareth Betts, Natalie Bath, Luca Melchiori, Daniel E. Lowther, Indu Ramachandran, Gabor Kari, Samik Basu, Gwendolyn Binder-Scholl, Karen Chagin, Lini Pandite, Tom Holdich, Rafael Amado, Hua Zhang, John Glod, Donna Bernstein, Bent Jakobsen, Crystal Mackall, Ryan Wong, Jonathan D. Silk, Katherine Adams, Garth Hamilton, Alan D. Bennett, Sara Brett, Junping Jing, Adriano Quattrini, Manoj Saini, Guy Wiedermann, Joanna Brewer, MyLinh Duong, An Lu, Peter Chang, Aruna Mahendravada, Nicholas Shinners, Kevin Slawin, David M. Spencer, Aaron E. Foster, J. Henri Bayle, Cristina Bergamaschi, Sinnie Sin Man Ng, Bethany Nagy, Shawn Jensen, Xintao Hu, Candido Alicea, Bernard Fox, Barbara Felber, George Pavlakis, Jessica Chacon, Tori Yamamoto, Thomas Garrabrant, Luis Cortina, Daniel J. Powell, Marco Donia, Julie Westerlin Kjeldsen, Rikke Andersen, Marie Christine Wulff Westergaard, Valentina Bianchi, Mateusz Legut, Meriem Attaf, Garry Dolton, Barbara Szomolay, Sascha Ott, Rikke Lyngaa, Sine Reker Hadrup, Andrew Kelvin Sewell, Inge Marie Svane, Aaron Fan, Takumi Kumai, Esteban Celis, Ian Frank, Amanda Stramer, Michelle A. Blaskovich, Seth Wardell, Maria Fardis, James Bender, Michael T. Lotze, Stephanie L. Goff, Nikolaos Zacharakis, Yasmine Assadipour, Todd D. Prickett, Jared J. Gartner, Robert Somerville, Mary Black, Hui Xu, Harshini Chinnasamy, Isaac Kriley, Lily Lu, John Wunderlich, Paul F. Robbins, Steven Rosenberg, Steven A. Feldman, Kasia Trebska-McGowan, Parisa Malekzadeh, Eden Payabyab, Richard Sherry, Aishwarya Gokuldass, Charlene Kopits, Brian Rabinovich, Daniel S. Green, Olena Kamenyeva, Kathryn C. Zoon, Christina M. Annunziata, Joanne Hammill, Christopher Helsen, Craig Aarts, Jonathan Bramson, Yui Harada, Yoshikazu Yonemitsu, Kenneth Mwawasi, Galina Denisova, Rajanish Giri, Benjamin Jin, Tracy Campbell, Lindsey M. Draper, Sanja Stevanovic, Zhiya Yu, Bianca Weissbrich, Nicholas P. Restifo, Cornelia L. Trimble, Christian S. Hinrichs, Kwong Tsang, Massimo Fantini, James W. Hodge, Rika Fujii, Ingrid Fernando, Caroline Jochems, Christopher Heery, James Gulley, Patrick Soon-Shiong, Jeffrey Schlom, Weiqing Jing, Jill Gershan, Grace Blitzer, James Weber, Laura McOlash, Bryon D. Johnson, Simin Kiany, Huang Gangxiong, Eugenie S. Kleinerman, Michael Klichinsky, Marco Ruella, Olga Shestova, Saad Kenderian, Miriam Kim, John Scholler, Carl H. June, Saar Gill, Duane Moogk, Shi Zhong, Ivan Liadi, William Rittase, Victoria Fang, Janna Dougherty, Arianne Perez-Garcia, Iman Osman, Cheng Zhu, Navin Varadarajan, Alan Frey, Michelle Krogsgaard, Daniel Landi, Kristen Fousek, Malini Mukherjee, Ankita Shree, Sujith Joseph, Kevin Bielamowicz, Tiara Byrd, Nabil Ahmed, Meenakshi Hegde, Sylvia Lee, David Byrd, John Thompson, Shailender Bhatia, Scott Tykodi, Judy Delismon, Liz Chu, Siddiq Abdul-Alim, Arpy Ohanian, Anna Marie DeVito, Stanley Riddell, Kim Margolin, Isabelle Magalhaes, Jonas Mattsson, Michael Uhlin, Satoshi Nemoto, Patricio Pérez Villarroel, Ryosuke Nakagawa, James J. Mule, Adam W. Mailloux, Melinda Mata, Phuong Nguyen, Claudia Gerken, Christopher DeRenzo, Stephen Gottschalk, Mélissa Mathieu, Sandy Pelletier, John Stagg, Simon Turcotte, Nicholas Minutolo, Prannda Sharma, Andrew Tsourkas, Nadine Mockel-Tenbrinck, Daniela Mauer, Katharina Drechsel, Carola Barth, Katharina Freese, Ulrike Kolrep, Silke Schult, Mario Assenmacher, Andrew Kaiser, John Mullinax, MacLean Hall, Julie Le, Krithika Kodumudi, Erica Royster, Allison Richards, Ricardo Gonzalez, Amod Sarnaik, Shari Pilon-Thomas, Morten Nielsen, Anders Krarup-Hansen, Dorrit Hovgaard, Michael Mørk Petersen, Anand Chainsukh Loya, Niels Junker, Charlotte Rivas, Robin Parihar, Cliona M. Rooney, Haiying Qin, Sang Nguyen, Paul Su, Chad Burk, Brynn Duncan, Bong-Hyun Kim, M. Eric Kohler, Terry Fry, Arjun A. Rao, Noam Teyssier, Jacob Pfeil, Nikolaos Sgourakis, Sofie Salama, David Haussler, Sarah A. Richman, Selene Nunez-Cruz, Zack Gershenson, Zissimos Mourelatos, David Barrett, Stephan Grupp, Michael Milone, Alba Rodriguez-Garcia, Matthew K. Robinson, Gregory P. Adams, João Santos, Riikka Havunen, Mikko Siurala, Víctor Cervera-Carrascón, Suvi Parviainen, Marjukka Antilla, Akseli Hemminki, Jyothi Sethuraman, Laurelis Santiago, Jie Qing Chen, Zhimin Dai, Huizi Sha, Shu Su, Naiqing Ding, Baorui Liu, Anna Pasetto, Sarah R. Helman, Steven A. Rosenberg, Melissa Burgess, Hui Zhang, Tien Lee, Hans Klingemann, Paul Nghiem, John M. Kirkwood, John M. Rossi, Marika Sherman, Allen Xue, Yueh-wei Shen, Lynn Navale, James N. Kochenderfer, Adrian Bot, Anandaraman Veerapathran, Doris Wiener, Edmund K. Waller, Jian-Ming Li, Christopher Petersen, Bruce R. Blazar, Jingxia Li, Cynthia R. Giver, Ziming Wang, Steven K. Grossenbacher, Ian Sturgill, Robert J. Canter, William J. Murphy, Congcong Zhang, Michael C. Burger, Lukas Jennewein, Anja Waldmann, Michel Mittelbronn, Torsten Tonn, Joachim P. Steinbach, Winfried S. Wels, Jason B. Williams, Yuanyuan Zha, Thomas F. Gajewski, LaTerrica C. Williams, Giedre Krenciute, Mamta Kalra, Chrystal Louis, Gang Xin, David Schauder, Aimin Jiang, Nikhil Joshi, Weiguo Cui, Xue Zeng, Zeguo Zhao, Mohamad Hamieh, Justin Eyquem, Gertrude Gunset, Neil Bander, Michel Sadelain, David Askmyr, Milad Abolhalaj, Kristina Lundberg, Lennart Greiff, Malin Lindstedt, Helen K. Angell, Kyoung-Mee Kim, Seung-Tae Kim, Sung Kim, Alan D. Sharpe, Julia Ogden, Anna Davenport, Darren R. Hodgson, Carl Barrett, Jeeyun Lee, Elaine Kilgour, Jodi Hanson, Richard Caspell, Alexey Karulin, Paul Lehmann, Tameem Ansari, Annemarie Schiller, Srividya Sundararaman, Diana Roen, Mark Ayers, Diane Levitan, Gladys Arreaza, Fang Liu, Robin Mogg, Yung-Jue Bang, Bert O’Neil, Razvan Cristescu, Philip Friedlander, Karl Wassman, Chrisann Kyi, William Oh, Nina Bhardwaj, Svetlana Bornschlegl, Michael P. Gustafson, Dennis A. Gastineau, Ian F. Parney, Allan B. Dietz, Daniel Carvajal-Hausdorf, Nikita Mani, Kurt Schalper, David Rimm, Serena Chang, John Kurland, Christoph Matthias Ahlers, Maria Jure-Kunkel, Lewis Cohen, Holden Maecker, Holbrook Kohrt, Shuming Chen, George Crabill, Theresa Pritchard, Tracee McMiller, Drew Pardoll, Fan Pan, Suzanne Topalian, Patrick Danaher, Sarah Warren, Lucas Dennis, Andrew M. White, Leonard D’Amico, Melissa Geller, Mary L. Disis, Joseph Beechem, Kunle Odunsi, Steven Fling, Roshanak Derakhshandeh, Tonya J. Webb, Sigrid Dubois, Kevin Conlon, Bonita Bryant, Jennifer Hsu, Nancy Beltran, Jürgen Müller, Thomas Waldmann, Rebekka Duhen, Thomas Duhen, Lucas Thompson, Ryan Montler, Andrew Weinberg, Max Kates, Brandon Early, Erik Yusko, Taylor H. Schreiber, Trinity J. Bivalacqua, Jared Lunceford, Michael Nebozhyn, Erin Murphy, Andrey Loboda, David R. Kaufman, Andrew Albright, Jonathan Cheng, S. Peter Kang, Veena Shankaran, Sarina A. Piha-Paul, Jennifer Yearley, Tanguy Seiwert, Antoni Ribas, Terrill K. McClanahan, Xinwei Sher, Xiao Qiao Liu, Andrew Joe, Elizabeth Plimack, Alex Forrest-Hay, Cheryl A. Guyre, Kohei Narumiya, Marc Delcommenne, Heather A. Hirsch, Amit Deshpande, Jason Reeves, Jenny Shu, Tong Zi, Jennifer Michaelson, Debbie Law, Elizabeth Trehu, Sriram Sathyanaryanan, Brendan P. Hodkinson, Natalie A. Hutnick, Michael E. Schaffer, Michael Gormley, Tyler Hulett, Carmen Ballesteros-Merino, Christopher Dubay, Michael Afentoulis, Ashok Reddy, Larry David, Kumar Jayant, Swati Agrawal, Rajendra Agrawal, Ghayathri Jeyakumar, Seongho Kim, Heejin Kim, Cynthia Silski, Stacey Suisham, Elisabeth Heath, Ulka Vaishampayan, Natalie Vandeven, Natasja Nielsen Viller, Alison O’Connor, Hui Chen, Bolette Bossen, Eric Sievers, Robert Uger, Lisa Johnson, Hsiang-Fong Kao, Chin-Fu Hsiao, Shu-Chuan Lai, Chun-Wei Wang, Jenq-Yuh Ko, Pei-Jen Lou, Tsai-Jan Lee, Tsang-Wu Liu, Ruey-Long Hong, Staci J. Kearney, Joshua C. Black, Benjamin J. Landis, Sally Koegler, Brooke Hirsch, Roberto Gianani, Jeffrey Kim, Ming-Xiao He, Bingqing Zhang, Nan Su, Yuling Luo, Xiao-Jun Ma, Emily Park, Dae Won Kim, Domenico Copploa, Nishi Kothari, Young doo Chang, Richard Kim, Namyong Kim, Melvin Lye, Ee Wan, Hanna A. Knaus, Sofia Berglund, Hubert Hackl, Judith E. Karp, Ivana Gojo, Leo Luznik, Henoch S. Hong, Sven D. Koch, Birgit Scheel, Ulrike Gnad-Vogt, Karl-Josef Kallen, Volker Wiegand, Linus Backert, Oliver Kohlbacher, Ingmar Hoerr, Mariola Fotin-Mleczek, James M. Billingsley, Yoshinobu Koguchi, Valerie Conrad, William Miller, Iliana Gonzalez, Tomasz Poplonski, Tanisha Meeuwsen, Ana Howells-Ferreira, Rogan Rattray, Mary Campbell, Carlo Bifulco, Keith Bahjat, Brendan Curti, E-K Vetsika, G. Kallergi, Despoina Aggouraki, Z. Lyristi, P. Katsarlinos, Filippos Koinis, V. Georgoulias, Athanasios Kotsakis, Nathan T. Martin, Famke Aeffner, Logan Cerkovnik, Luke Pratte, Rebecca Kim, Joseph Krueger, Amaia Martínez-Usatorre, Camilla Jandus, Alena Donda, Laura Carretero-Iglesia, Daniel E. Speiser, Dietmar Zehn, Nathalie Rufer, Pedro Romero, Anshuman Panda, Janice Mehnert, Kim M. Hirshfield, Greg Riedlinger, Sherri Damare, Tracie Saunders, Levi Sokol, Mark Stein, Elizabeth Poplin, Lorna Rodriguez-Rodriguez, Ann Silk, Nancy Chan, Melissa Frankel, Michael Kane, Jyoti Malhotra, Joseph Aisner, Howard L. Kaufman, Siraj Ali, Jeffrey Ross, Eileen White, Gyan Bhanot, Shridar Ganesan, Anne Monette, Derek Bergeron, Amira Ben Amor, Liliane Meunier, Christine Caron, Antigoni Morou, Daniel Kaufmann, Moishe Liberman, Igor Jurisica, Anne-Marie Mes-Masson, Kamel Hamzaoui, Rejean Lapointe, Ann Mongan, Yuan-Chieh Ku, Warren Tom, Yongming Sun, Alex Pankov, Tim Looney, Janice Au-Young, Fiona Hyland, Jeff Conroy, Carl Morrison, Sean Glenn, Blake Burgher, He Ji, Mark Gardner, Angela R. Omilian, Wiam Bshara, Omilian Angela, Joseph M. Obeid, Gulsun Erdag, Mark E. Smolkin, Donna H. Deacon, James W. Patterson, Lieping Chen, Timothy N. Bullock, Craig L. Slingluff, John T. Loffredo, Raja Vuyyuru, Sophie Beyer, Vanessa M. Spires, Maxine Fox, Jon M. Ehrmann, Katrina A. Taylor, Alan J. Korman, Robert F. Graziano, David Page, Katherine Sanchez, Maritza Martel, Mariana Petaccia De Macedo, Yong Qin, Alex Reuben, Christine Spencer, Michele Guindani, Adriana Racolta, Brian Kelly, Tobin Jones, Nathan Polaske, Noah Theiss, Mark Robida, Jeffrey Meridew, Iva Habensus, Liping Zhang, Lidija Pestic-Dragovich, Lei Tang, Ryan J. Sullivan, Thomas Olencki, Thomas Hutson, Joanna Roder, Shauna Blackmon, Heinrich Roder, John Stewart, Asim Amin, Marc S. Ernstoff, Joseph I. Clark, Michael B. Atkins, Jeffrey Sosman, David F. McDermott, Harriet Kluger, Ruth Halaban, Mario Snzol, Senait Asmellash, Arni Steingrimsson, Chichung Wang, Kristin Roman, Amanda Clement, Sean Downing, Clifford Hoyt, Nathalie Harder, Guenter Schmidt, Ralf Schoenmeyer, Nicolas Brieu, Mehmet Yigitsoy, Gabriele Madonna, Gerardo Botti, Antonio Grimaldi, Paolo A. Ascierto, Ralf Huss, Maria Athelogou, Harald Hessel, Alexander Buchner, Christian Stief, Gerd Binnig, Thomas Kirchner, Shankar Sellappan, Sheeno Thyparambil, Sarit Schwartz, Fabiola Cecchi, Andrew Nguyen, Charles Vaske, Todd Hembrough, Jan Spacek, Michal Vocka, Eva Zavadova, Helena Skalova, Pavel Dundr, Lubos Petruzelka, Nicole Francis, Rau T. Tilman, Arndt Hartmann, Irena Netikova, Julia Stump, Amanda Tufman, Frank Berger, Michael Neuberger, Rudolf Hatz, Michael Lindner, Rachel E. Sanborn, John Handy, Rudolf M. Huber, Hauke Winter, Simone Reu, Cheng Sun, Weihua Xiao, Zhigang Tian, Kshitij Arora, Niyati Desai, Anupriya Kulkarni, Mihir Rajurkar, Miguel Rivera, Vikram Deshpande, David Ting, Katy Tsai, Adi Nosrati, Simone Goldinger, Omid Hamid, Alain Algazi, Paul Tumeh, Jimmy Hwang, Jacqueline Liu, Lawrence Chen, Reinhard Dummer, Michael Rosenblum, Adil Daud, Tsu-Shuen Tsao, Julia Ashworth-Sharpe, Donald Johnson, Srabani Bhaumik, Christopher Bieniarz, Joseph Couto, Michael Farrell, Mahsa Ghaffari, Antony Hubbard, Jerome Kosmeder, Cleo Lee, Erin Marner, Diana Uribe, Hongjun Zhang, Jian Zhang, Wenjun Zhang, Yifei Zhu, Larry Morrison, Takahiro Tsujikawa, Rohan N. Borkar, Vahid Azimi, Sushil Kumar, Guillaume Thibault, Motomi Mori, Edward El Rassi, Daniel R. Clayburgh, Molly F. Kulesz-Martin, Paul W. Flint, Lisa M. Coussens, Lisa Villabona, Giuseppe V. Masucci, Gary Geiss, Brian Birditt, Qian Mei, Alan Huang, Maribeth A. Eagan, Eduardo Ignacio, Nathan Elliott, Dwayne Dunaway, Jaemyeong Jung, Chris Merritt, Isaac Sprague, Philippa Webster, Yan Liang, Jessica Wenthe, Gunilla Enblad, Hannah Karlsson, Magnus Essand, Barbara Savoldo, Gianpietro Dotti, Martin Höglund, Malcolm K. Brenner, Hans Hagberg, Angelica Loskog, Matthew J. Bernett, Gregory L. Moore, Michael Hedvat, Christine Bonzon, Seung Chu, Rumana Rashid, Kendra N. Avery, Umesh Muchhal, John Desjarlais, Matthew Kraman, Katarzyna Kmiecik, Natalie Allen, Mustapha Faroudi, Carlo Zimarino, Mateusz Wydro, Jacqueline Doody, Sreesha P. Srinivasa, Nagaraja Govindappa, Praveen Reddy, Aparajita Dubey, Sankar Periyasamy, Madhukara Adekandi, Chaitali Dey, Mary Joy, Pieter Fokko van Loo, Henrike Veninga, Setareh Shamsili, Mark Throsby, Harry Dolstra, Lex Bakker, Ajjai Alva, Juergen Gschwendt, Yohann Loriot, Joaquim Bellmunt, Dai Feng, Christian Poehlein, Thomas Powles, Emmanuel S. Antonarakis, Charles G. Drake, Haiyan Wu, Johann De Bono, Rajat Bannerji, John Byrd, Gareth Gregory, Stephen Opat, Jake Shortt, Andrew J. Yee, Noopur Raje, Seth Thompson, Arun Balakumaran, Shaji Kumar, Brian I. Rini, Toni K. Choueiri, Mariangela Mariani, Laurence Albiges, John B. Haanen, James Larkin, Manuela Schmidinger, Domenico Magazzù, Alessandra di Pietro, Robert J. Motzer, Troels Holz Borch, Per Kongsted, Magnus Pedersen, Özcan Met, Karim Boudadi, Hao Wang, James Vasselli, Jan E. Baughman, Jon Wigginton, Rehab Abdallah, Ashley Ross, Jiwon Park, Steven Grossenbacher, Jesus I. Luna, Sita Withers, William Culp, Mingyi Chen, Arta Monjazeb, Michael S. Kent, Smita Chandran, David Danforth, James Yang, Christopher Klebanoff, Stephanie Goff, Biman Paria, Arvind Sabesan, Abhishek Srivastava, Udai Kammula, Jon Richards, Mark Faries, Robert H. I. Andtbacka, Luis A. Diaz, Dung T. Le, Takayuki Yoshino, Thierry André, Johanna Bendell, Minori Koshiji, Yayan Zhang, S Peter Kang, Bao Lam, Dirk Jäger, Todd M. Bauer, Judy S. Wang, Jean K. Lee, Gulam A. Manji, Ragini Kudchadkar, John S. Kauh, Shande Tang, Naomi Laing, Gerald Falchook, Edward B. Garon, Balazs Halmos, Hui Rina, Natasha Leighl, Sung Sook Lee, William Walsh, Konstanin Dragnev, Bilal Piperdi, Luis Paz-Ares Rodriguez, Nabeegha Shinwari, Ziewn Wei, Mary L Maas, Michael Deeds, Adam Armstrong, Tim Peterson, Sue Steinmetz, Thomas Herzog, Floor J. Backes, Larry Copeland, Maria Del Pilar Estevez Diz, Thomas W. Hare, Warner Huh, Byoung-Gie Kim, Kathleen M. Moore, Ana Oaknin, William Small, Krishnansu S. Tewari, Bradley J. Monk, Ashish M. Kamat, Kijoeng Nam, Maria De Santis, Robert Dreicer, Noah M. Hahn, Rodolfo Perini, Arlene Siefker-Radtke, Guru Sonpavde, Ronald de Wit, J. Alfred Witjes, Stephen Keefe, Dean Bajorin, Philippe Armand, John Kuruvilla, Craig Moskowitz, Mehdi Hamadani, Pier Luigi Zinzani, Sabine Chlosta, Nancy Bartlett, Rachel Sabado, Yvonne Saenger, Loging William, Michael Joseph Donovan, Erlinda Sacris, John Mandeli, Andres M. Salazar, John Powderly, Joshua Brody, John Nemunaitis, Leisha Emens, Amita Patnaik, Ian McCaffery, Richard Miller, Ginna Laport, Andrew L. Coveler, David C. Smith, Juneko E. Grilley-Olson, Sanjay Goel, Shyra J. Gardai, Che-Leung Law, Gary Means, Thomas Manley, Kristen A. Marrone, Gary Rosner, Valsamo Anagnostou, Joanne Riemer, Jessica Wakefield, Cynthia Zanhow, Stephen Baylin, Barbara Gitlitz, Julie Brahmer, Sabina Signoretti, Wenting Li, Charles Schloss, Jean-Marie Michot, Wei Ding, Beth Christian, Patricia Marinello, Margaret Shipp, Yana G. Najjar, null Lin, Lisa H. Butterfield, Ahmad A. Tarhini, Diwakar Davar, Hassane Zarour, Elizabeth Rush, Cindy Sander, Siqing Fu, Todd Bauer, Chris Molineaux, Mark K. Bennett, Keith W. Orford, Kyriakos P. Papadopoulos, Sukhmani K. Padda, Sumit A. Shah, A Dimitrios Colevas, Sujata Narayanan, George A. Fisher, Dana Supan, Heather A. Wakelee, Rhonda Aoki, Mark D. Pegram, Victor M. Villalobos, Jie Liu, Chris H. Takimoto, Mark Chao, Jens-Peter Volkmer, Ravindra Majeti, Irving L. Weissman, Branimir I. Sikic, Wendy Yu, Alison Conlin, Janet Ruzich, Stacy Lewis, Anupama Acheson, Kathleen Kemmer, Kelly Perlewitz, Nicole M. Moxon, Staci Mellinger, Heather McArthur, Trine Juhler-Nøttrup, Jayesh Desai, Ben Markman, Shahneen Sandhu, Hui Gan, Michael L. Friedlander, Ben Tran, Tarek Meniawy, Joanne Lundy, Duncan Colyer, Malaka Ameratunga, Christie Norris, Jason Yang, Kang Li, Lai Wang, Lusong Luo, Zhen Qin, Song Mu, Xuemei Tan, James Song, Michael Millward, Matthew H. G. Katz, Todd W. Bauer, Gauri R. Varadhachary, Nicolas Acquavella, Nipun Merchant, Gina Petroni, Osama E. Rahma, Mei Chen, Yang Song, Markus Puhlmann, Arun Khattri, Ryan Brisson, Christopher Harvey, Jatin Shah, Maria Victoria Mateos, Morio Matsumoto, Hilary Blacklock, Albert Oriol Rocafiguera, Hartmut Goldschmidt, Shinsuke Iida, Dina Ben Yehuda, Enrique Ocio, Paula Rodríguez-Otero, Sundar Jagannath, Sagar Lonial, Uma Kher, Jesus San-Miguel, Moacyr Ribeiro de Oliveira, Habte Yimer, Robert Rifkin, Fredrik Schjesvold, Razi Ghori, Anna Spreafico, Victor Lee, Roger K. C. Ngan, Ka Fai To, Myung Ju Ahn, Quan Sing Ng, Jin-Ching Lin, Ramona F. Swaby, Christine Gause, Sanatan Saraf, Anthony T. C. Chan, Elaine Lam, Nizar M. Tannir, Funda Meric-Bernstam, Matt Gross, Andy MacKinnon, Sam Whiting, Martin Voss, Evan Y. Yu, Mark R. Albertini, Erik A. Ranheim, Jacquelyn A. Hank, Cindy Zuleger, Thomas McFarland, Jennifer Collins, Erin Clements, Sharon Weber, Tracey Weigel, Heather Neuman, Greg Hartig, David Mahvi, MaryBeth Henry, Jacek Gan, Richard Yang, Lakeesha Carmichael, KyungMann Kim, Stephen D. Gillies, Paul M. Sondel, Vivek Subbiah, Lori Noffsinger, Kyle Hendricks, Marnix Bosch, Jay M. Lee, Mi-Heon Lee, Jonathan W. Goldman, Felicita E. Baratelli, Dorthe Schaue, Gerald Wang, Frances Rosen, Jane Yanagawa, Tonya C. Walser, Ying Q. Lin, Sharon Adams, Franco M. Marincola, Paul C. Tumeh, Fereidoun Abtin, Robert Suh, Karen Reckamp, William D. Wallace, Gang Zeng, David A. Elashoff, Sherven Sharma, Steven M. Dubinett, Anna C. Pavlick, Brian Gastman, Brent Hanks, Tibor Keler, Tom Davis, Laura A. Vitale, Elad Sharon, Chihiro Morishima, Martin Cheever, Christopher R. Heery, Joseph W. Kim, Elizabeth Lamping, Jennifer Marte, Sheri McMahon, Lisa Cordes, Farhad Fakhrejahani, Ravi Madan, Rachel Salazar, Maggie Zhang, Christoph Helwig, James L Gulley, Roger Li, John Amrhein, Zvi Cohen, Monique Champagne, Ashish Kamat, M. Angela Aznar, Sara Labiano, Angel Diaz-Lagares, Manel Esteller, Juan Sandoval, Susannah D. Barbee, David I. Bellovin, John C. Timmer, Nebiyu Wondyfraw, Susan Johnson, Johanna Park, Amanda Chen, Mikayel Mkrtichyan, Amir S. Razai, Kyle S. Jones, Chelsie Y. Hata, Denise Gonzalez, Quinn Deveraux, Brendan P. Eckelman, Luis Borges, Rukmini Bhardwaj, Raj K. Puri, Akiko Suzuki, Pamela Leland, Bharat H. Joshi, Todd Bartkowiak, Ashvin Jaiswal, Casey Ager, Midan Ai, Pratha Budhani, Renee Chin, David Hong, Michael Curran, William D. Hastings, Maria Pinzon-Ortiz, Masato Murakami, Jason R. Dobson, David Quinn, Joel P. Wagner, Xianhui Rong, Pamela Shaw, Ernesta Dammassa, Wei Guan, Glenn Dranoff, Alexander Cao, Ross B. Fulton, Steven Leonardo, Kathryn Fraser, Takashi O. Kangas, Nadine Ottoson, Nandita Bose, Richard D. Huhn, Jeremy Graff, Jamie Lowe, Keith Gorden, Mark Uhlik, Thomas O’Neill, Jenifer Widger, Andrea Crocker, Li-Zhen He, Jeffrey Weidlick, Karuna Sundarapandiyan, Venky Ramakrishna, James Storey, Lawrence J. Thomas, Joel Goldstein, Henry C. Marsh, Jamison Grailer, Julia Gilden, Pete Stecha, Denise Garvin, Jim Hartnett, Frank Fan, Mei Cong, Zhi-jie Jey Cheng, Marlon J. Hinner, Rachida-Siham Bel Aiba, Corinna Schlosser, Thomas Jaquin, Andrea Allersdorfer, Sven Berger, Alexander Wiedenmann, Gabriele Matschiner, Julia Schüler, Ulrich Moebius, Christine Rothe, Olwill A. Shane, Brendan Horton, Stefani Spranger, Dayson Moreira, Tomasz Adamus, Xingli Zhao, Piotr Swiderski, Sumanta Pal, Marcin Kortylewski, Alyssa Kosmides, Kevin Necochea, Kathleen M. Mahoney, Sachet A. Shukla, Nikolaos Patsoukis, Apoorvi Chaudhri, Hung Pham, Ping Hua, Xia Bu, Baogong Zhu, Nir Hacohen, Catherine J. Wu, Edward Fritsch, Vassiliki A. Boussiotis, Gordon J. Freeman, Amy E. Moran, Fanny Polesso, Lisa Lukaesko, Emelie Rådestad, Lars Egevad, Berit Sundberg, Lars Henningsohn, Victor Levitsky, William Rafelson, John L. Reagan, Loren Fast, Pottayil Sasikumar, Naremaddepalli Sudarshan, Raghuveer Ramachandra, Nagesh Gowda, Dodheri Samiulla, Talapaneni Chandrasekhar, Sreenivas Adurthi, Jiju Mani, Rashmi Nair, Amit Dhudashia, Nagaraj Gowda, Murali Ramachandra, Alexander Sankin, Benjamin Gartrell, Kerwin Cumberbatch, Hongying Huang, Joshua Stern, Mark Schoenberg, Xingxing Zang, Ryan Swanson, Michael Kornacker, Lawrence Evans, Erika Rickel, Martin Wolfson, Sandrine Valsesia-Wittmann, Tala Shekarian, François Simard, Rodrigo Nailo, Aurélie Dutour, Anne-Catherine Jallas, Christophe Caux, and Aurélien Marabelle more...
- Subjects
Pharmacology ,0303 health sciences ,Cancer Research ,Side effect ,business.industry ,medicine.drug_class ,Immunology ,Phases of clinical research ,Monoclonal antibody ,Phase i study ,Clinical trial ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,Pharmacokinetics ,030220 oncology & carcinogenesis ,Molecular Medicine ,Immunology and Allergy ,Medicine ,In patient ,Programmed death 1 ,business ,030304 developmental biology - Published
- 2016
- Full Text
- View/download PDF
50. Myeloid derived suppressor cell subset accumulation in renal cell carcinoma parenchyma is associated with intratumoral expression of IL-1β, IL-8, CXCL5 and Mip-1α
- Author
-
Paul G. Pavicic, Charles S. Tannenbaum, Thomas A. Hamilton, Peter A. Cohen, James H. Finke, C. Marcela Diaz-Montero, Samuel Haywood, Xuefei Jia, Patricia Rayman, Jennifer S. Ko, Yana G. Najjar, and Brian I. Rini more...
- Subjects
0301 basic medicine ,Cancer Research ,Chemokine ,Pathology ,medicine.medical_specialty ,Chemokine CXCL5 ,Interleukin-1beta ,Programmed Cell Death 1 Receptor ,Article ,Monocytes ,Receptors, Interleukin-8B ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Renal cell carcinoma ,Cell Line, Tumor ,Parenchyma ,Antineoplastic Combined Chemotherapy Protocols ,Carcinoma ,medicine ,Animals ,Humans ,CXC chemokine receptors ,Carcinoma, Renal Cell ,Parenchymal Tissue ,Chemokine CCL3 ,biology ,business.industry ,Myeloid-Derived Suppressor Cells ,Interleukin-8 ,hemic and immune systems ,medicine.disease ,Tumor Burden ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,CXCL5 ,030220 oncology & carcinogenesis ,Myeloid-derived Suppressor Cell ,biology.protein ,business ,CD8 - Abstract
Purpose: Little is known about the association between myeloid-derived suppressor cell (MDSC) subsets and various chemokines in patients with renal cell carcinoma (RCC) or the factors that draw MDSC into tumor parenchyma. Experimental Design: We analyzed polymorphonuclear MDSC (PMN-MDSC), monocytic MDSC (M-MDSC), and immature MDSC (I-MDSC) from the parenchyma and peripheral blood of 48 patients with RCC, isolated at nephrectomy. We analyzed levels of IL1β, IL8, CXCL5, Mip-1α, MCP-1, and Rantes. Furthermore, we performed experiments in a Renca murine model to assess therapeutic synergy between CXCR2 and anti-PD1 and to elucidate the impact of IL1β blockade on MDSC. Results: Parenchymal PMN-MDSC have a positive correlation with IL1β, IL8, CXCL5, and Mip-1α, and I-MDSC correlate with IL8 and CXCL5. Furthermore, peripheral PMN-MDSC correlate with tumor grade. Given that PMN-MDSC express CXCR2 and parenchymal PMN-MDSC correlated with IL8 and CXCL5, we assessed the response of CXCR2 blockade with or without anti-PD1. Combination therapy reduced tumor weight and enhanced CD4+ and CD8+ T-cell infiltration. In addition, anti-IL1β decreased PMN-MDSC and M-MDSC in the periphery, PMN-MDSC in the tumor, and peripheral CXCL5 and KC. Anti-IL1β also delayed tumor growth. Conclusions: Parenchymal PMN-MDSC have a positive correlation with IL1β, IL8, CXCL5, and Mip-1α, suggesting they may attract PMN-MDSC into the tumor. Peripheral PMN-MDSC correlate with tumor grade, suggesting prognostic significance. Anti-CXCR2 and anti-PD1 synergized to reduce tumor weight and enhanced CD4+ and CD8+ T-cell infiltration in a Renca murine model, suggesting that CXCR2+ PMN-MDSC are important in reducing activity of anti-PD1 antibody. Finally, anti-IL1β decreases MDSC and delayed tumor growth, suggesting a potential target for MDSC inhibition. Clin Cancer Res; 23(9); 2346–55. ©2016 AACR. more...
- Published
- 2016
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.