21 results on '"Haven R. Garber"'
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2. Abstract P2-14-14: Durvalumab and tremelimumab before surgery in patients with hormone receptor positive, HER2 negative stage II-III breast cancer
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Haven R. Garber, Sreyashi Basu, Sonali Jindal, Akshara Singareeka Raghavendra, Lumarie Santiago, Beatriz E. Adrada, Padmanee Sharma, James P. Allison, and Jennifer Litton
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Cancer Research ,Oncology - Abstract
Background: The checkpoint inhibitors atezolizumab (anti-PD-L1) and pembrolizumab (anti-PD-1) are FDA approved for the treatment of patients with PD-L1 positive, metastatic triple negative breast cancer in combination with chemotherapy. The response rates to checkpoint blockade in hormone receptor positive, HER2 negative metastatic breast cancer have been less encouraging (RR 12% for pembrolizumab in KEYNOTE-028 and RR 2.8% for avelumab in the phase 1b trial JAVELIN). We conducted a feasibility trial and enrolled patients with Stage II-III hormone receptor positive, HER2 negative breast cancer to treatment with 2 cycles of durvalumab (anti-PD-L1) plus tremelimumab (anti-CTLA-4) prior to standard neoadjuvant chemotherapy and breast surgery.Methods: Eligible patients were treated with durvalumab at a dose of 1500 mg and tremelimumab at a dose of 75 mg, both administered intravenously, on days 1 and 28. Pre- and post-treatment tumor biopsies and blood samples were available for 5 out of 8 patients and were analyzed by CyTOF, IHC, and NanoString. Patients then received standard neoadjuvant chemotherapy prior to breast surgery. The target enrollment was 20 patients. Results: After 8 patients were enrolled and treated on protocol, the trial was stopped early due to toxicity, slow accrual, and delays in patients receiving standard neoadjuvant chemotherapy. The median age of the patients was 55 (range 39-66) and all 8 patients were women. All patients had ER/PR positive, HER2 negative invasive ductal carcinoma (2 with lobular features, 1 with focal mucinous features) and all patients had clinical Stage II disease. Five patients received both cycles of durvalumab/tremelimumab and the remaining 3 patients only received the first cycle. One patient discontinued therapy out of concern for progression, though repeat breast and lymph node biopsies were benign and she went on to have a pathologic complete response after standard neoadjuvant chemotherapy. The remaining 2 patients discontinued treatment after the first cycle due to Grade 3 colitis (Patient #1) and Grade 3 thyroiditis/adrenal insufficiency (Patient #8). Both patients required treatment with steroids and experienced delays in receiving standard therapy due to these adverse events (AEs). The other AEs reported were all Grade 1 or 2. A post-durvalumab/tremelimumab breast ultrasound was performed in 7 of 8 patients and the percentage change in volume of each patient’s primary breast mass was: -55%, +104% (biopsy benign), +65%, -30%, +90%, -8%, and -53%. Patient #1 (colitis) had chemotherapy administered adjuvantly and Patient #8 (thyroiditis, adrenal insufficiency) declined chemotherapy. Only 1 of 8 patients had a pathologic complete response at the time of surgery. IHC, CYTOF, and gene expression analyses showed an increase in immune cell subsets in tumor stroma post neoadjuvant immunotherapy. Conclusions: We conducted a feasibility trial of neoadjuvant durvalumab plus tremelimumab administered prior to standard neoadjuvant chemotherapy in patients with hormone receptor positive/HER2 negative Stage II or III breast cancer. The trial was stopped early after 2 of 8 patients experienced Grade 3 immune-related adverse events (colitis in 1 patient and thyroiditis/adrenal insufficiency in another patient). Citation Format: Haven R. Garber, Sreyashi Basu, Sonali Jindal, Akshara Singareeka Raghavendra, Lumarie Santiago, Beatriz E. Adrada, Padmanee Sharma, James P. Allison, Jennifer Litton. Durvalumab and tremelimumab before surgery in patients with hormone receptor positive, HER2 negative stage II-III breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-14-14.
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- 2022
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3. Immune Phenotype and Response to Neoadjuvant Therapy in Triple-Negative Breast Cancer
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Anne V. Philips, Jason B White, Jennifer A. Wargo, Sahil Seth, Xiangjie Sun, Senthil Damodaran, Andrew Futreal, Gabriel N. Hortobagyi, Er-Yen Yen, Clinton Yam, Baohua Sun, Gheath Alatrash, Stacy L. Moulder, Qingqing Ding, Edwin Roger Parra Cuentas, Ignacio I. Wistuba, Fei Yang, Elizabeth A. Mittendorf, Jeffrey T. Chang, Elizabeth Ravenberg, Haven R. Garber, Jennifer L. Guerriero, Bora Lim, Jennifer K. Litton, Ryan Sun, Lei Huo, Kasthuri Kannan, Naoto T. Ueno, Roland L. Bassett, Gaiane M. Rauch, and William Fraser Symmans
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Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,CD3 ,Triple Negative Breast Neoplasms ,Article ,B7-H1 Antigen ,Lymphocytes, Tumor-Infiltrating ,Immune system ,Breast cancer ,Internal medicine ,Tumor Microenvironment ,medicine ,Humans ,Neoadjuvant therapy ,Triple-negative breast cancer ,biology ,business.industry ,Odds ratio ,Prognosis ,medicine.disease ,Neoadjuvant Therapy ,Phenotype ,Nat ,biology.protein ,Immunohistochemistry ,business - Abstract
Purpose: Increasing tumor-infiltrating lymphocytes (TIL) is associated with higher rates of pathologic complete response (pCR) to neoadjuvant therapy (NAT) in patients with triple-negative breast cancer (TNBC). However, the presence of TILs does not consistently predict pCR, therefore, the current study was undertaken to more fully characterize the immune cell response and its association with pCR. Experimental Design: We obtained pretreatment core-needle biopsies from 105 patients with stage I–III TNBC enrolled in ARTEMIS (NCT02276443) who received NAT from Oct 22, 2015 through July 24, 2018. The tumor-immune microenvironment was comprehensively profiled by performing T-cell receptor (TCR) sequencing, programmed death-ligand 1 (PD-L1) IHC, multiplex immunofluorescence, and RNA sequencing on pretreatment tumor samples. The primary endpoint was pathologic response to NAT. Results: The pCR rate was 40% (42/105). Higher TCR clonality (median = 0.2 vs. 0.1, P = 0.03), PD-L1 positivity (OR: 2.91, P = 0.020), higher CD3+:CD68+ ratio (median = 14.70 vs. 8.20, P = 0.0128), and closer spatial proximity of T cells to tumor cells (median = 19.26 vs. 21.94 μm, P = 0.0169) were associated with pCR. In a multivariable model, closer spatial proximity of T cells to tumor cells and PD-L1 expression enhanced prediction of pCR when considered in conjunction with clinical stage. Conclusions: In patients receiving NAT for TNBC, deep immune profiling through detailed phenotypic characterization and spatial analysis can improve prediction of pCR in patients receiving NAT for TNBC when considered with traditional clinical parameters.
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- 2021
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4. Abstract P2-16-09: Residual cancer burden in patients with early stage triple negative breast cancer who progress on anthracycline-based neoadjuvant chemotherapy in an ongoing clinical trial (ARTEMIS)
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Helen Piwnica-Worms, Jennifer K. Litton, Banu Arun, Beatriz E. Adrada, Haven R. Garber, Gaiane M. Rauch, Debu Tripathy, Senthil Damodaran, Elizabeth A. Mittendorf, Vicente Valero, Rashmi Krishna Murthy, Fraser Symmans, Stacy L. Moulder, Lei Huo, Alastair M. Thompson, Naoto T. Ueno, Nuhad K. Ibrahim, Rosalind P. Candelaria, and Bora Lim
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Bevacizumab ,Anthracycline ,medicine.medical_treatment ,Targeted therapy ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Breast cancer ,Internal medicine ,medicine ,Triple-negative breast cancer ,Taxane ,business.industry ,Cancer ,medicine.disease ,Carboplatin ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,business ,medicine.drug - Abstract
BACKGROUND: Current treatment for early stage triple negative breast cancer (TNBC) includes neoadjuvant systemic chemotherapy (NAST), which is used to assess disease biology and the need for adjuvant treatment in case of residual disease at the time of surgery, also known as residual cancer burden (RCB). Patients with TNBC who experience RCB-0 (pathologic complete response [pCR]) or RCB-I after NAST have an excellent prognosis whereas patients with significant residual disease (RCB-II or RCB-III) are at a high risk of relapse. Standard NAST for TNBC achieves pCR in 30-50% of cases. NAST typically consists of anthracycline-based chemotherapy followed or preceded by a taxane +/- carboplatin. Disease progression (PD) is uncommon in TNBC patients receiving NAST and little is known regarding outcomes in patients who have PD during the initial phase of NAST. METHODS: Total 316 TNBC patients were evaluated from two prospectively accrued clinical trials of NAST (NCT02276443 and NCT01334021). The ARTEMIS trial (NCT02276443) aims to improve pCR rates by adding targeted therapy to chemotherapy as the second phase of NAST for those patients who do not experience at least a 70% volumetric reduction after 4 cycles of doxorubicin/cyclophosphamide (AC). Unique histopathologic features including % stromal tumor-infiltrating lymphocytes (sTIL), presence of mesenchymal histology (high vimentin expression by IHC), and androgen receptor expression are used to guide second phase therapy. RESULTS: 31 TNBC patients had PD while receiving AC as the first phase of NAST (10%; 95% CI= 6.69-13.31%). 9 of 31 patients proceeded to standard chemotherapy and all had RCB II/III disease. 22 of 31 patients were enrolled to targeted therapy trials. 6 were treated with the EGFR inhibitor panitumumab + carboplatin/paclitaxel, 9 with atezolizumab + nab-paclitaxel, and 7 with everolimus, bevacizumab, and liposomal doxorubicin (DAE). Of these 22 patients, 3 (13.6%) had pCR/RCB-0, 1 (4.5%) RCB-I and 18 (81.8%) had RCB II/III. All 4 patients who experienced RCB-0/I had T2N0 disease at diagnosis. 2 had sTIL < 5% and 2 patients had 70% sTIL. CONCLUSION: PD is uncommon while receiving NAST. Patients with TNBC and progression on initial NAST with AC are unlikely to achieve pCR or RCB-I status despite subsequent standard chemotherapy. Combination chemotherapy with targeted therapy on clinical trial resulted in a numerically higher rate of pCR+RCB-I (18%) as salvage therapy, but this was not statistically significant and requires confirmation in larger trials. Citation Format: Haven Garber, Gaiane Rauch, Beatriz Adrada, Rosalind Candelaria, Elizabeth Mittendorf, Alastair Thompson, Jennifer Litton, Senthil Damodaran, Bora Lim, Banu Arun, Naoto Ueno, Vicente Valero, Nuhad Ibrahim, Rashmi Murthy, Debu Tripathy, Helen Piwnica-Worms, Fraser Symmans, Lei Huo, Stacy Moulder. Residual cancer burden in patients with early stage triple negative breast cancer who progress on anthracycline-based neoadjuvant chemotherapy in an ongoing clinical trial (ARTEMIS) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-09.
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- 2020
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5. Serine Proteases Enhance Immunogenic Antigen Presentation on Lung Cancer Cells
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Karen Clise-Dwyer, John V. Heymach, Boris Sepesi, Jack A. Roth, Satyendra C. Tripathi, Chantale Bernatchez, Don L. Gibbons, Celine Kerros, Stephen G. Swisher, Ismail M. Meraz, Hiroyuki Katayama, Haley L. Peters, Samir M. Hanash, Gheath Alatrash, Jeffrey J. Molldrem, Mourad Majidi, Jason Roszik, Lorenzo Federico, Kathryn Ruisaard, Haven R. Garber, and Lisa S. St. John
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0301 basic medicine ,Cancer Research ,Lung Neoplasms ,Immunology ,Antigen presentation ,Human leukocyte antigen ,Biology ,Lymphocyte Activation ,Article ,Immunophenotyping ,Immunomodulation ,03 medical and health sciences ,Immune system ,Antigen ,Antigens, Neoplasm ,T-Lymphocyte Subsets ,Cell Line, Tumor ,HLA-A2 Antigen ,medicine ,Humans ,Cytotoxic T cell ,Amino Acid Sequence ,Lung cancer ,Antigen Presentation ,Tumor microenvironment ,Histocompatibility Antigens Class I ,medicine.disease ,Acquired immune system ,030104 developmental biology ,Leukocytes, Mononuclear ,Cytokines ,Serine Proteases ,Peptides ,Biomarkers - Abstract
Immunotherapies targeting immune checkpoints have proven efficacious in reducing the burden of lung cancer in patients; however, the antigenic targets of these reinvigorated T cells remain poorly defined. Lung cancer tumors contain tumor-associated macrophages (TAM) and neutrophils, which release the serine proteases neutrophil elastase (NE) and proteinase 3 (P3) into the tumor microenvironment. NE and P3 shape the antitumor adaptive immune response in breast cancer and melanoma. In this report, we demonstrate that lung cancer cells cross-presented the tumor-associated antigen PR1, derived from NE and P3. Additionally, NE and P3 enhanced the expression of human leukocyte antigen (HLA) class I molecules on lung cancer cells and induced unique, endogenous peptides in the immunopeptidome, as detected with mass spectrometry sequencing. Lung cancer patient tissues with high intratumoral TAMs were enriched for MHC class I genes and T-cell markers, and patients with high TAM and cytotoxic T lymphocyte (CTL) infiltration had improved overall survival. We confirmed the immunogenicity of unique, endogenous peptides with cytotoxicity assays against lung cancer cell lines, using CTLs from healthy donors that had been expanded against select peptides. Finally, CTLs specific for serine proteases–induced endogenous peptides were detected in lung cancer patients using peptide/HLA-A2 tetramers and were elevated in tumor-infiltrating lymphocytes. Thus, serine proteases in the tumor microenvironment of lung cancers promote the presentation of HLA class I immunogenic peptides that are expressed by lung cancer cells, thereby increasing the antigen repertoire that can be targeted in lung cancer. Cancer Immunol Res; 5(4); 319–29. ©2017 AACR.
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- 2017
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6. Cathepsin G is broadly expressed in acute myeloid leukemia and is an effective immunotherapeutic target
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L.S. St. John, Greg Lizee, Gheath Alatrash, Haroon Jakher, Jason Roszik, Pariya Sukhumalchandra, Paul M. Armistead, Dean A. Lee, Hong He, Anna Sergeeva, Suk-Young Yoo, Steve Kornblau, Qing Ma, David H. Hawke, Jeffrey J. Molldrem, Minying Zhang, Alexander A. Perakis, Haven R. Garber, Amjad H. Talukder, Kevin R. Coombes, Elizabeth A. Mittendorf, Yihua Qiu, Lisa M. Becker, Karen C. Dwyer, and Vladimir Senyukov
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Cathepsin G ,Myeloid ,medicine.medical_treatment ,Gene Expression ,Article ,Fusion gene ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Animals ,Humans ,Hematology ,business.industry ,Myeloid leukemia ,Immunotherapy ,medicine.disease ,Leukemia, Myeloid, Acute ,Haematopoiesis ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,chemistry ,Immunology ,Heterografts ,business - Abstract
Cathepsin G is broadly expressed in acute myeloid leukemia and is an effective immunotherapeutic target
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- 2016
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7. PR1-specific cytotoxic T lymphocytes are relatively frequent in umbilical cord blood and can be effectively expanded to target myeloid leukemia
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Haven R. Garber, Liping Wan, Katayoun Rezvani, Karen Clise-Dwyer, Gheath Alatrash, Lisa S. St. John, Elizabeth J. Shpall, Jeffrey J. Molldrem, Hong He, Qing Ma, and Catherine M. Bollard
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Adult ,0301 basic medicine ,Cancer Research ,Myeloid ,Myeloblastin ,Immunology ,Population ,Immunotherapy, Adoptive ,03 medical and health sciences ,Antigen ,HLA-A2 Antigen ,medicine ,Humans ,Immunology and Allergy ,Cytotoxic T cell ,Lymphocyte Count ,education ,Cells, Cultured ,Genetics (clinical) ,Transplantation ,education.field_of_study ,business.industry ,Antibody-Dependent Cell Cytotoxicity ,Myeloid leukemia ,U937 Cells ,Cell Biology ,Fetal Blood ,medicine.disease ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Leukemia, Myeloid ,K562 Cells ,business ,CD8 ,T-Lymphocytes, Cytotoxic ,K562 cells - Abstract
Background aims PR1 is an HLA-A2 restricted leukemia-associated antigen derived from neutrophil elastase and proteinase 3, both of which are normally stored in the azurophil granules of myeloid cells but overexpressed in myeloid leukemic cells. PR1-specific cytotoxic lymphocytes (PR1-CTLs) have activity against primary myeloid leukemia in vitro and in vivo and thus could have great potential in the setting of adoptive cellular therapy (ACT). Adult peripheral blood–derived PR1-CTLs are infrequent but preferentially lyse myeloid leukemia cells. We sought to examine PR1-CTLs in umbilical cord blood (UCB) because UCB units provide a rapidly available cell source and a lower risk of graft-versus-host disease, even in the setting of mismatched human leukocyte antigen (HLA) loci. Methods We first determined the frequency of PR1-CTLs in HLA-A2 + UCB units and then successfully expanded them ex vivo using repeated stimulation with PR1 peptide-pulsed antigen-presenting cells (APCs). After expansion, we assessed the PR1-CTL phenotype (naive, effector, memory) and function against PR1-expressing target cells. Results PR1-CTLs are detected at an average frequency of 0.14% within the CD8 + population of fresh UCB units, which is 45 times higher than in healthy adult peripheral blood. UCB PR1-CTLs are phenotypically naive, consistent with the UCB CD8 + population as a whole. In addition, the cells can be expanded by stimulation with PR1 peptide-pulsed APCs. Expansion results in an increased frequency of PR1-CTLs, up to 4.56%, with an average 20-fold increase in total number. After expansion, UCB PR1-CTLs express markers consistent with effector memory T cells. Expanded UCB PR1-CTLs are functional in vitro as they are able to produce cytokines and lyse PR1-expressing leukemia cell lines. Conclusions This study is the first report to show that T cells specific for a leukemia-associated antigen are found at a significantly higher frequency in UCB than adult blood. Our results also demonstrate specific cytotoxicity of expanded UCB-derived PR1-CTLs against PR1-expressing targets. Together, our data suggest that UCB PR1-CTLs could be useful to prevent or treat leukemia relapse in myeloid leukemia patients.
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- 2016
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8. Abstract 1516: Deep profiling of T-cell repertoire and tumor heterogeneity in chronic lymphocytic leukemia patients following allogeneic T-cell therapy
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John P. Miller, Celine Kerros, Paul G. Leonard, Jianhua Zhang, Huandong Sun, Shoudan Liang, Pei Lin, Hannah C. Beird, Xizeng Mao, Li Zhao, Koppikar Priya, Jeffrey J. Molldrem, Sahil Seth, Jason Roszik, Haven R. Garber, Karen Clise-Dwyer, Issa F. Khouri, Andrew Futreal, and William G. Wierda
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Oncology ,Cancer Research ,medicine.medical_specialty ,biology ,business.industry ,medicine.medical_treatment ,Chronic lymphocytic leukemia ,CD3 ,T cell ,Human leukocyte antigen ,medicine.disease ,Donor lymphocyte infusion ,Targeted therapy ,Leukemia ,medicine.anatomical_structure ,Internal medicine ,medicine ,biology.protein ,Refractory Chronic Lymphocytic Leukemia ,business - Abstract
Chemotherapy/ targeted therapy are both known to trigger evolution of treatment resistant clones that can lead to relapse. Allogeneic stem cell transplant (alloSCT) for refractory Chronic Lymphocytic Leukemia (CLL) patients is associated with better outcomes. We hypothesized that allogeneic T-cell immunotherapies, including alloSCT and donor lymphocyte infusion (DLI) would impact tumor evolution through the application of selective immunologic pressure with reciprocal changes in the T-cell compartment. Here, we tested a cohort of 24 heavily pre-treated CLL patients treated. Treatments consisted of alloSCT alone, or with follow-up DLI, which are two established mediators of effective Graft versus Leukemia (GVL). Our cohort included 11 patients who relapsed (denoted as non-responder, NR) after alloSCT and 13 patients who had complete response (CR) after alloSCT, with 11/13 patients showing durable CR with a median post-transplant overall survival (OS) of 9.8 years. We mapped the evolutionary trajectories of tumor cells by whole exome sequencing (WES) of sort purified CLL in post-transplant relapsed patients. To investigate changes in immune repertoire and gene expression post-transplant, CD3 positive T-cells from peripheral blood and bone marrows of CLL patients at complete donor chimerism were analyzed both at bulk and at the single cell level. We found evidence of subclonal leukemic evolution in the majority of our CLL patient cohort after nonmyeloablative HLA-matched alloSCT. Different patterns of CLL evolution were observed, and these changes included putative CLL drivers in every case. In all of the 11 patients with longitudinal post-alloSCT samples available, we observed branched CLL evolution in 4 patients, linear evolution in 4 patients, and no evolution in 3 patients. These data suggest that differential sensitivity of leukemic subclones to allogeneic T cell killing may underlie the branched and linear evolution that we observed, and therefore can shape leukemic subclonal architecture after transplant. Of note, we found that clonal CLL was more responsive to alloSCT in comparison to CLL with subclonal disease architecture.To identify T-cells with GVL potential, we first cataloged potential neoantigens by screening mutated regions in CLL with in silico HLA binding prediction models. Neoantigen specific T-cells were then sorted from longitudinal peripheral blood samples using tetramers, followed by identification of GVL specific TCR in both bulk and single cell setting. We were able to identify T-cells that coevolved with specific tumorigenic lesions in a subset of CLL patients. Taken together, our results suggest that donor-derived antigen-specific T-cells mediate clonal selection of CLL with concurrent changes in allogeneic T-cells, and that these changes can be monitored in longitudinal patient samples. Citation Format: Celine Kerros, John P. Miller, Xizeng Mao, Haven R. Garber, Hannah C. Beird, Jianhua Zhang, Jason Roszik, Paul Leonard, Li Zhao, Sahil Seth, Pei Lin, Huandong Sun, William G. Wierda, Issa F. Khouri, Karen Clise-Dwyer, Andrew Futreal, Shoudan Liang, Koppikar Priya, Jeffrey Molldrem. Deep profiling of T-cell repertoire and tumor heterogeneity in chronic lymphocytic leukemia patients following allogeneic T-cell therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1516.
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- 2020
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9. The incidence and impact of brain metastasis in patients with hereditary BRCA1/2 mutated invasive breast cancer in a prospectively followed cohort
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Nuhad K. Ibrahim, Angelica M. Gutierrez-Barrera, Michael J. Lehner, Jennifer K. Litton, Akshara Singareeka Raghavendra, Haven R. Garber, Banu Arun, and Debu Tripathy
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Incidence (epidemiology) ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,030220 oncology & carcinogenesis ,Internal medicine ,Cohort ,Medicine ,In patient ,business ,030215 immunology ,Brain metastasis - Abstract
1096 Background: Previous reports suggest the incidence of brain metastasis is higher in patients with hereditary BRCA1 mutations compared to BRCA1 noncarriers among breast cancer patients who develop recurrent disease. PARP inhibitors are now standard therapies for metastatic breast cancer patients with germline BRCA1 or BRCA2 mutations ( gBRCA1/2) based on their efficacy in treating systemic disease. However, as management of systemic disease improves, a concern is that patients with hereditary BRCA mutations may experience higher rates of disease progression in the CNS. We aimed to estimate the incidence of brain metastasis in breast cancer patients with gBRCA1/2 using a prospectively maintained gBRCA database and to assess the impact of brain metastasis on survival. Methods: To determine incidence, we queried a prospectively maintained electronic database that included patients referred to the MDACC genetics department and who underwent gBRCA1/2 testing. We identified patients with stage I-III invasive breast cancer who were treated between 2000-2017 and assessed for disease recurrence and brain metastasis. To expand our cohort for descriptive characteristics (separate from the incidence analysis), we queried the Breast Medical Oncology database for patients with brain metastasis who had undergone BRCA1/2 testing outside the genetics department or at outside institutions. Results: Of 474 patients with Stage I-III breast cancer and gBRCA1, 77 (16.2%) developed distant metastasis (median f/u: 9.1 years). Of these patients, 34/77 (44.2%) developed brain metastasis. In comparison, 42 of 318 (13.2%) of gBRCA2 patients with Stage I-III breast cancer developed distant recurrence (median f/u: 8.4 years), and 7/42 (16.7%) experienced brain metastasis. In gBRCA1 patients with brain metastasis, 45/48 (83.8%) had triple negative disease, and the median time from diagnosis to brain metastasis was 2.45 years. The brain was among the initial sites of disease recurrence in 24/48 (50%) of gBRCA1 patients. For gBRCA1 patients with distantly recurrent disease, median OS from diagnosis was 3.19 years for patients with brain metastasis vs. 5.37 years for patients without brain mets (HR 0.54; 95% CI 0.34 to 0.85; P = 0.0082). Conclusions: Brain metastasis is frequent among breast cancer patients with recurrent disease and hereditary BRCA1 mutations. Development and testing of agents with intracranial activity is critical for improving long-term outcomes in gBRCA1 patients with metastatic breast cancer.
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- 2020
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10. Immune phenotype and response to neoadjuvant systemic therapy (NAST) in triple negative breast cancer (TNBC)
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Gaiane M. Rauch, Haven R. Garber, Edwin Roger Parra Cuentas, Er-Yen Yen, Gheath Alatrash, Clinton Yam, Anne V. Philips, Sahil Seth, Gabriel N. Hortobagyi, Xiangjie Sun, Roland L. Bassett, Fei Yang, Senthil Damodaran, Jason B White, Jennifer A. Wargo, Lei Huo, Elizabeth A. Mittendorf, Stacy L. Moulder, Jennifer K. Litton, and William Fraser Symmans
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Cancer Research ,business.industry ,Tumor-infiltrating lymphocytes ,chemical and pharmacologic phenomena ,Systemic therapy ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Medicine ,business ,Complete response ,Triple-negative breast cancer ,030215 immunology ,Immune phenotype - Abstract
509 Background: In TNBC patients (pts) receiving NAST, increasing tumor infiltrating lymphocytes (TILs) is associated with higher pathologic complete response (pCR) rates. However, since the presence of TIL do not consistently predict pCR, the current study was undertaken to more fully characterize the immune cell response and its association with pCR. Methods: T cell receptor (TCR) sequencing, PD-L1 immunohistochemistry and multiplex immunofluorescence were performed on prospectively collected pre-NAST tumor samples from 98 pts with stage I-III TNBC enrolled in ARTEMIS (NCT: 02276443). TCR clonality was calculated using Shannon’s entropy. PD-L1+ was defined as ≥1% immune cell staining. Response to NAST was defined using the residual cancer burden (RCB) index. Associations between TCR clonality, immune phenotype, and response were examined with the Wilcoxon rank sum test, Spearman’s rank correlation and multivariable logistic regression using stepwise elimination (threshold p > 0.2), as appropriate. Results: The pCR rate was 39% (38/98). pCR was associated with higher TCR clonality (median = 0.2 [in pts with pCR] vs 0.1 [in pts with residual disease], p = 0.05). Notably, the association between pCR and higher TCR clonality was observed in pts with ≥5% TIL (n = 61; p = 0.05) but not in pts with < 5% TIL (n = 37; p = 0.87). Among pts with ≥5% TIL, TCR clonality emerged as the only independent predictor of response in a multivariable model of tumor immune characteristics (odds ratio/0.1 increase in TCR clonality: 3.0, p = 0.021). PD-L1+ status was associated with higher TCR clonality (median = 0.2 [in PD-L1+] vs 0.1 [in PD-L1-], p = 0.004). Higher TCR clonality was associated with higher CD3+ (rho = 0.32, p = 0.0018) and CD3+CD8+ (rho = 0.33, p = 0.0013) infiltration but lower expression of PD-1 on CD3+ (rho = -0.24, p = 0.021) and CD3+CD8+ cells (rho = -0.21, p = 0.037). Conclusions: In TNBC, a more clonal T cell population is associated with an immunologically active microenvironment (higher CD3+ and CD3/8+ T cell; lower PD-1+CD3+ and PD-1+CD3/8+ T cell; PD-L1+) and favorable response to NAST, especially in pts with ≥5% TIL, suggesting a role for deep immune phenotyping in further refining the predictive value of TILs.
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- 2020
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11. Abstract B59: Co-evolution between tumor cells and immune system in the setting of T-cell immunotherapy
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Herbert Levine, Haven R. Garber, Jeffrey J. Molldrem, and Jason T. George
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Cancer Research ,Immune system ,business.industry ,Immunology ,Cancer research ,Medicine ,Tumor cells ,business ,T cell immunotherapy - Abstract
It is now well established that the host’s adaptive immune system plays an important role in identifying and eliminating cancer cells in much the same way that intracellular pathogens are cleared during an adaptive immune response to infection. From a therapeutic standpoint, the adaptive immune system is unique in that it can co-evolve alongside a developing tumor. However, tumor acquisition of immune evasive phenotypes, such as class-I MHC downregulation, remains a major limitation of successful T-cell immunotherapy. We propose a stochastic model that couples tumor and CD8+ T-cell adaptive immune compartments. This framework accurately models relevant empirical findings, including the growth-threshold conjecture of immune activation, and predicts experimental observations including “sneak-through,” wherein intermediate-growth threats are penalized relative to their slower- and faster-growing counterparts. We demonstrate that predicted optimal growth strategies depend on whether or not the threat may acquire an immune-evasive phenotype as well as the mode of immune detection. The model is able to accurately characterize age-dependent cancer incidence data as a function of decreasing T-cell turnover and repertoire diversity. Lastly, we quantify therapeutic efficacy of immunotherapy in the setting of an immune-evasive threat. Our model serves as a first attempt at modeling stochastic cancer evolution sculpted by an adaptive immune compartment. Citation Format: Jason T. George, Haven R. Garber, Jeffrey J. Molldrem, Herbert Levine. Co-evolution between tumor cells and immune system in the setting of T-cell immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B59.
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- 2020
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12. Fucosylation Enhances the Efficacy of Adoptively Transferred Antigen-Specific Cytotoxic T Lymphocytes
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Pariya Sukhumalchandra, Na Qiao, Alexander A. Perakis, Lisa S. St. John, Jeffrey J. Molldrem, Celine Kerros, Gheath Alatrash, Hiep Khong, Anne V. Philips, Leonard P. Miller, Karen Clise-Dwyer, Madhushree Zope, Elizabeth J. Shpall, Maria Khouri, Qing Ma, Stephen D Wolpe, Haven R. Garber, Willem W. Overwijk, Mao Zhang, and Elizabeth A. Mittendorf
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0301 basic medicine ,Cytotoxicity, Immunologic ,Cancer Research ,Glycosylation ,medicine.medical_treatment ,Epitopes, T-Lymphocyte ,Biology ,Lymphocyte Activation ,Immunotherapy, Adoptive ,Article ,Immunophenotyping ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Antigen ,Cell Line, Tumor ,medicine ,Cytotoxic T cell ,Animals ,Humans ,Fucosylation ,Transendothelial and Transepithelial Migration ,Immunotherapy ,CTL ,Chemotaxis, Leukocyte ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,Cancer research ,Bone marrow ,Peptides ,Ex vivo ,Biomarkers ,Homing (hematopoietic) ,T-Lymphocytes, Cytotoxic - Abstract
Purpose: Inefficient homing of adoptively transferred cytotoxic T lymphocytes (CTLs) to tumors is a major limitation to the efficacy of adoptive cellular therapy (ACT) for cancer. However, through fucosylation, a process whereby fucosyltransferases (FT) add fucose groups to cell surface glycoproteins, this challenge may be overcome. Endogenously fucosylated CTLs and ex vivo fucosylated cord blood stem cells and regulatory T cells were shown to preferentially home to inflamed tissues and marrow. Here, we show a novel approach to enhance CTL homing to leukemic marrow and tumor tissue. Experimental Design: Using the enzyme FT-VII, we fucosylated CTLs that target the HLA-A2–restricted leukemia antigens CG1 and PR1, the HER2-derived breast cancer antigen E75, and the melanoma antigen gp-100. We performed in vitro homing assays to study the effects of fucosylation on CTL homing and target killing. We used in vivo mouse models to demonstrate the effects of ex vivo fucosylation on CTL antitumor activities against leukemia, breast cancer, and melanoma. Results: Our data show that fucosylation increases in vitro homing and cytotoxicity of antigen-specific CTLs. Furthermore, fucosylation enhances in vivo CTL homing to leukemic bone marrow, breast cancer, and melanoma tissue in NOD/SCID gamma (NSG) and immunocompetent mice, ultimately boosting the antitumor activity of the antigen-specific CTLs. Importantly, our work demonstrates that fucosylation does not interfere with CTL specificity. Conclusions: Together, our data establish ex vivo CTL fucosylation as a novel approach to improving the efficacy of ACT, which may be of great value for the future of ACT for cancer.
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- 2018
13. Membrane-Associated Proteinase 3 on Granulocytes and Acute Myeloid Leukemia Inhibits T Cell Proliferation
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Celine Kerros, Jeffrey J. Molldrem, Karen Clise-Dwyer, Tian Hui Yang, Qing Ma, Gheath Alatrash, Haven R. Garber, Lisa S. St. John, and Kathryn Ruisaard
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0301 basic medicine ,Adult ,CD4-Positive T-Lymphocytes ,Male ,Myeloid ,Neutrophils ,medicine.medical_treatment ,T cell ,Myeloblastin ,Immunology ,CD8-Positive T-Lymphocytes ,Immune Regulation ,03 medical and health sciences ,0302 clinical medicine ,Proteinase 3 ,hemic and lymphatic diseases ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Humans ,Cell Proliferation ,Cell growth ,Chemistry ,Myeloid leukemia ,medicine.disease ,Neoplasm Proteins ,Leukemia ,Leukemia, Myeloid, Acute ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,Cancer research ,Female ,030215 immunology - Abstract
Proteinase 3 (P3), a serine protease expressed by myeloid cells, localized within azurophil granules, and also expressed on the cellular membrane of polymorphonuclear neutrophils (PMN), is the target of autoimmunity in granulomatosis with polyangiitis. PR1, an HLA-A2 restricted nonameric peptide derived from P3, has been targeted effectively in myeloid leukemia. We previously showed (Molldrem et al. 2003. J. Clin. Invest. 111: 639–647) that overexpression of P3 in chronic myeloid leukemia induces apoptosis of high-affinity PR1-specific T cells, leading to deletional tolerance and leukemia outgrowth. In this study, we investigated the effect of membrane P3 (mP3)–expressing PMN and acute myeloid leukemia (AML) blasts on the proliferation of CD4 and CD8 T cells in vitro. We demonstrate that mP3-expressing PMN significantly inhibits autologous healthy donor T cell proliferation but does not affect cytokine production in activated T cells and that this effect requires cell proximity and was abrogated by P3 blockade. This inhibition required P3 enzyme activity. However, suppression was not reversed by either the addition of catalase or the inhibition of arginase I. In addition to P3 blockade, anti–low density lipoprotein receptor-related protein 1 (LRP1) Ab also restored T cells’ capacity to proliferate. Last, we show dose-dependent inhibition of T cell proliferation by mP3-expressing AML blasts. Together, our findings demonstrate a novel mechanism whereby PMN- and AML-associated mP3 inhibits T cell proliferation via direct LRP1 and mP3 interaction, and we identify P3 as a novel target to modulate immunity in myeloid leukemia and autoimmune disease.
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- 2018
14. Targeting the Leukemia Antigen PR1 with Immunotherapy for the Treatment of Multiple Myeloma
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Na Qiao, Alexander A. Perakis, Jinsheng Weng, Madhushree Zope, Haroon Jakher, Haven R. Garber, Gheath Alatrash, Anne V. Philips, Amanda M. Cernosek, Lisa S. St. John, Mao Zhang, Pariya Sukhumalchandra, Sijie Lu, Anna Sergeeva, Rebecca Patenia, Shuhua Yi, Jeffrey J. Molldrem, Haley L. Peters, Qing Ma, Elizabeth A. Mittendorf, Celine Kerros, Ken H. Young, and Karen Clise-Dwyer
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0301 basic medicine ,Cytotoxicity, Immunologic ,Cancer Research ,Proteasome Endopeptidase Complex ,medicine.medical_treatment ,Antigen-Presenting Cells ,Human leukocyte antigen ,Immunomodulation ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Cross-Priming ,Antigen ,hemic and lymphatic diseases ,Cell Line, Tumor ,HLA-A2 Antigen ,medicine ,Animals ,Humans ,Immunologic Factors ,Complement Activation ,Multiple myeloma ,Antigen Presentation ,biology ,Antigen processing ,business.industry ,Cancer ,Biological Transport ,Immunotherapy ,medicine.disease ,Xenograft Model Antitumor Assays ,Peptide Fragments ,Leukemia ,Disease Models, Animal ,030104 developmental biology ,Oncology ,Cancer research ,biology.protein ,Antibody ,business ,Multiple Myeloma ,030215 immunology ,T-Lymphocytes, Cytotoxic - Abstract
Purpose: PR1 is a human leukocyte antigen (HLA)-A2 nonameric peptide derived from neutrophil elastase (NE) and proteinase 3 (P3). We have previously shown that PR1 is cross-presented by solid tumors, leukemia, and antigen-presenting cells, including B cells. We have also shown that cross-presentation of PR1 by solid tumors renders them susceptible to killing by PR1-targeting immunotherapies. As multiple myeloma is derived from B cells, we investigated whether multiple myeloma is also capable of PR1 cross-presentation and subsequently capable of being targeted by using PR1 immunotherapies. Experimental Design: We tested whether multiple myeloma is capable of cross-presenting PR1 and subsequently becomes susceptible to PR1-targeting immunotherapies, using multiple myeloma cell lines, a xenograft mouse model, and primary multiple myeloma patient samples. Results: Here we show that multiple myeloma cells lack endogenous NE and P3, are able to take up exogenous NE and P3, and cross-present PR1 on HLA-A2. Cross-presentation by multiple myeloma utilizes the conventional antigen processing machinery, including the proteasome and Golgi, and is not affected by immunomodulating drugs (IMiD). Following PR1 cross-presentation, we are able to target multiple myeloma with PR1-CTL and anti-PR1/HLA-A2 antibody both in vitro and in vivo. Conclusions: Collectively, our data demonstrate that PR1 is a novel tumor-associated antigen target in multiple myeloma and that multiple myeloma is susceptible to immunotherapies that target cross-presented antigens. Clin Cancer Res; 24(14); 3386–96. ©2018 AACR.
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- 2017
15. Stochastic cancer-immune coevolution: Implications for cancer incidence and immunotherapeutic efficacy
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Jason T. George, Herbert Levine, Haven R. Garber, and Jeffrey J. Molldrem
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Cancer ,Disease ,medicine.disease ,Immune system ,Cancer incidence ,Internal medicine ,medicine ,Treatment strategy ,business ,Coevolution - Abstract
e14023 Background: Despite recent progress, robust treatment strategies that lead to durable remission are still lacking for many cancer types. This disease is difficult to treat owing in part to the complexity introduced by a heterogeneous population of cancer cells capable of evolving mechanisms of resistance to traditional therapy. Nonetheless, the discovery and continued optimization of T-cell immunotherapy has revolutionized the treatment of many cancers. This treatment strategy stands out from other approaches in its unique ability to co-evolve alongside an evading tumor. While promising, such therapies are also complex. For example, allogeneic stem cell transplantation leverages a donor-derived T-cell repertoire to treat patients with refractory hematologic malignancies and relies upon a delicate balance between desirable anti-tumor effects and potentially life-threatening graft-versus-host-disease. Currently, the decision to utilize this therapy and others like it is largely influenced by prior empirical evidence. Thus, there is great need for quantitative models of the cancer-immune interaction to generate testable predictions of treatment outcome, which could then be validated prior to T-cell immunotherapy administration. Methods: We develop a foundational mathematical model to investigate the properties of stochastic tumor-immune co-evolution using applied stochastic process theory and probabilistic analysis. We use this model to predict the effects of reduced immunity, T-cell diversity, and thymic turnover rates on cancer incidence, and compare model simulations to cancer evolutionary data. Results: We predict that changes in T-cell diversity, and to a lesser degree thymic turnover, increase the chance of tumor progression. When applied to experimental data, we demonstrate that the observations are consistent with co-evolution between an indolent cancer population and the adaptive immune system prior to clinical disease. Conclusions: Our results provide a fundamental framework for analyzing the interaction dynamics of an evolving threat like cancer and the adaptive immune system in order to better understand and predict immunotherapeutic efficacy.
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- 2019
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16. Tumor immune microenvironment (TiME) changes by multiplex IF staining in a pilot study of neoadjuvant talazoparib for early-stage breast cancer patients with a BRCA mutation
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Jennifer K. Litton, Haven R. Garber, Alejandro Contreras, Evthokia A. Hobbs, Banu Arun, Elizabeth A. Mittendorf, Marion E. Scoggins, Tapsi Kumar, Gary J. Whitman, Beatriz E. Adrada, Fei Yang, and Edwin Roger Parra Cuentas
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Immune microenvironment ,BRCA mutation ,medicine.disease ,Staining ,Time changes ,chemistry.chemical_compound ,Breast cancer ,chemistry ,Internal medicine ,Medicine ,Talazoparib ,Multiplex ,Stage (cooking) ,business - Abstract
585 Background: We previously reported a median tumor volume loss of 88% (range 30-98%) in 13 patients with early stage BRCA1/2 mutant breast cancer treated on a neoadjuvant trial of the PARP inhibitor talazoparib. The effects of PARP inhibition on immune aspects of the TiME in early-stage breast cancer has not been well described. The goal of this study was to evaluate the TiME in pre and post-treatment core biopsies from enrolled patients. Methods: Eleven paired core biopsies were available for examination. Tumor infiltrating lymphocytes (TILs) were quantified by H&E stained slides by a central pathologist. Specimens were assessed by multiplex immunofluorescence (mIF) using a panel of 6 biomarkers (PD-1, PD-L1, CD3, CD8, CD68 and CK) with the Opal 7-color Kit in LEICA BOND auto stainer, Vectra automated quantitative pathology imaging system and inForm software (PerkinElmer). Results: In the analyzed core biopsies, there was an increase in TILs evaluated by H&E in post-treatment compared to baseline (mean 36 vs 11%). By mIF there was an increase in CD3+ T cell and CD3+CD8+ cytotoxic T cell density in post-treatment samples compared to baseline, summarized in table. PD-L1 expression in tumor cells was rare in the cohort. There was no difference in CD3+PD-1+ or CD3+CD8+ PD-1+ lymphocytes in pre and post-treatment specimens. There was also no differences in macrophages (CD68+). Evaluation of immune phenotype and imaging response will be presented in the final analysis. Conclusions: This is the first study phenotyping the immune response to neoadjuvant talazoparib in BRCA-mutant breast cancer patients. In this small cohort, intratumoral and stromal CD3+ T cells and CD3+CD8+ cytotoxic T cells increased after two months of talazoparib. Clinical trial information: NCT02282345. [Table: see text]
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- 2019
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17. A novel TCR-like CAR with specificity for PR1/HLA-A2 effectively targets myeloid leukemia in vitro when expressed in human adult peripheral blood and cord blood T cells
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Xiaoling Ding, Gianpietro Dotti, Michael Scott Wood, Jeffrey J. Molldrem, Sijie Lu, Anna Sergeeva, Haven R. Garber, Eran Tallis, Gheath Alatrash, Katayoun Rezvani, Kathryn Ruisaard, Barbara Salvado, Elizabeth J. Shpall, Lisa S. St. John, Karen Clise-Dwyer, Hong He, and Qing Ma
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0301 basic medicine ,Adult ,Cancer Research ,CD3 ,Myeloblastin ,Recombinant Fusion Proteins ,T-Lymphocytes ,Immunology ,Receptors, Antigen, T-Cell ,T-Cell Antigen Receptor Specificity ,Immunotherapy, Adoptive ,Epitope ,Article ,Cell Line ,03 medical and health sciences ,Epitopes ,0302 clinical medicine ,Antigen ,HLA-A2 Antigen ,medicine ,Immunology and Allergy ,Humans ,Genetics (clinical) ,Transplantation ,biology ,Myeloid leukemia ,CD28 ,Antibodies, Monoclonal ,Cell Biology ,Genetic Therapy ,medicine.disease ,Fetal Blood ,Virology ,Chimeric antigen receptor ,Peptide Fragments ,Immunoglobulin Fc Fragments ,Leukemia ,Leukemia, Myeloid, Acute ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Leukocytes, Mononuclear ,Stem cell - Abstract
Background aims The PR1 peptide, derived from the leukemia-associated antigens proteinase 3 and neutrophil elastase, is overexpressed on HLA-A2 in acute myeloid leukemia (AML). We developed a T-cell receptor (TCR)-like monoclonal antibody (8F4) that binds the PR1/HLA-A2 complex on the surface of AML cells, efficiently killing them in vitro and eliminating them in preclinical models. Humanized 8F4 (h8F4) with high affinity for the PR1/HLA-A2 epitope was used to construct an h8F4- chimeric antigen receptor (CAR) that was transduced into T cells to mediate anti-leukemia activity. Methods Human T cells were transduced to express the PR1/HLA-A2-specific CAR (h8F4-CAR-T cells) containing the scFv of h8F4 fused to the intracellular signaling endo-domain of CD3 zeta chain through the transmembrane and intracellular costimulatory domain of CD28. Results Adult human normal peripheral blood (PB) T cells were efficiently transduced with the h8F4-CAR construct and predominantly displayed an effector memory phenotype with a minor population (12%) of central memory cells in vitro . Umbilical cord blood (UCB) T cells could also be efficiently transduced with the h8F4-CAR. The PB and UCB-derived h8F4-CAR-T cells specifically recognized the PR1/HLA-A2 complex and were capable of killing leukemia cell lines and primary AML blasts in an HLA-A2-dependent manner. Conclusions Human adult PB and UCB-derived T cells expressing a CAR derived from the TCR-like 8F4 antibody rapidly and efficiently kill AML in vitro . Our data could lead to a new treatment paradigm for AML in which targeting leukemia stem cells could transfer long-term immunity to protect against relapse.
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- 2016
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18. Abstract 2392: Genomic and immune heterogeneity in synchronous melanoma metastases is associated with differential tumor growth and response to therapy
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Courtney W. Hudgens, Alexander J. Lazar, Padmanee Sharma, Mariana Petaccia de Macedo, Pei-Ling Chen, Rodabe N. Amaria, Michael A. Davies, Ignacio I. Wistuba, Lynda Chin, Vancheswaran Gopalakrishnan, Andrew Futreal, Wei-Shen Chen, Haven R. Garber, Patrick Hwu, Hannah Cheung, Karen C. Dwyer, Michael T. Tetzlaff, James P. Allison, Alexandre Reuben, Cara Haymaker, Hong Jiang, John P. Miller, Sapna Pradyuman Patel, Scott E. Woodman, Zachary A. Cooper, Christine N. Spencer, Jennifer A. Wargo, Jianhua Zhang, Jason Roszik, Peter A. Prieto, Jacob Austin-Breneman, and Xizeng Mao
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Oncology ,Cancer Research ,medicine.medical_specialty ,Response to therapy ,business.industry ,Melanoma ,medicine.disease ,Immune system ,Internal medicine ,medicine ,Tumor growth ,business ,Differential (mathematics) - Abstract
There have been significant advances in the treatment of metastatic melanoma through targeted and immunotherapy, however a significant proportion of patients still progress on these regimens with many experiencing mixed responses. Intense research efforts to better understand resistance are underway, and multiple molecular resistance mechanisms to targeted therapy have been identified. The appreciation of genetic heterogeneity as a contributor to resistance to therapy has grown, though immune heterogeneity has been poorly characterized. The goal of the present study is to better understand the molecular and immune heterogeneity in synchronous melanoma metastases at the time of disease progression. In this study, we prospectively evaluated 32 tumors from 15 patients who were treatment-naïve (n = 4), or had received prior targeted (n = 4) or immunotherapy (n = 7). Whole exome sequencing demonstrated between 4-41% of non-synonymous exonic mutations (NSEM) were restricted to individual tumors within a patient. Deep profiling of infiltrating immune cell subsets by flow cytometry and immunohistochemistry analyses confirmed the immune infiltrate between synchronous metastases to be highly heterogeneous, specifically in regards to CD4 and CD8 T lymphocytes. In aggregate, 92% of these T cell clones were unique to distinct tumors within the same patient, with limited overlap with clones detected in the blood. NetMHC3.4 neoantigen prediction demonstrated a large fraction of predicted neoantigens were restricted to individual tumors, with over 10% of these presenting extremely high predicted affinity. Importantly, analysis of RECIST measurements of individual lesions within the same patient suggested this molecular and immune heterogeneity could contribute to differential tumor growth and response to therapy within the same patient. This has important clinical implications, and suggests a single tumor biopsy may not be sufficiently representative of the molecular and immune landscape of multiple tumors within the same individual. Citation Format: Alexandre Reuben, Christine N. Spencer, Peter A. Prieto, John P. Miller, Xizeng Mao, Wei-Shen Chen, Hannah Cheung, Hong Jiang, Cara Haymaker, Mariana Petaccia De Macedo, Haven R. Garber, Pei-Ling Chen, Vancheswaran Gopalakrishnan, Jacob Austin-Breneman, Courtney W. Hudgens, Jason Roszik, Patrick Hwu, Scott E. Woodman, Lynda Chin, Michael A. Davies, Rodabe N. Amaria, Sapna P. Patel, Alexander J. Lazar, Michael T. Tetzlaff, Karen C. Dwyer, Ignacio I. Wistuba, Padmanee Sharma, James P. Allison, Jianhua Zhang, Andrew Futreal, Zachary A. Cooper, Jennifer A. Wargo. Genomic and immune heterogeneity in synchronous melanoma metastases is associated with differential tumor growth and response to therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2392.
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- 2016
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19. Abstract LB-222: Long-term subclonal evolution of CLL from immune selective pressure after allogeneic stem cell transplant and donor lymphocyte infusion
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Xingzhi Song, Jeffrey J. Molldrem, P. Andrew Futreal, Pei Lin, Sahil Seth, Huandong Sun, Karen Clise-Dwyer, Jianhua Zhang, Lisa S. St. John, Gheath Alatrash, Hannah C. Beird, Xizeng Mao, Haven R. Garber, Yu Cao, and Rachel L. Sargent
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Cancer Research ,Mutation ,Genetic heterogeneity ,medicine.medical_treatment ,Cancer ,Immunotherapy ,Biology ,medicine.disease_cause ,medicine.disease ,Donor lymphocyte infusion ,Leukemia ,Oncology ,Immunology ,medicine ,Cancer research ,CHEK2 ,Exome sequencing - Abstract
Next-generation sequencing (NGS) has revealed that the malignant subclones comprising a patient's cancer can possess tremendous genetic heterogeneity at different sites of disease and over time. In leukemia, chemotherapy can hasten subclonal evolution allowing for rare leukemic subclones with aggressive driver mutations to gain a competitive advantage and to predominate at relapse, often portending an inferior treatment response. The impact of immunotherapy on subclonal evolution is less well studied. To determine the effects of allogeneic stem cell transplant (alloSCT) and donor lymphocyte infusion (DLI) on subclonal evolution, we performed whole exome sequencing (WES) on longitudinal peripheral blood and bone marrow from 4 patients with CLL. Specifically, timepoints analyzed included pre-transplant, post-transplant relapse, and post-DLI relapse over a period of up to 8.5 years. B-CLL cells (CD19+CD5+) and normal T cells (CD3+) were sort-purified by fluorescence-activated cell sorting prior to genomic DNA extraction. Libraries for WES were constructed and sequenced to an average depth of 300x on an Illumina HiSeq 2000 using 76 bp paired-end reads. Somatic single nucleotide variants (sSNVs) and indels were called using MuTect and Pindel, respectively, and copy number changes were assessed using an in-house algorithm. In general, these patients had more nonsynonymous mutations per pre-alloSCT sample than reported in other CLL NGS studies (average 30.3; range 8-45), likely related to the significant amount of pre-transplant therapies. Heterogeneous patterns of linear and branched subclonal evolution were seen after alloSCT and DLI in both responders and non-responders. Mutations in several candidate CLL driver genes were seen in this cohort, including SF3B1, SAMHD1, BCOR, EGR2, TP53, and DDX3X. Interestingly, sSNVs in multiple recurrently mutated CLL or cancer census genes (e.g. MAP2K1) rose to levels of detection only after alloSCT or DLI, suggesting they may play a role in immune evasion. In addition, several subclonal genetic variants, including missense mutations in FAM126B and LTBP3, were no longer detected after alloSCT or DLI and may thus represent potential neoantigens. In one treatment-refractory patient, a somatic nonsynonymous clonal CHEK2 mutation was found in 8 longitudinal samples and may represent a novel unique driver mutation. Finally, in one patient who experienced a durable complete remission after DLI, concurrent CLL WES and T-cell receptor beta chain CDR3 NGS was performed, which demonstrated a rapidly evolving T-cell repertoire at the time of complete remission after DLI. For CLL, alloSCT and DLI offer a potentially curative treatment strategy and a better understanding of the genes that confer susceptibility or resistance to these immunotherapies may help unlock the mechanisms that underlie these durable responses. Citation Format: Haven R. Garber, Hannah Beird, Yu Cao, Jianhua Zhang, Rachel Sargent, Pei Lin, Sahil Seth, Xingzhi Song, Huandong Sun, Xizeng Mao, Lisa St John, Karen Clise-Dwyer, Gheath Alatrash, P. Andrew Futreal, Jeffrey J. Molldrem. Long-term subclonal evolution of CLL from immune selective pressure after allogeneic stem cell transplant and donor lymphocyte infusion. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-222. doi:10.1158/1538-7445.AM2015-LB-222
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- 2015
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20. Abstract 958: Treatment with a selective inhibitor of BRAFV600E increases melanocyte antigen expression and CD8 T cell infiltrate in tumors of patients with metastatic melanoma
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Alex Cogdill, Ridhi Gupta, Haven R. Garber, Andrea Boni, Adriano Piris, David E. Fisher, Ping Dang, Keith T. Flaherty, Lindsay P. Newton, Hensin Tsao, Jennifer A. Wargo, Harald C. Ott, and Donald P. Lawrence
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Cancer Research ,business.industry ,medicine.medical_treatment ,Melanoma ,T cell ,Cancer ,Immunotherapy ,medicine.disease ,Targeted therapy ,medicine.anatomical_structure ,Oncology ,Melanocyte differentiation ,Antigen ,Immunology ,medicine ,Cancer research ,Cytotoxic T cell ,business - Abstract
Targeted therapy against oncogenic BRAF (BRAFV600E) is a promising new therapeutic approach for the treatment of melanoma with up to 80% of patients with stage IV melanoma responding to treatment. Despite these results, the median duration of response is only 8.5 months. Investigators propose combining this therapy with other targeted agents to address redundancy and signaling through different oncogenic pathways in hopes to improve the durability of response. An alternate approach is to combine BRAF-targeted agents with immunotherapy based on evidence that oncogenic BRAF contributes to immune escape. We recently reported data supporting this hypothesis, showing that treatment of melanoma cell lines with MEK or selective BRAFV600E inhibition results in increased expression of melanocyte differentiation antigens (MDAs) which is associated with enhanced recognition by antigen-specific T cells. The purpose of these studies was to validate these findings by assaying expression of MDAs in patients with metastatic melanoma treated with BRAFV600E inhibition. We also sought to test immune cell infiltrate in tumors to analyze host immune response. Patients with metastatic melanoma undergoing treatment with a selective BRAFV600E inhibitor were consented on a tissue procurement protocol approved through the IRB at the Massachusetts General Hospital. Patients underwent treatment with the BRAFV600E inhibitor (PLX4032) per protocol (960 mg given twice daily). Tumor biopsies and blood draws were performed pre-treatment and 10-14 days after initiation of treatment. RNA was harvested and expression of MDAs was assayed by quantitative RT-PCR. The level of MITF, the master transcriptional regulator of melanocyte which controls MDA expression, was also assayed. Immunohistochemistry was performed on formalin-fixed, paraffin embedded tissue for MDAs, as well as CD4 and CD8. The effect of BRAFV600E inhibition on T lymphocyte function was analyzed by assaying fold-expansion and viability in blood samples collected before and during treatment. Treatment with a selective inhibitor of BRAFV600E resulted in significantly increased levels of MDAs (up to 95-fold) which was associated with higher levels of MITF. In addition, CD8 T cell infiltrate also increased after treatment. Of note, T cell function was preserved after treatment with a specific inhibitor of BRAFV600E. These data provide in vivo correlates to our in vitro findings that selective BRAFV600E inhibition enhances MDA expression in melanoma and suggest a possible improved host immune response. The studies provide further support for potential synergy between BRAF-targeted therapy and immunotherapy in the treatment of melanoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 958. doi:10.1158/1538-7445.AM2011-958
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- 2011
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21. Molecular and immune heterogeneity in synchronous melanoma metastases
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Marie-Andree Forget, Alexandre Reuben, Christine N. Spencer, Michael Davies, Parra Cuentas, Rodabe N. Amaria, Whijae Roh, Scott E. Woodman, Edwin Roger, Vancheswaran Gopalakrishnan, Yu Cao, Lawrence N. Kwong, Karen C. Dwyer, Lynda Chin, Pei-Ling Chen, John P. Miller, Chantale Bernatchez, Jennifer A. Wargo, Latasha Little, Jaime Rodriguez, Andrew Futreal, Hong Jiang, Haven R. Garber, Jason Roszik, Cara Haymaker, Jacob Austin-Breneman, Zachary A. Cooper, James P. Allison, Padmanee Sharma, and Michael T. Tetzlaff
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Pharmacology ,Oncology ,Cancer Research ,medicine.medical_specialty ,Metastatic melanoma ,business.industry ,Melanoma ,medicine.medical_treatment ,Immunology ,Immunotherapy ,Bioinformatics ,medicine.disease ,Immune system ,Internal medicine ,Poster Presentation ,medicine ,Molecular Medicine ,Immunology and Allergy ,business - Abstract
Meeting abstracts Despite recent advances in the treatment of metastatic melanoma through targeted and immunotherapy, the majority of patients do not achieve a durable response. Research efforts to better understand responses are underway, and numerous molecular mechanisms of resistance to targeted
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