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1. Modulation of the gut microbiota engages antigen cross-presentation to enhance antitumor effects of CAR T cell immunotherapy

Author

Mireia Uribe-Herranz, Silvia Beghi, Marco Ruella, Kalpana Parvathaneni, Silvano Salaris, Nektarios Kostopoulos, Subin S. George, Stefano Pierini, Elisavet Krimitza, Francesca Costabile, Guido Ghilardi, Kimberly V. Amelsberg, Yong Gu Lee, Raymone Pajarillo, Caroline Markmann, Bevin McGettigan-Croce, Divyansh Agarwal, Noelle Frey, Simon F. Lacey, John Scholler, Khatuna Gabunia, Gary Wu, Elise Chong, David L. Porter, Carl H. June, Stephen J. Schuster, Vijay Bhoj, and Andrea Facciabene

Subjects
Pharmacology, Drug Discovery, Genetics, Molecular Medicine, Molecular Biology
Published
2023
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2. Moderate Colitis Not Requiring Intravenous Steroids Is Associated with Improved Survival in Stage IV Melanoma after Anti-CTLA4 Monotherapy, But Not Combination Therapy

Author

Emily J Anstadt, Brian Chu, Nikhil Yegya-Raman, Xiaoyan Han, Abigail Doucette, Kendra Poirier, Jahan J Mohiuddin, Amit Maity, Andrea Facciabene, Ravi K Amaravadi, Giorgos C Karakousis, Justine V Cohen, Tara C Mitchell, Lynn M Schuchter, and John N Lukens

Subjects
Cancer Research, Oncology, Humans, Steroids, Colitis, Ipilimumab, Melanoma, Retrospective Studies
Abstract

Background For patients with melanoma, gastrointestinal immune-related adverse events are common after receipt of anti-CTLA4 therapy. These present difficult decision points regarding whether to discontinue therapy. Detailing the situations in which colitis might predict for improved survival and how this is affected by discontinuation or resumption of therapy can help guide clinical decision-making. Materials and Methods Patients with stage IV melanoma receiving anti-CTLA4 therapy from 2008 to 2019 were analyzed. Immune-related colitis treated with ≥50 mg prednisone or equivalent daily or secondary immunosuppression was included. Moderate colitis was defined as receipt of oral glucocorticoids only; severe colitis was defined as requiring intravenous glucocorticoids or secondary immunosuppression. The primary outcome was overall survival (OS). Results In total, 171 patients received monotherapy, and 91 received dual checkpoint therapy. In the monotherapy group, 25 patients developed colitis and a nonsignificant trend toward improved OS was observed in this group. Notably, when colitis was categorized as none, moderate or severe, OS was significantly improved for moderate colitis only. This survival difference was not present after dual checkpoint therapy. There were no differences in known prognostic variables between groups, and on multivariable analysis neither completion of all ipilimumab cycles nor resumption of immunotherapy correlated with OS, while the development of moderate colitis did significantly affect OS. Conclusion This single-institution retrospective series suggests moderate colitis correlates with improved OS for patients with stage IV melanoma treated with single-agent anti-CTLA4, but not dual agent, and that this is true regardless of whether the immune-checkpoint blockade is permanently discontinued.

Published
2022
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4. Supplemental Figures from Integrative Development of a TLR8 Agonist for Ovarian Cancer Chemoimmunotherapy

Author

George Coukos, Robert M. Hershberg, Alexander Malykhin, Carolyn K. McCourt, Katherine M. Bell-McGuinn, Gwenn-äel H. Danet-Desnoyers, Kristi L. Manjarrez, Heather A. Lankes, Joan L. Walker, Paula M. Fracasso, Carol A. Aghajanian, William E. Brady, Andrea Facciabene, and Bradley J. Monk

Abstract

Supplemental Figure 1 Species-specific activation of TLR8 by motolimod. Supplemental Figure 2 Full human immune cell reconstitution in NSG-HIS mice. Supplemental Figure 3 Response to PLD + motolimod is not schedule-sensitive in the NSG-HIS mouse. Supplemental Figure 4 Assessment of macrophage-induced apoptosis using motolimod in combination with PLD. Supplemental Figure 5 Isolation of tumor-infiltrating T cells with specific tumor recognition and lysis ex vivo. Supplemental Figure 6 Pharmacokinetic (PK) evaluations. Supplemental Figure 7 Biological efficacy of motolimod in combination with paclitaxel.

Published
2023
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5. Supplemental Tables from Integrative Development of a TLR8 Agonist for Ovarian Cancer Chemoimmunotherapy

Author

George Coukos, Robert M. Hershberg, Alexander Malykhin, Carolyn K. McCourt, Katherine M. Bell-McGuinn, Gwenn-äel H. Danet-Desnoyers, Kristi L. Manjarrez, Heather A. Lankes, Joan L. Walker, Paula M. Fracasso, Carol A. Aghajanian, William E. Brady, Andrea Facciabene, and Bradley J. Monk

Abstract

Table S1. Subject demographics and baseline characteristics Table S2. Tumor response as assessed by RECIST 1.1 and biochemical response

Published
2023
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8. Author Correction: Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy

Author

Melody Smith, Anqi Dai, Guido Ghilardi, Kimberly V. Amelsberg, Sean M. Devlin, Raymone Pajarillo, John B. Slingerland, Silvia Beghi, Pamela S. Herrera, Paul Giardina, Annelie Clurman, Emmanuel Dwomoh, Gabriel Armijo, Antonio L. C. Gomes, Eric R. Littmann, Jonas Schluter, Emily Fontana, Ying Taur, Jae H. Park, Maria Lia Palomba, Elizabeth Halton, Josel Ruiz, Tania Jain, Martina Pennisi, Aishat Olaide Afuye, Miguel-Angel Perales, Craig W. Freyer, Alfred Garfall, Shannon Gier, Sunita Nasta, Daniel Landsburg, James Gerson, Jakub Svoboda, Justin Cross, Elise A. Chong, Sergio Giralt, Saar I. Gill, Isabelle Riviere, David L. Porter, Stephen J. Schuster, Michel Sadelain, Noelle Frey, Renier J. Brentjens, Carl H. June, Eric G. Pamer, Jonathan U. Peled, Andrea Facciabene, Marcel R. M. van den Brink, and Marco Ruella

Subjects
General Medicine, General Biochemistry, Genetics and Molecular Biology
Published
2022
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9. Association of Antibiotic Exposure With Survival and Toxicity in Patients With Melanoma Receiving Immunotherapy

Author

Jacob E. Shabason, Cathy Zheng, Alexander Lin, Jahan J. Mohiuddin, Andrea Facciabene, Amit Maity, Alexander C. Huang, Wei Xu, John N. Lukens, Emily J. Anstadt, Samuel Swisher-McClure, Tara C. Mitchell, Brian Chu, Abigail Doucette, Lynn M. Schuchter, Xingmei Wang, Kendra Poirier, Giorgos C. Karakousis, and Ravi K. Amaravadi

Subjects
Adult, Male, Cancer Research, medicine.medical_specialty, Adolescent, medicine.drug_class, Antibiotics, Disease-Free Survival, Young Adult, 03 medical and health sciences, Antineoplastic Agents, Immunological, 0302 clinical medicine, Internal medicine, Humans, Immunologic Factors, Medicine, Colitis, Immune Checkpoint Inhibitors, Melanoma, Aged, Neoplasm Staging, 030304 developmental biology, Aged, 80 and over, 0303 health sciences, Proportional hazards model, business.industry, Incidence (epidemiology), Hazard ratio, Genetic Variation, Cancer, Articles, Middle Aged, medicine.disease, Confidence interval, Anti-Bacterial Agents, Gastrointestinal Microbiome, Oncology, 030220 oncology & carcinogenesis, Toxicity, Female, Immunotherapy, business
Abstract

Background Gut microbial diversity is associated with improved response to immune checkpoint inhibitors (ICI). Based on the known detrimental impact that antibiotics have on microbiome diversity, we hypothesized that antibiotic receipt prior to ICI would be associated with decreased survival. Methods Patients with stage III and IV melanoma treated with ICI between 2008 and 2019 were selected from an institutional database. A window of antibiotic receipt within 3 months prior to the first infusion of ICI was prespecified. The primary outcome was overall survival (OS), and secondary outcomes were melanoma-specific mortality and immune-mediated colitis requiring intravenous steroids. All statistical tests were two-sided. Results There were 568 patients in our database of which 114 received antibiotics prior to ICI. Of the patients, 35.9% had stage III disease. On multivariable Cox proportional hazards analysis of patients with stage IV disease, the antibiotic-exposed group had statistically significantly worse OS (hazard ratio [HR] = 1.81, 95% confidence interval [CI] = 1.27 to 2.57; P Conclusion Patients with stage III and IV melanoma exposed to antibiotics prior to ICI had statistically significantly worse OS than unexposed patients. Antibiotic exposure was associated with greater incidence of moderate to severe immune-mediated colitis. Given the large number of antibiotics prescribed annually, physicians should be judicious with their use in cancer populations likely to receive ICI.

Published
2020
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11. Salvage radiotherapy for relapsed/refractory non‐Hodgkin lymphoma following CD19 chimeric antigen receptor T-cell (CART) therapy

Author

Nikhil Yegya-Raman, Christopher M. Wright, Michael J. LaRiviere, Jonathan A. Baron, Daniel Y. Lee, Daniel J. Landsburg, Jakub Svoboda, Sunita D. Nasta, James N. Gerson, Stefan K. Barta, Elise A. Chong, Stephen J. Schuster, Amit Maity, Andrea Facciabene, Ima Paydar, and John P. Plastaras

Subjects
Oncology, Radiology, Nuclear Medicine and imaging
Published
2023
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13. Mouse Bone Marrow-Derived Mesenchymal Stem Cells Alleviate Perinatal Brain Injury Via a CD8+ T Cell Mechanism in a Model of Intrauterine Inflammation

Author

Michael W. McLane, Jun Lei, Hongxi Zhao, Irina Burd, Mia C. Feller, Julia L. Clemens, Yan Zhu, Bei Jia, Li Xie, Maide Ozen, Andreas Facciabene, Hattan Arif, and Lu Zong

Subjects
0301 basic medicine, Fetus, 030219 obstetrics & reproductive medicine, Offspring, business.industry, T cell, Mesenchymal stem cell, Obstetrics and Gynecology, Andrology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Placenta, medicine, Cytotoxic T cell, Bone marrow, business, CD8
Abstract

The objective of this study was to determine if mouse bone marrow-derived mesenchymal stem cells (BMMSCs) ameliorate preterm birth and perinatal brain injury induced by intrauterine inflammation (IUI). A mouse model of IUI-induced perinatal brain injury at embryonic (E) day 17 was utilized. BMMSCs were derived from GFP-transgenic mice and phenotypically confirmed to be CD44+, Sca-1+, CD45−, CD34−, CD11b−, and CD11c− by flow cytometry and sorted by fluorescence-activated cell sorting (FACS). Dams were assigned to four groups: phosphate-buffered saline (PBS) + PBS, PBS + BMMSCs, lipopolysaccharide (LPS) + PBS, and LPS + BMMSCs. Following maternal IUI, there was a significant increase in CD8+ T cells in the placentas. Maternally administered BMMSCs trafficked to the fetal side of the placenta and resulted in significantly decreased placental CD8+ T cells. Furthermore, fetal trafficking of maternally administered BMMSCs correlated with an improved performance on offspring neurobehavioral testing in LPS + BMMSC group compared with LPS + PBS group. Our data support that maternal administration of BMMSCs can alleviate perinatal inflammation-induced brain injury and improve neurobehavioral outcomes in the offspring via CD8+ T cell immunomodulation at the feto-placental interface.

Published
2020
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14. Gut microbiota modulate dendritic cell antigen presentation and radiotherapy-induced antitumor immune response

Author

Stavros Rafail, Renzo Perales-Linares, Frederic D. Bushman, Ioannis I. Verginadis, Nathaniel W. Snyder, Kyle Bittinger, Andrea Facciabene, Clementina Mesaros, Sergey Pustylnikov, Luis Gil-de-Gómez, Mireia Uribe-Herranz, Ian A. Blair, Constantinos Koumenis, Silvia Beghi, and Stefano Pierini

Subjects
0301 basic medicine, T cell, Antigen presentation, CD8-Positive T-Lymphocytes, Gut flora, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, Antigen, Antigens, Neoplasm, medicine, Animals, Mice, Knockout, Antigen Presentation, biology, business.industry, Cross-presentation, Dendritic Cells, Neoplasms, Experimental, General Medicine, Dendritic cell, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, Gastrointestinal Microbiome, Butyrates, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Female, business, CD8, Research Article
Abstract

Alterations in gut microbiota impact the pathophysiology of several diseases, including cancer. Radiotherapy (RT), an established curative and palliative cancer treatment, exerts potent immune modulatory effects, inducing tumor-associated antigen (TAA) cross-priming with antitumor CD8(+) T cell elicitation and abscopal effects. We tested whether the gut microbiota modulates antitumor immune response following RT distal to the gut. Vancomycin, an antibiotic that acts mainly on gram-positive bacteria and is restricted to the gut, potentiated the RT-induced antitumor immune response and tumor growth inhibition. This synergy was dependent on TAA cross presentation to cytolytic CD8(+) T cells and on IFN-γ. Notably, butyrate, a metabolite produced by the vancomycin-depleted gut bacteria, abrogated the vancomycin effect. In conclusion, depletion of vancomycin-sensitive bacteria enhances the antitumor activity of RT, which has important clinical ramifications.

Published
2019
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15. Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy

Author

Melody Smith, Anqi Dai, Guido Ghilardi, Kimberly V. Amelsberg, Sean M. Devlin, Raymone Pajarillo, John B. Slingerland, Silvia Beghi, Pamela S. Herrera, Paul Giardina, Annelie Clurman, Emmanuel Dwomoh, Gabriel Armijo, Antonio L. C. Gomes, Eric R. Littmann, Jonas Schluter, Emily Fontana, Ying Taur, Jae H. Park, Maria Lia Palomba, Elizabeth Halton, Josel Ruiz, Tania Jain, Martina Pennisi, Aishat Olaide Afuye, Miguel-Angel Perales, Craig W. Freyer, Alfred Garfall, Shannon Gier, Sunita Nasta, Daniel Landsburg, James Gerson, Jakub Svoboda, Justin Cross, Elise A. Chong, Sergio Giralt, Saar I. Gill, Isabelle Riviere, David L. Porter, Stephen J. Schuster, Michel Sadelain, Noelle Frey, Renier J. Brentjens, Carl H. June, Eric G. Pamer, Jonathan U. Peled, Andrea Facciabene, Marcel R. M. van den Brink, and Marco Ruella

Subjects
Receptors, Chimeric Antigen, Antigens, CD19, Humans, Neurotoxicity Syndromes, General Medicine, Prospective Studies, Immunotherapy, Adoptive, Article, General Biochemistry, Genetics and Molecular Biology, Gastrointestinal Microbiome, Retrospective Studies
Abstract

Anti-CD19 chimeric antigen receptor (CAR) T cell therapy has led to unprecedented responses in patients with high-risk hematologic malignancies. However, up to 60% of patients still experience disease relapse and up to 80% of patients experience CAR-mediated toxicities, such as cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. We investigated the role of the intestinal microbiome on these outcomes in a multicenter study of patients with B cell lymphoma and leukemia. We found in a retrospective cohort (n = 228) that exposure to antibiotics, in particular piperacillin/tazobactam, meropenem and imipenem/cilastatin (P-I-M), in the 4 weeks before therapy was associated with worse survival and increased neurotoxicity. In stool samples from a prospective cohort of CAR T cell recipients (n = 48), the fecal microbiome was altered at baseline compared to healthy controls. Stool sample profiling by 16S ribosomal RNA and metagenomic shotgun sequencing revealed that clinical outcomes were associated with differences in specific bacterial taxa and metabolic pathways. Through both untargeted and hypothesis-driven analysis of 16S sequencing data, we identified species within the class Clostridia that were associated with day 100 complete response. We concluded that changes in the intestinal microbiome are associated with clinical outcomes after anti-CD19 CAR T cell therapy in patients with B cell malignancies.

Published
2021

17. Abstract 3449: Radiation therapy for bridging and improving CAR-T cells therapy

Author

Nektarios Kostopoulos, Costanitnos Koumeins, John P. Plastaras, Stephen J. Schuster, and Andrea Facciabene

Subjects
Cancer Research, Oncology
Abstract

CD19-targeted chimeric antigen receptor (CAR) T cells have transformed the treatment of patients with relapsed or refractory CD19-positive hematologic malignancies. However, a significant subset of these patients either fails to respond or eventually relapses. Moreover, patients who are candidates for CART-19 therapy often have symptomatic disease that requires some form of treatment to support them during the manufacture period. An ideal bridging therapy would simultaneously both (1) sensitize the tumor to CART-19 attack to increase antitumor control and (2) debulk the disease during manufacture. Radiotherapy (RT) is an established curative and palliative cancer treatment regimen, with approximately half of cancer patients with solid tumors receiving RT some time during their disease. Several reports have underscored the existence of threshold doses (and regimens) that are able to switch on different damage programs that profoundly affect responses to therapy by eliciting potent immune modulatory effects, prompting immunologically mediated tumor cell death. These effects have been attributed to multiple pathways, including the activation of the cGMP-cAMP Synthetase (cGAS), Stimulator of Interferon Genes (STING) pathway with Type I Interferons expression, and tumor associated antigen (TAA) cross priming with anti-tumor CD8+ T cell elicitation, ultimately inducing “abscopal” effects. By virtue of the immunomodulatory effects of RT, we hypothesize that RT could serve as a successful bridging strategy for CAR T-cell therapy. To investigate this hypothesis we established the A20 Lymphoma CART-19 therapy mouse model in our lab and use it to perform preliminaries experiments. A20 cells were implanted into both flanks of the animals. Mimicking human immune adjuvant dose used in our institute for RT bridging, 20 days after the A20 challenge we RT treated one of the two tumors using a dose of 8Gy divided in two fractions of 4Gy each. Twenty-four hours later 1x10ep6 CART-19 cells were infused intravenously. While the effects of RT in combination with CART-19 have similar impact on the tumor growth of the irradiated mass a significant increase of the antitumor effects of the single therapy was observed on the non-irradiated tumor. FACS studies demonstrated heavy leukocytes infiltration with increased presence of infused CART-19 as well indigenous T cells. To investigate possible molecular mechanisms involved in the increased effects on the non-irradiated tumor, we perform a qPCR array and observed increased expression of genes linked to cross priming, including IFN type I and Batf3. A20 cells express the ectopic retroviral antigen gp70 with well characterized AH1 immune-dominant epitope. AH1 tetramer staining on infiltrating T cells demonstrated increase staining in tumor from mice treated with the combination. Overall these results suggest RT may serve as optimal debulking and adjuvant bridging therapy for CAR-T cells therapy. Citation Format: Nektarios Kostopoulos, Costanitnos Koumeins, John P. Plastaras, Stephen J. Schuster, Andrea Facciabene. Radiation therapy for bridging and improving CAR-T cells therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3449.

Published
2022
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18. Abstract 3846: Parkin regulates tumor evasion by controlling antigen processing and presentation through the PTEN/AKT network

Author

Renzo Perales Linares, Hesham Mohei, Nektaria M. Leli, Silvia Beghi, Nektarios Kostopoulos, Amit Maity, Costantinos Koumenis, and Andrea Facciabene

Subjects
Cancer Research, Oncology
Abstract

A growing body of evidence supports the role of Parkin as a tumor suppressor involved in a number of cellular processes, including the downregulation of cell cycle and proliferation, migration, invasion, metastasis, mitophagy, and energy metabolic reprogramming. Indeed, epidemiological, genetic, and bioinformatic studies have shown multiple degrees of defects in the PARK2 gene, localized in human chromosome 6q25-27, a region frequently lost in cancers. In the present study, we show a novel role of Parkin in tumor immune surveillance through dysregulation of the PTEN/PI3k/AKT pathway, involving the modulation of antigen presentation machinery and antitumor-specific CD8+ T cell reactivity. We generated murine and human models that resemble the advanced-stage tumors where Parkin deficiencies are mostly found. In the mouse models, we observed a striking increase of tumor aggressiveness in the absence of Parkin that was associated with loss of antigen presentation and a significant decrease in the infiltration of antitumor CD8+ T cells. Importantly, loss of PARK2 also affected the efficacy of a Tumor-Associated Mitochondria Antigens (TAMAs) based vaccine showing the crucial role of Parkin in tumor development and in the context of antitumor cellular therapeutic strategies. Moreover, we also found that the lack of Parkin in the B16-OVA melanoma model also negatively impacts cytosol-derived antigen presentation and CD8+ T cell immunity. Finally, the analysis of TCGA tumor atlas validates the relevance of PARK2 loss on cancer immunotherapy effectiveness. Thus, during the progression and immunotherapy of cancer, the presence of Parkin mutations that result in loss of its functionality impact antigen presentation and facilitate tumor evasion. Citation Format: Renzo Perales Linares, Hesham Mohei, Nektaria M. Leli, Silvia Beghi, Nektarios Kostopoulos, Amit Maity, Costantinos Koumenis, Andrea Facciabene. Parkin regulates tumor evasion by controlling antigen processing and presentation through the PTEN/AKT network [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3846.

Published
2022
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19. Gut Microbiota Tuning Promotes Tumor-Associated Antigen Cross Presentation and Enhances CAR T Antitumor Effects

Author

Khatuna Gabunia, Stephen J. Schuster, Noelle V. Frey, David L. Porter, Nektarios Kostopoulos, Simon F. Lacey, Carl H. June, Andrea Facciabene, Raymone Pajarillo, Mireia Uribe-Herranz, Vijay Bhoj, Guido Ghilardi, Kalpana Parvathaneni, Elise A. Chong, John Scholler, Marco Ruella, Silvia Beghi, Yong Gu Gu Lee, and Kimberly Amelsberg

Subjects
Immunology, Cross-presentation, Cell Biology, Hematology, Biology, Gut flora, Car t cells, biology.organism_classification, Biochemistry, Tumor associated antigen
Abstract

Background: Chimeric Antigen Receptor (CAR) T cell immunotherapy has revolutionized the treatment of B-cell malignancies. However, a significant subset of these patients either fails to respond or eventually relapses. Moreover, in solid cancers, CAR T immunotherapy has had little to no success in the clinic so far. In recent years, several studies have shown the influence of commensal gut microbes on T cell function, in particular in the setting of checkpoint immunotherapy. Our group has recently demonstrated that modulation of the gut microbiota using antibiotics such as oral vancomycin (vanco) can enhance the efficacy of tumor-specific T cells in animal models. In this study, we sought to study the effect of vanco-induced dysbiosis on CART immunotherapy using murine models and clinical correlates. Methods and Results: We used the CD19+ A20 lymphoma and the B16 melanoma (transduced with CD19) murine models. Lymphoma- and melanoma-bearing mice were randomized to received oral vanco or vehicle alone (CTR), or in combination with either control untransduced murine T cells (UTD) or murine CART19 (4-1BB). Oral vanco or vehicle treatments started on the day of A20 cells injection and throughout the duration of the experiment (40-45 days). A20-bearing mice treated with CART19+vanco showed strikingly improved tumor control compared to either vanco alone or UTD+vanco (day 40 tumor volume in mm 3 (mean ± s.e.m): CTR=1,678.8±279.4, UTD=1,803.2±180, UTD+vanco=1,477±174, CART19=1,219±208, CART19+vanco=439.5±122.5 , CART versus CART+vanco Two Way Anova P Conclusions: These results suggest that the modulation of the gut microbiota using vancomycin affects the outcome of CART therapy in preclinical models with better anti-tumor effect via cross-priming and enhanced CART expansion in tumor samples. In a retrospective cohort of patients with B-ALL receiving vancomycin after CART19 therapy, we observed higher CART expansion and serum inflammatory cytokines. Based on these observations, a clinical trial of oral vanco in patients receiving CD19-directed CAR T cells for B-cell lymphomas is planned. Disclosures Ruella: viTToria biotherapeutics: Research Funding; Tmunity: Patents & Royalties; Novartis: Patents & Royalties; BMS, BAYER, GSK: Consultancy; AbClon: Consultancy, Research Funding. Frey: Novartis: Research Funding; Sana Biotechnology: Consultancy; Kite Pharma: Consultancy; Syndax Pharmaceuticals: Consultancy. June: Tmunity, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Current equity holder in publicly-traded company; AC Immune, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Consultancy; Novartis: Patents & Royalties. Porter: American Society for Transplantation and Cellular Therapy: Honoraria; ASH: Membership on an entity's Board of Directors or advisory committees; DeCart: Membership on an entity's Board of Directors or advisory committees; Genentech: Current Employment, Current equity holder in publicly-traded company; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Unity: Patents & Royalties; Wiley and Sons Publishing: Honoraria. Schuster: TG Theraputics: Research Funding; Incyte: Research Funding; Adaptive Biotechnologies: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Genentech/Roche: Consultancy, Research Funding; Tessa Theraputics: Consultancy; Loxo Oncology: Consultancy; Juno Theraputics: Consultancy, Research Funding; BeiGene: Consultancy; Alimera Sciences: Consultancy; Acerta Pharma/AstraZeneca: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Abbvie: Consultancy, Research Funding; Nordic Nanovector: Consultancy; Celgene: Consultancy, Honoraria, Research Funding.

Published
2021
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20. The Intestinal Microbiota Correlates with Response and Toxicity after CAR T Cell Therapy in Patients with B-Cell Malignancies

Author

Sean M. Devlin, Eric G. Pamer, Elizabeth Halton, Guido Ghilardi, Raymone Pajarillo, Emmanuel A Dwomoh, Andrea Facciabene, James N. Gerson, Maria Lia Palomba, Noelle V. Frey, Jonathan U. Peled, Elise A. Chong, Annelie Clurman, David L. Porter, Aishat Afuye, Kimberly Amelsberg, Melody Smith, Martina Pennisi, Marcel R.M. van den Brink, Alfred L. Garfall, Josel D. Ruiz, Emily Fontana, Marco Ruella, Justin R. Cross, Isabelle Riviere, Antonio L.C. Gomes, John B. Slingerland, Anqi Dai, Tania Jain, Ying Taur, Daniel J. Landsburg, Carl H. June, Silvia Beghi, Eric R. Littmann, Renier J. Brentjens, Jonas Schluter, Sunita D. Nasta, Pamela S Herrera, Jakub Svoboda, Paul A Giardina, Michel Sadelain, Craig W. Freyer, Miguel-Angel Perales, Stephen J. Schuster, Gabriel K Armijo, Saar Gill, Jae H. Park, Sergio Giralt, and Shannon H. Gier

Subjects
business.industry, Immunology, Cell Biology, Hematology, Biochemistry, medicine.anatomical_structure, Toxicity, medicine, Cancer research, CAR T-cell therapy, In patient, business, health care economics and organizations, B cell
Abstract

Introduction: Cellular immunotherapy with CD19-targeted chimeric antigen receptor (CAR) T cells has provided new therapeutic options for patients with high-risk hematologic malignancies. Following this therapy, patients may experience disease relapse or CAR-mediated toxicity due to cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Recent studies have confirmed that the intestinal microbiome can modulate the anti-tumor immune response to chemotherapy, immune checkpoint blockade, graft-versus-host disease after allogeneic hematopoietic cell transplantation, and adoptive cellular therapy. The contribution of the intestinal microbiome on the function of CAR T cells in vivo both with respect to their anti-tumor function and their propensity to induce toxicities is not known. Hence, in a multi-center study we analyzed the association between clinical outcomes and (1) antibiotic exposure prior to CAR T cell infusion and (2) the composition and diversity of the fecal microbiome. Methods and Results: We retrospectively collected clinical data and antibiotic exposures from patients with acute lymphoblastic leukemia (ALL, n=91) and non-Hodgkin lymphoma (NHL, n=137) treated with investigational or commercial CD19 CAR T cells at Memorial Sloan Kettering Cancer Center (MSK) and the University of Pennsylvania (Penn). We considered any antibiotic exposure between day -30 and the day of CAR T cell infusion. We focused our analysis on anaerobe-targeting antibiotics used in the setting of neutropenic fever: piperacillin-tazobactam, imipenem-cilastatin, and meropenem (here referred to as "P-I-M"). We found that forty-seven (20.6%) of 228 patients were exposed to P-I-M in the four weeks before CAR T cell infusion. Patient characteristics at the time of CAR T cell infusion were similar between the P-I-M-exposed and not-exposed groups, although a worse performance status was observed in patients with NHL treated with P-I-M. We found that overall survival (OS) was significantly decreased following CAR T cell infusion in patients exposed to P-I-M (Fig 1A; OS HR, 2.58; 95% CI, 1.68 - 3.98; p= We also prospectively collected baseline fecal samples prior to cell infusion from CD19 CAR T cells recipients (n=48) at MSK and Penn. Samples were submitted for 16S RNA sequencing of the V4-V5 region on the Illumina MiSeq platform and the amplicon sequence variants (ASVs) were annotated according to the NCBI 16S database using BLAST. In comparison to healthy controls (n=30), we found that alpha-diversity was significantly lower in fecal samples from CAR T cell patients (p= 0.0023, Fig 1B) and the composition of fecal samples was significantly different (p= Conclusion: Our results suggest that exposure to antibiotics, in particular P-I-M, in the four weeks before therapy was associated with worse survival. Profiling of the baseline fecal microbiome samples by 16S revealed that CD19 CAR T cell patients presented with evidence of an altered fecal microbiome as measured by lower alpha-diversity and a composition that is distinct from that of healthy controls. Finally, we identified bacterial taxa that were associated with Day 100 CR and CAR-mediated toxicity. Our findings indicate that the intestinal microbiome can affect the efficacy of CD19 CAR T cell therapy and provides a rationale to target the intestinal microbiome to improve clinical outcomes of patients treated with cellular therapies. Figure 1 Figure 1. Disclosures Smith: Janssen: Consultancy, Honoraria. Gomes: Xbiome: Current Employment. Schluter: Postbiotics Plus LLC: Other: cofounder. Park: Kura Oncology: Consultancy; BMS: Consultancy; Servier: Consultancy; Autolus: Consultancy; Curocel: Consultancy; Artiva: Consultancy; Kite Pharma: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Affyimmune: Consultancy; Intellia: Consultancy; Innate Pharma: Consultancy; Minerva: Consultancy; PrecisionBio: Consultancy. Palomba: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Jain: Targeted Healthcare Communications: Consultancy; Bristol Myers Squibb: Other: for advisory board participation; CareDx: Other: for advisory board participation; CTI Biopharma: Research Funding; Syneos Health: Research Funding. Pennisi: Gilead Sciences: Consultancy. Perales: Miltenyi Biotec: Honoraria, Other; Novartis: Honoraria, Other; Omeros: Honoraria; NexImmune: Honoraria; Bristol-Myers Squibb: Honoraria; Merck: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Kite/Gilead: Honoraria, Other; Medigene: Honoraria; Nektar Therapeutics: Honoraria, Other; Cidara: Honoraria; Servier: Honoraria; Sellas Life Sciences: Honoraria; Karyopharm: Honoraria; MorphoSys: Honoraria; Equilium: Honoraria; Incyte: Honoraria, Other. Garfall: Amgen: Honoraria; CRISPR Therapeutics: Research Funding; GlaxoSmithKline: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Research Funding; Tmunity: Research Funding. Landsburg: Triphase: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member; Incyte: Membership on an entity's Board of Directors or advisory committees; ADCT: Membership on an entity's Board of Directors or advisory committees; Curis: Research Funding; Takeda: Research Funding. Gerson: Kite: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy; TG Therapeutics: Consultancy. Svoboda: Imbrium: Consultancy; Genmab: Consultancy; Astra Zeneca: Consultancy, Research Funding; Atara: Consultancy; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Incyte: Research Funding; Merck: Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; TG: Research Funding. Giralt: AMGEN: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; SANOFI: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; JENSENN: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees. Gill: Interius Biotherapeutics: Current holder of stock options in a privately-held company, Research Funding; Novartis: Other: licensed intellectual property, Research Funding; Carisma Therapeutics: Current holder of stock options in a privately-held company, Research Funding. Rivière: FloDesign Sonics: Other: Provision of Services; Centre for Commercialization of Cancer Immunotherapy: Other: Provision of Services; Fate Therapeutics: Other: Provision of Services, Patents & Royalties; The Georgia Tech Research Corporation (GTRC): Other: Provision of Services (uncompensated); Juno Therapeutics: Patents & Royalties. Porter: Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Wiley and Sons Publishing: Honoraria; Tmunity: Patents & Royalties; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; ASH: Membership on an entity's Board of Directors or advisory committees; DeCart: Membership on an entity's Board of Directors or advisory committees; Genentech: Current equity holder in publicly-traded company, Ended employment in the past 24 months; American Society for Transplantation and Cellular Therapy: Honoraria; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees. Schuster: Abbvie: Consultancy, Research Funding; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; Adaptive Biotechnologies: Research Funding; BeiGene: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; DTRM: Research Funding; Genetech: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Incyte: Research Funding; Juno Theraputics: Consultancy, Research Funding; Loxo Oncology: Consultancy; Merck: Research Funding; Nordic Nanovector: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Pharmaclcyclics: Research Funding; Tessa Theraputics: Consultancy; TG Theraputics: Research Funding. Sadelain: NHLBI Gene Therapy Resource Program: Other: Provision of Services (uncompensated); Fate Therapeutics: Other: Provision of Services (uncompensated), Patents & Royalties; Atara Biotherapeutics: Patents & Royalties; Ceramedix: Patents & Royalties; Mnemo Therapeutics: Patents & Royalties; Takeda Pharmaceuticals: Other: Provision of Services, Patents & Royalties; St. Jude Children's Research Hospital: Other: Provision of Services; Juno Therapeutics: Patents & Royalties; Minerva Biotechnologies: Patents & Royalties. Frey: Novartis: Research Funding; Kite Pharma: Consultancy; Sana Biotechnology: Consultancy; Syndax Pharmaceuticals: Consultancy. Brentjens: Gracell Biotechnologies, Inc: Consultancy, Ended employment in the past 24 months; BMS: Consultancy, Patents & Royalties, Research Funding; sanofi: Patents & Royalties; Caribou: Patents & Royalties. June: AC Immune, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Consultancy; Novartis: Patents & Royalties; Tmunity, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Current equity holder in publicly-traded company. Pamer: Diversigen: Other: Advisory board; Bristol Myers Squibb, Celgene, Seres Therapeutics, MedImmune, Novartis and Ferring Pharmaceuticals: Honoraria. Peled: DaVolterra: Consultancy; MaaT Pharma: Consultancy; CSL Behring: Consultancy; Seres Therapeutics: Research Funding. Ruella: BMS, BAYER, GSK: Consultancy; Novartis: Patents & Royalties; AbClon: Consultancy, Research Funding; Tmunity: Patents & Royalties; viTToria biotherapeutics: Research Funding. van den Brink: WindMILTherapeutics: Honoraria; Pluto Therapeutics: Current holder of stock options in a privately-held company, Other: has consulted, received honorarium from or participated in advisory boards ; Priothera: Research Funding; Forty-Seven, Inc.: Honoraria; MagentaTherapeutics: Honoraria; GlaskoSmithKline: Other: has consulted, received honorarium from or participated in advisory boards; Ceramedix: Other: has consulted, received honorarium from or participated in advisory boards ; Merck & Co, Inc: Honoraria; Synthekine (Spouse): Other: has consulted, received honorarium from or participated in advisory boards; Kite Pharmaceuticals: Other; Amgen: Honoraria; Frazier Healthcare Partners: Honoraria; Seres: Other: Honorarium, Intellectual Property Rights, Research Fundingand Stock Options; Rheos: Honoraria; Therakos: Honoraria; Jazz Pharmaceuticals: Honoraria; Notch Therapeutics: Honoraria; Nektar Therapeutics: Honoraria; Wolters Kluwer: Patents & Royalties; Juno Therapeutics: Other; DKMS (nonprofit): Other; Pharmacyclics: Other; Da Volterra: Other: has consulted, received honorarium from or participated in advisory boards; Novartis (Spouse): Other: has consulted, received honorarium from or participated in advisory boards; Lygenesis: Other: has consulted, received honorarium from or participated in advisory boards .

Published
2021
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21. Integrative Development of a TLR8 Agonist for Ovarian Cancer Chemoimmunotherapy

Author

Katherine M. Bell-McGuinn, George Coukos, Carolyn K. McCourt, Alexander Malykhin, Kristi Manjarrez, Heather A. Lankes, Andrea Facciabene, Robert M. Hershberg, Gwenn Danet-Desnoyers, Joan L. Walker, Carol Aghajanian, Paula M. Fracasso, William E. Brady, and Bradley J. Monk

Subjects
Male, 0301 basic medicine, Agonist, Cancer Research, Maximum Tolerated Dose, medicine.drug_class, medicine.medical_treatment, Blotting, Western, Phases of clinical research, Mice, SCID, Pharmacology, Article, Polyethylene Glycols, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, Mice, Inbred NOD, In vivo, Chemoimmunotherapy, Antineoplastic Combined Chemotherapy Protocols, Animals, Humans, Medicine, Aged, Ovarian Neoplasms, business.industry, Cancer, Immunotherapy, Benzazepines, Middle Aged, medicine.disease, Macaca fascicularis, 030104 developmental biology, Oncology, Doxorubicin, Toll-Like Receptor 8, 030220 oncology & carcinogenesis, Female, business, Ovarian cancer
Abstract

Purpose: Immunotherapy is an emerging paradigm for the treatment of cancer, but the potential efficacy of many drugs cannot be sufficiently tested in the mouse. We sought to develop a rational combination of motolimod—a novel Toll-like receptor 8 (TLR8) agonist that stimulates robust innate immune responses in humans but diminished responses in mice—with pegylated liposomal doxorubicin (PLD), a chemotherapeutic that induces immunogenic cell death. Experimental Design: We followed an integrative pharmacologic approach including healthy human volunteers, non-human primates, NSG-HIS (“humanized immune system”) mice reconstituted with human CD34+ cells, and patients with cancer to test the effects of motolimod and to assess the combination of motolimod with PLD for the treatment of ovarian cancer. Results: The pharmacodynamic effects of motolimod monotherapy in NSG-HIS mice closely mimicked those in non-human primates and healthy human subjects, whereas the effects of the motolimod/PLD combination in tumor-bearing NSG-HIS mice closely mimicked those in patients with ovarian cancer treated in a phase Ib trial (NCT01294293). The NSG-HIS mouse helped elucidate the mechanism of action of the combination and revealed a positive interaction between the two drugs in vivo. The combination produced no dose-limiting toxicities in patients with ovarian cancer. Two subjects (15%) had complete responses and 7 subjects (53%) had disease stabilization. A phase II study was consequently initiated. Conclusions: These results are the first to demonstrate the value of pharmacologic approaches integrating the NSG-HIS mouse, non-human primates, and patients with cancer for the development of novel immunomodulatory anticancer agents with human specificity. Clin Cancer Res; 23(8); 1955–66. ©2016 AACR.

Published
2017
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22. Combination of CHEK1/2 inhibition and ionizing radiation results in abscopal tumor response through increased micronuclei formation

Author

Andrea Facciabene, Constantinos Koumenis, Noelle Francois, Hann-Hsiang Chao, Amit Maity, Ilias V. Karagounis, and Christoforos Thomas

Subjects
0301 basic medicine, Cancer Research, Cell cycle checkpoint, medicine.medical_treatment, Melanoma, Experimental, Ionizing radiation, 0302 clinical medicine, Interferon, Cytotoxic T cell, Urea, RNA, Small Interfering, education.field_of_study, Micronucleus Tests, Neoplasm Proteins, Tumor Burden, G2 Phase Cell Cycle Checkpoints, STAT1 Transcription Factor, abscopal response, 030220 oncology & carcinogenesis, Micronucleus test, immune signaling, Female, RNA Interference, medicine.drug, Population, Chk1, Chk2, Thiophenes, Biology, Article, 03 medical and health sciences, Cell Line, Tumor, Genetics, medicine, Animals, Humans, CHEK1, education, Molecular Biology, Cell Nucleus, Membrane Proteins, Interferon-beta, Xenograft Model Antitumor Assays, Radiation therapy, Mice, Inbred C57BL, radiation, Checkpoint Kinase 2, 030104 developmental biology, micronuclei, Checkpoint Kinase 1, Cancer research
Abstract

We explore a novel strategy of activating immune signaling through increased micronuclei formation utilizing a cell cycle checkpoint inhibitor to drive cell cycle progression following ionizing radiation. The Chk1/2 inhibitor AZD7762 is used to abrogate radiation therapy (RT)-induced G2/M cell cycle arrest in multiple cell lines and, we find that this therapeutic combination promotes increased micronuclei formation in vitro and subsequently drives increased type I interferon signaling and cytotoxic T-cell activation. In vivo studies using B16-F10 melanoma cancer cells implanted in C57/BL6 mice demonstrate improved rates of tumor control at the abscopal (unirradiated) site, located outside of the radiation field, only in the AZD7762 + RT group, with a corresponding reduction in mean tumor volume, increase in the CD8 T-cell population, and immune activated gene signaling. Our results demonstrate that targeted inhibition of cell cycle checkpoint activation following ionizing radiation drives increased production of immunogenic micronuclei, leading to systemic tumor response with potential future clinical benefit.

Published
2019

23. Mouse Bone Marrow-Derived Mesenchymal Stem Cells Alleviate Perinatal Brain Injury Via a CD8

Author

Hongxi, Zhao, Li, Xie, Julia L, Clemens, Lu, Zong, Michael W, McLane, Hattan, Arif, Mia C, Feller, Bei, Jia, Yan, Zhu, Andreas, Facciabene, Maide, Ozen, Jun, Lei, and Irina, Burd

Subjects
Inflammation, Uterus, Mesenchymal Stem Cells, Mice, Transgenic, CD8-Positive T-Lymphocytes, Mesenchymal Stem Cell Transplantation, Disease Models, Animal, Mice, Animals, Newborn, Bone Marrow, Pregnancy, Brain Injuries, Animals, Premature Birth, Female, Cells, Cultured
Abstract

The objective of this study was to determine if mouse bone marrow-derived mesenchymal stem cells (BMMSCs) ameliorate preterm birth and perinatal brain injury induced by intrauterine inflammation (IUI). A mouse model of IUI-induced perinatal brain injury at embryonic (E) day 17 was utilized. BMMSCs were derived from GFP-transgenic mice and phenotypically confirmed to be CD44

Published
2019

25. Abstract IA-004: The impact of gut microbiota on the radiotherapy-induced antitumor immune response

Author

Mireia Uribe-Herranz, Costantinos Koumenis, Stavros Rafail, Andrea Facciabene, Ioannis I. Verginadis, Silvia Beghi, and Clementina Mesaros

Subjects
Radiation therapy, Cancer Research, Immune system, Oncology, biology, business.industry, medicine.medical_treatment, Immunology, Medicine, Gut flora, biology.organism_classification, business
Abstract

Alterations in gut microbiota impact the pathophysiology of several diseases, including cancer. Radiotherapy (RT), an established curative and palliative cancer treatment, exerts potent immune modulatory effects, inducing tumor-associated antigen (TAA) cross-priming with antitumor CD8+ T cell elicitation and abscopal effects. We tested whether the gut microbiota modulates antitumor immune response following RT distal to the gut. Vancomycin, an antibiotic that acts mainly on gram-positive bacteria and is restricted to the gut, potentiated the RT-induced antitumor immune response and tumor growth inhibition. This synergy was dependent on TAA cross presentation to cytolytic CD8+ T cells and on IFN-γ. Notably, butyrate, a metabolite produced by the vancomycin-depleted gut bacteria, abrogated the vancomycin effect. In conclusion, depletion of vancomycin-sensitive bacteria enhances the antitumor activity of RT, which has important clinical ramifications. Citation Format: Mireia Uribe-Herranz, Stavros Rafail, Silvia Beghi, Ioannis Verginadis, Clementina Mesaros, Costantinos Koumenis, Andrea Facciabene. The impact of gut microbiota on the radiotherapy-induced antitumor immune response [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-004.

Published
2021
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26. Abstract 6509: Hypofractionated radiotherapy as a vaccine in combination with the TLR7/8 agonist resiquimod leads to significant abscopal tumor response and persistence antitumor immunity

Author

Amit Maity, Noelle Francois, Andrea Facciabene, Ilias V. Karagounis, Stefano Pierini, Xiaowei Xu, Christoforos Thomas, and Constantinos Koumenis

Subjects
Cancer Research, Combination therapy, business.industry, ELISPOT, medicine.medical_treatment, Melanoma, Immunotherapy, medicine.disease, Primary tumor, Radiation therapy, chemistry.chemical_compound, Oncology, chemistry, medicine, Cancer research, Immunogenic cell death, Resiquimod, business
Abstract

High doses of ionizing radiation (IR) as delivered with hypofractionated radiotherapy (HFRT) can generate immunogenic cell death and elicit adaptive anti-tumor immunity through cross priming of tumor associated antigens. Resiquimod (R-848), a TLR7/8 agonist, generates a systemic antitumor immunity resulting in tumor regression and enhanced T-cell effector function in cutaneous T-cell lymphomas clinically. We hypothesized that combining HFRT with immunotherapy would boost the antitumorigenic effects of either monotherapies, and if so, could lead to a readily translated clinical modality. B16F10 (murine melanoma) and SCC7 (murine squamous cell carcinoma) cells were used as to grow flank subcutaneous syngeneic tumor models in C57BL/6J and C3H/HeJ mice respectively. Our studies indicate that intratumoral administration of resiquimod combined with HFRT to those tumors leads to a significantly stronger antitumor response than either single treatment in both tumor models. The combination therapy in the primary tumor led to complete tumor regression of the SCC7 tumors in 86% of the treated mice to just 14% rejection in the HFRT group alone. Tumor re-challenge of those mice led to tumor rejection in 83% in the combination group compared to 0% of the HFRT group indicating a potent systemic effect of the combined therapy. Furthermore, the combination therapy led to significant reduction of the index (treated) but moreover in the abscopal (untreated) tumors compared to either monotherapy confirming a systemic antitumor effect in this dual-tumor in vivo model. RT-qPCR analysis revealed an increase expression of Th-1 signature (IFNγ, IL-12, Prf1, GzmB) in both primary and abscopal tumors and flowcytometric analysis of the abscopal B16F10 tumors revealed an increase in CD8+ infiltration. A more thorough flowcytometric analysis following staining with the gp100 tetramer revealed an increased cross-priming against gp100 (PMEL) and enhanced gp100-specific T-cell infiltration within the tumor. Moreover, splenocytes that were re-stimulated in vitro with the gp100 peptide in an IFNγ ELISPOT assay, they increased in mice treated with the dual therapy. Finally, an in vitro study of B16F10 cells, which express TLR7/8 receptors, revealed a substantial increase in IFNβ and CCL5 expression with the dual treatment. Knocking down TLR7 and Tmem173 (STING) in those cells with siRNAs completely reversed the phenotypic IFN type I expression signature. In conclusion, the combination of HFRT with Resiquimod leads to very potent antitumor effects in both primary and abscopal melanoma and squamous cell carcinoma tumors driven by an enhanced systemic immunologic response. Our findings provide the rational for translating therapies combining radiotherapy and intratumoral resiquimod into early-phase clinical trials. Citation Format: Ilias V. Karagounis, Stefano Pierini, Noëlle François, Christoforos Thomas, Xiaowei Xu, Constantinos Koumenis, Andrea Facciabene, Amit Maity. Hypofractionated radiotherapy as a vaccine in combination with the TLR7/8 agonist resiquimod leads to significant abscopal tumor response and persistence antitumor immunity [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 6509.

Published
2020
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27. The Microbiota and Ovarian Cancer

Author

Janos L. Tanyi and Andrea Facciabene

Subjects
Immune system, biology, Tumor progression, Immunology, medicine, Human microbiome, Cancer, Microbiome, Gut flora, medicine.disease, biology.organism_classification, Acquired immune system, Dysbiosis
Abstract

The cellular components of the immune system and the inflammatory milieu that it can generate is a central theme in many diseases including cancer. Immune cells can be manipulated by tumor cells to favor a pro-tumor microenvironment resulting in tumor progression. Ovarian cancer can alter its microenvironment favoring tumor growth by suppressing effector T cells as well as recruiting myeloid-derived cells, Th17 cells, γδ T cells, as well as non-immune cells such as adipose cells to aid in the generation or the propagation of the pro-inflammatory milieu. The human microbiome maintains a delicate balance between pro- and anti-inflammatory mechanisms, essential for gut homeostasis, and has critical roles in immune system development and metabolism. Alterations in the microbiome results in dysbiosis, quantitative and qualitative shifts in microbial populations, and contributes to chronic inflammation in various diseases including cancer. We highlight the role that the gut microbiota may play in cancer initiation and/or progression as well as its impact on cancer therapy. The association and interactions between the microbiome, both gut microbiota as well as infectious virus, with ovarian cancer, is reviewed here. Understanding the mechanisms by which the microbiome modulates the innate and adaptive immune response and contributes to an inflammatory milieu in cancer may offer insights into novel therapeutic targets.

Published
2019
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28. Abstract IA25: Tumors alter gut microbiota to suppress immunity and foster progression

Author

Stefano Pierini, Ceylan Tanes, Kyle Bittinger, Edgar Ben-Joseph, Janos L. Tanyi, Mireia Hribe-Herranz, Stavros Rafail, and Andrea Facciabene

Subjects
Cancer Research, biology, business.industry, Antimicrobial peptides, Cancer, Gut flora, medicine.disease, biology.organism_classification, Gut Epithelium, Immune system, Oncology, Tumor progression, Immunity, Immunology, Medicine, Microbiome, business
Abstract

Immune dysfunction is commonly observed in patients with cancer contributing to tumor progression. While previous work established a connection between the gut microbiota and the immune system, the mechanisms by which microbiotas contribute to cancer-associated immune dysfunction are not well understood. Using multiple mouse cancer models, we demonstrated robust alterations of gut microbiota in tumor-bearing mice and a substantial change in antimicrobial peptides produced by the gut epithelium. We identified an overall reduction in IFN-γ T cells in tumor-bearing mice, which was rescued with antibiotics treatment or by co-housing tumor-bearing mice with healthy mice. Similar to mouse, we observed changes in gut microbiota and antimicrobial peptides levels of patients diagnosed with ovarian or lung cancer. We identify Firmicutes Ruminococcus members as key promoters of immune dysfunctions and tumor development. These findings identify a new mechanism of immune modulation utilized by tumors to undermine the immune responses and promote tumor progression. Citation Format: Mireia Hribe-Herranz, Kyle Bittinger, Ceylan Tanes, Stavros Rafail, Stefano Pierini, Edgar Ben-Joseph, Janos Tanyi, Andrea Facciabene. Tumors alter gut microbiota to suppress immunity and foster progression [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr IA25.

Published
2020
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29. Targeting mitochondria in cancer: current concepts and immunotherapy approaches

Author

Francesca Costabile, Andrea Facciabene, Silvia Beghi, and Sergey Pustylnikov

Subjects
0301 basic medicine, Mitochondrial DNA, medicine.medical_treatment, T-Lymphocytes, Mitochondrion, Biology, medicine.disease_cause, DNA, Mitochondrial, Mitochondrial Dynamics, Article, 03 medical and health sciences, Physiology (medical), Neoplasms, medicine, Animals, Humans, Biochemistry (medical), Public Health, Environmental and Occupational Health, Cancer, General Medicine, Immunotherapy, medicine.disease, Acquired immune system, Cell biology, Mitochondria, 030104 developmental biology, Mitochondrial biogenesis, Cancer cell, Carcinogenesis
Abstract

An essential advantage during eukaryotic cell evolution was the acquisition of a network of mitochondria as a source of energy for cell metabolism and contrary to conventional wisdom, functional mitochondria are essential for the cancer cell. Multiple aspects of mitochondrial biology beyond bioenergetics support transformation including mitochondrial biogenesis, fission and fusion dynamics, cell death susceptibility, oxidative stress regulation, metabolism, and signaling. In cancer, the metabolism of cells is reprogrammed for energy generation from oxidative phosphorylation to aerobic glycolysis and impacts cancer mitochondrial function. Furthermore cancer cells can also modulate energy metabolism within the cancer microenvironment including immune cells and induce “metabolic anergy” of antitumor immune response. Classical approaches targeting the mitochondria of cancer cells usually aim at inducing changing energy metabolism or directly affecting functions of mitochondrial antiapoptotic proteins but most of such approaches miss the required specificity of action and carry important side effects. Several types of cancers harbor somatic mitochondrial DNA mutations and specific immune response to mutated mitochondrial proteins has been observed. An attractive alternative way to target the mitochondria in cancer cells is the induction of an adaptive immune response against mutated mitochondrial proteins. Here, we review the cancer cell-intrinsic and cell-extrinsic mechanisms through which mitochondria influence all steps of oncogenesis, with a focus on the therapeutic potential of targeting mitochondrial DNA mutations or Tumor Associated Mitochondria Antigens using the immune system. (Translational Research 2018; 202:35—51)

Published
2018

30. Tumor Infiltrating Lymphocytes in Occult Primary HPV+ Oropharyngeal Squamous Cell Carcinoma (OPSCC): Comparison of the Primary Tumor and Regional Lymph Node Metastases

Author

Samuel Swisher-McClure, G.S. Weinstein, Sergey Pustylnikov, Alex W. H. Lin, Kathleen T. Montone, Andrea Facciabene, Roger B. Cohen, John N. Lukens, and A. Fotouhi Ghiam

Subjects
Cancer Research, Pathology, medicine.medical_specialty, Radiation, business.industry, Tumor-infiltrating lymphocytes, medicine.disease, Occult, Primary tumor, medicine.anatomical_structure, Oncology, medicine, Radiology, Nuclear Medicine and imaging, Oropharyngeal squamous cell carcinoma, business, Lymph node
Published
2019
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31. Gut microbiota modulates adoptive cell therapy via CD8α dendritic cells and IL-12

Author

Janos L. Tanyi, Stavros Rafail, Kyle Bittinger, Ceylan Tanes, Frederic D. Bushman, Mireia Uribe-Herranz, Mark A. Morgan, Saar Gill, Alex Ganetsky, Carl H. June, Andrea Facciabene, Sonia Guedan, and Stefano Pierini

Subjects
Male, 0301 basic medicine, T-Lymphocytes, medicine.medical_treatment, Antibiotics, lcsh:Medicine, Gut flora, Immunotherapy, Adoptive, Cohort Studies, Cell therapy, Mice, Cancer immunotherapy, Neoplasms, Medicine, Mice, Knockout, biology, Hematopoietic Stem Cell Transplantation, General Medicine, Fecal Microbiota Transplantation, Middle Aged, Interleukin-12, Treatment Outcome, medicine.anatomical_structure, Interleukin 12, Female, Research Article, Adult, medicine.drug_class, CD8 Antigens, T cell, Immunology, Heterologous, 03 medical and health sciences, Vancomycin, Cell Line, Tumor, Animals, Humans, Aged, Bacteria, Host Microbial Interactions, business.industry, lcsh:R, Neomycin, Dendritic Cells, biology.organism_classification, Gastrointestinal Microbiome, Mice, Inbred C57BL, Transplantation, Disease Models, Animal, 030104 developmental biology, business
Abstract

Adoptive T cell therapy (ACT) is a promising new modality for malignancies. Here, we report that adoptive T cell efficacy in tumor-bearing mice is significantly affected by differences in the native composition of the gut microbiome or treatment with antibiotics, or by heterologous fecal transfer. Depletion of bacteria with vancomycin decreased the rate of tumor growth in mice from The Jackson Laboratory receiving ACT, whereas treatment with neomycin and metronidazole had no effect, indicating the role of specific bacteria in host response. Vancomycin treatment induced an increase in systemic CD8α+ DCs, which sustained systemic adoptively transferred antitumor T cells in an IL-12–dependent manner. In subjects undergoing allogeneic hematopoietic cell transplantation, we found that oral vancomycin also increased IL-12 levels. Collectively, our findings demonstrate an important role played by the gut microbiota in the antitumor effectiveness of ACT and suggest potentially new avenues to improve response to ACT by altering the gut microbiota.

Published
2018
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32. Maternal CD8

Author

Jun, Lei, Li, Xie, Hongxi, Zhao, Candice, Gard, Julia L, Clemens, Michael W, McLane, Mia C, Feller, Maide, Ozen, Christopher, Novak, Wael, Alshehri, Nader, Alhejaily, Yahya, Shabi, Jason M, Rosenzweig, Andrea, Facciabene, and Irina, Burd

Subjects
Inflammation, Lipopolysaccharides, Neurons, Placenta, respiratory system, CD8-Positive T-Lymphocytes, Lymphocyte Depletion, Article, Chemokine CXCL10, Disease Models, Animal, Mice, Pregnancy, Brain Injuries, Animals, Cytokines, Premature Birth, Female, Chemokine CCL5, Chemokine CCL3
Abstract

PROBLEM: We investigated the mechanisms by which CD8(+) T cell trafficking in placenta contributes to perinatal brain injury by studying effects of maternal CD8(+) T cell depletion (DEP) in a mouse model of intrauterine inflammation (IUI). METHOD OF STUDY: Maternal CD8(+) T cells were depleted with anti-CD8(+) antibodies. IUI was induced with lipopolysaccharide (LPS). DEP was confirmed using flow cytometry. Preterm birth rate was evaluated. Offspring neurologic sequelae were assessed by Nissl staining, immune arrays, confirmatory individual TaqMan(®) gene assays, and neurobehavioral tests. RESULTS: DEP did not significantly prevent LPS-induced preterm birth, but improved neurobehavioral performance (p

Published
2017

33. Association of antibiotic exposure with overall survival and colitis in patients with stage III and IV melanoma receiving immune checkpoint inhibitors

Author

Lynn M. Schuchter, Jahan J. Mohiuddin, John N. Lukens, Brian Chu, Andrea Facciabene, Abigail Doucette, Ravi K. Amaravadi, Wei Xu, Xingmei Wang, Tara C. Mitchell, Giorgos C. Karakousis, Amit Maity, and Cathy Zheng

Subjects
Cancer Research, medicine.drug_class, business.industry, Melanoma, Immune checkpoint inhibitors, Antibiotics, Antibiotic exposure, computer.file_format, medicine.disease, Oncology, medicine, Cancer research, In patient, Stage (cooking), Colitis, ABX test, business, computer
Abstract

56 Background: Recent studies suggest that changes in the gut microbiome modulate response to cancer treatment, including immune checkpoint inhibitors (ICI). Broad-spectrum antibiotics (Abx) are known to cause significant dysbiosis. We hypothesize that recent Abx exposure worsens outcomes in patients (pts) with stage III/IV melanoma (MM) receiving ICI. Methods: We identified MM pts treated with ICI from our institutional database. All received their first ICI between 2004-2019. Antibiotic exposure was defined as receipt of Abx within 3 months prior to the first infusion of ICI. The primary outcome was overall survival (OS) and the secondary outcome was immune-mediated colitis requiring intravenous (IV) steroids. Stage III and IV pts were analyzed separately for the primary analysis. Results: Of 568 pts in our database, 20% received Abx within the 3 months prior to ICI. 36% of pts had stage III disease and 26% of pts were treated with either adjuvant or neoadjuvant ICI. 1.6% of pts died of causes other than MM. The Abx+ and Abx- groups were balanced in terms of stage, race, age, sex, BRAF status, LDH, prior systemic therapies, and class of ICI received. Only 4 pts were hospitalized due to the infection prompting the Abx, and no pts died due to the infection. In the Stage IV group, Abx+ pts had worse OS on MV analysis (HR 1.6, 95% CI 1.1-2.2). Stage III Abx+ also had worse OS (HR 2.8, 95% CI 1.3-5.9). In a sensitivity analysis excluding pts who received IV Abx or were admitted due to infection, survival was still worse for Abx+ pts (HR 1.7, 95% CI 1.2-2.4). In a Fine-Grey competing risk MV model, Abx+ had a higher rate of immune-mediated colitis requiring IV steroids (HR 2.1, 95% CI 1.02-4.5). Conclusions: In MM pts treated with ICI, receipt of Abx within 3 months prior to ICI initiation was associated with decreased OS and increased colitis. Future research should include prospective studies to better define the risk/benefit profile of antibiotics in close proximity to ICI. [Table: see text]

Published
2020
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34. Abstract 4084: Radiation enhances efficacy of TEM1-specific cancer vaccination

Author

Stefano Pierini, Mireia Uribe-Herranz, Renzo Perales-Linares, Silvia Beghi, Francesca Costabile, Sergei Pustylnikov, and Andrea Facciabene

Subjects
Cancer Research, Oncology
Abstract

Tumor endothelial marker 1 (TEM1 or CD248) is a protein found in both tumor vasculature and stroma. In prior experiments, we showed that immunizing with Tem1-TT plasmid-DNA (Tem1 cDNA fused to the minimal domain of the C fragment of tetanus toxoid) was effective in controlling tumor progression in three mouse tumor models in a T cell-dependent manner. Moreover, effective Tem1-TT vaccination reduced tumor vascularity without impacting normal angiogenesis. Radiation therapy (RT) is an established curative and palliative cancer treatment regimen which uses high-energy radiation to kill cancer cells. RT modulates the tumor microenvironment - by increasing MHC-I expression, inducing immunological cell death, and damaging the tumor-associated vasculature - potentially synergizing with anti-cancer immunotherapies. Here, we combined RT and Tem1-TT heterologous vaccination and showed that combination of the two therapies was more effective in controlling CT26 and TC1 tumor progression than either single therapy alone. Interestingly adding RT to Tem1-TT vaccine resulted in a stronger vaccine-specific immune response and increased epitope spreading toward gp70, a TAA expressed by CT26 tumor cell line. Further analysis of the tumor microenvironment revealed a significant increment of PD-L1 expression in both tumor cells and tumor vasculature after single or either combination therapy. This led us to test whether blocking the PD1/PD-L1 axe would further improve the efficacy of RT plus Tem1-TT therapy. Our results demonstrate that administration of anti-PD-L1 antibody further synergized with RT plus Tem1-TT and improved mice survival. In conclusion, triple combination of Tem1-TT vaccine, RT and anti-PD-L1 can offer a therapeutic advantage for TEM1-positive tumors which also express PD-L1. Citation Format: Stefano Pierini, Mireia Uribe-Herranz, Renzo Perales-Linares, Silvia Beghi, Francesca Costabile, Sergei Pustylnikov, Andrea Facciabene. Radiation enhances efficacy of TEM1-specific cancer vaccination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4084.

Published
2019
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35. Abstract 3218: Anti-PD1 and -CTLA-4 combination in vivo enhances DC-based tumor-associated mitochondria antigen immunotherapy efficacy

Author

Renzo F. Perales-Linares, Stefano Pierini, Mireia Uribe, Sergei Pustylnikov, Francesca Costabile, Silvia Beghi, and Andrea Facciabene

Subjects
Cancer Research, Oncology
Abstract

Somatic mitochondria DNA (mtDNA) abnormalities have been identified in various types of human cancers. Previously, we generated tumor protective immunity under prophylactic and therapeutic approaches employing a murine kidney tumor model system and dendritic cell (DC)-based vaccination containing RENCA-derived mitochondria enriched lysates. Our results shown that tumor-associated mitochondria antigens (TAMAs) are targetable antigens for cancer immunotherapy (PMID: 26378078). Preliminary data also revealed increased endogenous PD-L1 mRNA expression levels in RENCA tumors of treated mice versus healthy kidney tissue. To investigate the impact of PD1/PD-L1 axis antagonism, Balb/C mice were challenged with RENCA cells at day 0 followed by TAMA-vaccination at day 3 and concurrent administration of anti-PD1 (aPD1) 5 times every 3 days. Interestingly, the aPD1-TAMA treatment resulted in reduced tumor growth, greater T CD4+ and T CD8+ cell infiltration, and lower intratumoral-MDSC as compared to the TAMA vaccine alone. In addition, we observed higher T cell activation from the aPD1-TAMA group upon co-culture with bone marrow-derived dendritic cells exposed to RENCA mitochondria lysate, suggesting that the inhibition of PD1 also enhanced the immunogenicity of the TAMA vaccine. Further analysis of the tumor environment revealed that the PD1-PD-L1 axis antagonism correlated with an increment of intratumoral CTLA4 expression and recruitment of T regulatory (Treg) cells. We introduced a third arm of treatment including a CTLA4 antagonist antibody in combination with aPD1 and TAMA vaccine in vivo. Strikingly, the tumor progression was greatly impacted causing tumor rejection in the majority of tumor-bearing animals, sustained tumor volume reduction in the others, a decrease in Treg cell recruitment, and concomitant increment of T CD8+ cell infiltration and activation. Altogether, the combination of check point inhibitors in vivo significantly improved the efficacy of the TAMA immunotherapy by remodeling the tumor microenvironment, reducing the immunosuppressive potential, and facilitating the infiltration of effector T cells into the tumor. Citation Format: Renzo F. Perales-Linares, Stefano Pierini, Mireia Uribe, Sergei Pustylnikov, Francesca Costabile, Silvia Beghi, Andrea Facciabene. Anti-PD1 and -CTLA-4 combination in vivo enhances DC-based tumor-associated mitochondria antigen immunotherapy efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3218.

Published
2019
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36. Cooperation between Constitutive and Inducible Chemokines Enables T Cell Engraftment and Immune Attack in Solid Tumors

Author

Denarda Dangaj, Jaikumar Duraiswamy, Mauro Delorenzi, David Barras, Lana E. Kandalaft, Donald G. Jackson, Melita Irving, Catherine Ronet, Andrea Facciabene, Kathleen T. Montone, Alizée J. Grimm, Janos L. Tanyi, Sylvie Rusakiewicz, Priyanka Duttagupta, Lin Zhang, George Coukos, Evripidis Lanitis, Hena R. Ramay, Periklis G. Foukas, Stephen Hodi, Phyllis A. Gimotty, Fabian Benencia, Jeffrey S. Weber, Jose R. Conejo-Garcia, Marine Bruand, Daniel J. Powell, and Scott J. Rodig

Subjects
0301 basic medicine, Cancer Research, Chemokine, Myeloid, Lymphocyte, CD8-Positive T-Lymphocytes, Lymphocyte Activation, CXCR3, Chemokine CXCL9, Epigenesis, Genetic, Antineoplastic Agents, Immunological, 0302 clinical medicine, Chemokine CCL5, Ovarian Neoplasms, biology, virus diseases, hemic and immune systems, Gene Expression Regulation, Neoplastic, Chemotaxis, Leukocyte, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, DNA methylation, Cytokines, Female, Immunotherapy, Signal Transduction, Receptors, CXCR3, T cell, Article, CCL5, Interferon-gamma, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, Immune system, stomatognathic system, Cell Line, Tumor, Paracrine Communication, parasitic diseases, medicine, Animals, Humans, Macrophages, Dendritic Cells, DNA Methylation, Coculture Techniques, Mice, Inbred C57BL, stomatognathic diseases, 030104 developmental biology, biology.protein, Cancer research
Abstract

Summary We investigated the role of chemokines in regulating T cell accumulation in solid tumors. CCL5 and CXCL9 overexpression was associated with CD8+ T cell infiltration in solid tumors. T cell infiltration required tumor cell-derived CCL5 and was amplified by IFN-γ-inducible, myeloid cell-secreted CXCL9. CCL5 and CXCL9 coexpression revealed immunoreactive tumors with prolonged survival and response to checkpoint blockade. Loss of CCL5 expression in human tumors was associated with epigenetic silencing through DNA methylation. Reduction of CCL5 expression caused tumor-infiltrating lymphocyte (TIL) desertification, whereas forced CCL5 expression prevented Cxcl9 expression and TILs loss, and attenuated tumor growth in mice through IFN-γ. The cooperation between tumor-derived CCL5 and IFN-γ-inducible CXCR3 ligands secreted by myeloid cells is key for orchestrating T cell infiltration in immunoreactive and immunoresponsive tumors.

Published
2019
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38. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part two

Author

Casey Ager, Matthew Reilley, Courtney Nicholas, Todd Bartkowiak, Ashvin Jaiswal, Michael Curran, Tina C. Albershardt, Anshika Bajaj, Jacob F. Archer, Rebecca S. Reeves, Lisa Y. Ngo, Peter Berglund, Jan ter Meulen, Caroline Denis, Hormas Ghadially, Thomas Arnoux, Fabien Chanuc, Nicolas Fuseri, Robert W. Wilkinson, Nicolai Wagtmann, Yannis Morel, Pascale Andre, Michael B. Atkins, Matteo S. Carlino, Antoni Ribas, John A. Thompson, Toni K. Choueiri, F. Stephen Hodi, Wen-Jen Hwu, David F. McDermott, Victoria Atkinson, Jonathan S. Cebon, Bernie Fitzharris, Michael B. Jameson, Catriona McNeil, Andrew G. Hill, Eric Mangin, Malidi Ahamadi, Marianne van Vugt, Mariëlle van Zutphen, Nageatte Ibrahim, Georgina V. Long, Robyn Gartrell, Zoe Blake, Ines Simoes, Yichun Fu, Takuro Saito, Yingzhi Qian, Yan Lu, Yvonne M. Saenger, Sadna Budhu, Olivier De Henau, Roberta Zappasodi, Kyle Schlunegger, Bruce Freimark, Jeff Hutchins, Christopher A. Barker, Jedd D. Wolchok, Taha Merghoub, Elena Burova, Omaira Allbritton, Peter Hong, Jie Dai, Jerry Pei, Matt Liu, Joel Kantrowitz, Venus Lai, William Poueymirou, Douglas MacDonald, Ella Ioffe, Markus Mohrs, William Olson, Gavin Thurston, Cristian Capasso, Federica Frascaro, Sara Carpi, Siri Tähtinen, Sara Feola, Manlio Fusciello, Karita Peltonen, Beatriz Martins, Madeleine Sjöberg, Sari Pesonen, Tuuli Ranki, Lukasz Kyruk, Erkko Ylösmäki, Vincenzo Cerullo, Fabio Cerignoli, Biao Xi, Garret Guenther, Naichen Yu, Lincoln Muir, Leyna Zhao, Yama Abassi, Víctor Cervera-Carrascón, Mikko Siurala, João Santos, Riikka Havunen, Suvi Parviainen, Akseli Hemminki, Angus Dalgleish, Satvinder Mudan, Mark DeBenedette, Ana Plachco, Alicia Gamble, Elizabeth W. Grogan, John Krisko, Irina Tcherepanova, Charles Nicolette, Pooja Dhupkar, Ling Yu, Eugenie S. Kleinerman, Nancy Gordon, Italia Grenga, Lauren Lepone, Sofia Gameiro, Karin M. Knudson, Massimo Fantini, Kwong Tsang, James Hodge, Renee Donahue, Jeffrey Schlom, Elizabeth Evans, Holm Bussler, Crystal Mallow, Christine Reilly, Sebold Torno, Maria Scrivens, Cathie Foster, Alan Howell, Leslie Balch, Alyssa Knapp, John E. Leonard, Mark Paris, Terry Fisher, Siwen Hu-Lieskovan, Ernest Smith, Maurice Zauderer, William Fogler, Marilyn Franklin, Matt Thayer, Dan Saims, John L. Magnani, Jian Gong, Michael Gray, George Fromm, Suresh de Silva, Louise Giffin, Xin Xu, Jason Rose, Taylor H. Schreiber, Sofia R. Gameiro, Paul E. Clavijo, Clint T. Allen, James W. Hodge, Kwong Y. Tsang, Jane Grogan, Nicholas Manieri, Eugene Chiang, Patrick Caplazi, Mahesh Yadav, Patrick Hagner, Hsiling Chiu, Michelle Waldman, Anke Klippel, Anjan Thakurta, Michael Pourdehnad, Anita Gandhi, Ian Henrich, Laura Quick, Rob Young, Margaret Chou, Andrew Hotson, Stephen Willingham, Po Ho, Carmen Choy, Ginna Laport, Ian McCaffery, Richard Miller, Kimberly A. Tipton, Kenneth R. Wong, Victoria Singson, Chihunt Wong, Chanty Chan, Yuanhiu Huang, Shouchun Liu, Jennifer H. Richardson, W. Michael Kavanaugh, James West, Bryan A. Irving, Ritika Jaini, Matthew Loya, Charis Eng, Melissa L. Johnson, Alex A. Adjei, Mateusz Opyrchal, Suresh Ramalingam, Pasi A. Janne, George Dominguez, Dmitry Gabrilovich, Laura de Leon, Jeannette Hasapidis, Scott J. Diede, Peter Ordentlich, Scott Cruickshank, Michael L. Meyers, Matthew D. Hellmann, Pawel Kalinski, Amer Zureikat, Robert Edwards, Ravi Muthuswamy, Nataša Obermajer, Julie Urban, Lisa H. Butterfield, William Gooding, Herbert Zeh, David Bartlett, Olga Zubkova, Larissa Agapova, Marina Kapralova, Liudmila Krasovskaia, Armen Ovsepyan, Maxim Lykov, Artem Eremeev, Vladimir Bokovanov, Olga Grigoryeva, Andrey Karpov, Sergey Ruchko, Alexandr Shuster, Danny N. Khalil, Luis Felipe Campesato, Yanyun Li, Adam S. Lazorchak, Troy D. Patterson, Yueyun Ding, Pottayil Sasikumar, Naremaddepalli Sudarshan, Nagaraj Gowda, Raghuveer Ramachandra, Dodheri Samiulla, Sanjeev Giri, Rajesh Eswarappa, Murali Ramachandra, David Tuck, Timothy Wyant, Jasmin Leshem, Xiu-fen Liu, Tapan Bera, Masaki Terabe, Birgit Bossenmaier, Gerhard Niederfellner, Yoram Reiter, Ira Pastan, Leiming Xia, Yang Xia, Yangyang Hu, Yi Wang, Yangyi Bao, Fu Dai, Shiang Huang, Elaine Hurt, Robert E. Hollingsworth, Lawrence G. Lum, Alfred E. Chang, Max S. Wicha, Qiao Li, Thomas Mace, Neil Makhijani, Erin Talbert, Gregory Young, Denis Guttridge, Darwin Conwell, Gregory B. Lesinski, Rodney JM Macedo Gonzales, Austin P. Huffman, Ximi K. Wang, Ran Reshef, Andy MacKinnon, Jason Chen, Matt Gross, Gisele Marguier, Peter Shwonek, Natalija Sotirovska, Susanne Steggerda, Francesco Parlati, Amani Makkouk, Mark K. Bennett, Ethan Emberley, Tony Huang, Weiqun Li, Silinda Neou, Alison Pan, Jing Zhang, Winter Zhang, Netonia Marshall, Thomas U. Marron, Judith Agudo, Brian Brown, Joshua Brody, Christopher McQuinn, Matthew Farren, Hannah Komar, Reena Shakya, Thomas Ludwug, Y. Maurice Morillon, Scott A. Hammond, John W. Greiner, Pulak R. Nath, Anthony L. Schwartz, Dragan Maric, David D. Roberts, Aung Naing, Kyriakos P. Papadopoulos, Karen A. Autio, Deborah J. Wong, Manish Patel, Gerald Falchook, Shubham Pant, Patrick A. Ott, Melinda Whiteside, Amita Patnaik, John Mumm, Filip Janku, Ivan Chan, Todd Bauer, Rivka Colen, Peter VanVlasselaer, Gail L. Brown, Nizar M. Tannir, Martin Oft, Jeffrey Infante, Evan Lipson, Ajay Gopal, Sattva S. Neelapu, Philippe Armand, Stephen Spurgeon, John P. Leonard, Rachel E. Sanborn, Ignacio Melero, Thomas F. Gajewski, Matthew Maurer, Serena Perna, Andres A. Gutierrez, Raphael Clynes, Priyam Mitra, Satyendra Suryawanshi, Douglas Gladstone, Margaret K. Callahan, James Crooks, Sheila Brown, Audrey Gauthier, Marc Hillairet de Boisferon, Andrew MacDonald, Laura Rosa Brunet, William T. Rothwell, Peter Bell, James M. Wilson, Fumi Sato-Kaneko, Shiyin Yao, Shannon S. Zhang, Dennis A. Carson, Cristina Guiducci, Robert L. Coffman, Kazutaka Kitaura, Takaji Matsutani, Ryuji Suzuki, Tomoko Hayashi, Ezra E. W. Cohen, David Schaer, Yanxia Li, Julie Dobkin, Michael Amatulli, Gerald Hall, Thompson Doman, Jason Manro, Frank Charles Dorsey, Lillian Sams, Rikke Holmgaard, Krishnadatt Persaud, Dale Ludwig, David Surguladze, John S. Kauh, Ruslan Novosiadly, Michael Kalos, Kyla Driscoll, Hardev Pandha, Christy Ralph, Kevin Harrington, Brendan Curti, Wallace Akerley, Sumati Gupta, Alan Melcher, David Mansfield, David R. Kaufman, Emmett Schmidt, Mark Grose, Bronwyn Davies, Roberta Karpathy, Darren Shafren, Katerina Shamalov, Cyrille Cohen, Naveen Sharma, James Allison, Tala Shekarian, Sandrine Valsesia-Wittmann, Christophe Caux, Aurelien Marabelle, Brian M. Slomovitz, Kathleen M. Moore, Hagop Youssoufian, Marshall Posner, Poonam Tewary, Alan D. Brooks, Ya-Ming Xu, Kithsiri Wijeratne, Leslie A. A. Gunatilaka, Thomas J. Sayers, John P. Vasilakos, Tesha Alston, Simon Dovedi, James Elvecrog, Iwen Grigsby, Ronald Herbst, Karen Johnson, Craig Moeckly, Stefanie Mullins, Kristen Siebenaler, Julius SternJohn, Ashenafi Tilahun, Mark A. Tomai, Katharina Vogel, Eveline E. Vietsch, Anton Wellstein, Martin Wythes, Stefano Crosignani, Joseph Tumang, Shilpa Alekar, Patrick Bingham, Sandra Cauwenberghs, Jenny Chaplin, Deepak Dalvie, Sofie Denies, Coraline De Maeseneire, JunLi Feng, Kim Frederix, Samantha Greasley, Jie Guo, James Hardwick, Stephen Kaiser, Katti Jessen, Erick Kindt, Marie-Claire Letellier, Wenlin Li, Karen Maegley, Reece Marillier, Nichol Miller, Brion Murray, Romain Pirson, Julie Preillon, Virginie Rabolli, Chad Ray, Kevin Ryan, Stephanie Scales, Jay Srirangam, Jim Solowiej, Al Stewart, Nicole Streiner, Vince Torti, Konstantinos Tsaparikos, Xianxian Zheng, Gregory Driessens, Bruno Gomes, Manfred Kraus, Chunxiao Xu, Yanping Zhang, Giorgio Kradjian, Guozhong Qin, Jin Qi, Xiaomei Xu, Bo Marelli, Huakui Yu, Wilson Guzman, Rober Tighe, Rachel Salazar, Kin-Ming Lo, Jessie English, Laszlo Radvanyi, Yan Lan, Michael Postow, Yasin Senbabaoglu, Billel Gasmi, Hong Zhong, Cailian Liu, Daniel Hirschhorhn-Cymerman, Yuanyuan Zha, Gregory Malnassy, Noreen Fulton, Jae-Hyun Park, Wendy Stock, Yusuke Nakamura, Hongtao Liu, Xiaoming Ju, Rachelle Kosoff, Kimberly Ramos, Brandon Coder, Robert Petit, Michael Princiotta, Kyle Perry, Jun Zou, Ainhoa Arina, Christian Fernandez, Wenxin Zheng, Michael A. Beckett, Helena J. Mauceri, Yang-Xin Fu, Ralph R. Weichselbaum, Whitney Lewis, Yanyan Han, Yeting Wu, Chou Yang, Jing Huang, Dongyun Wu, Jin Li, Xiaoling Liang, Xiangjun Zhou, Jinlin Hou, Raffit Hassan, Thierry Jahan, Scott J. Antonia, Hedy L. Kindler, Evan W. Alley, Somayeh Honarmand, Weiqun Liu, Meredith L. Leong, Chan C. Whiting, Nitya Nair, Amanda Enstrom, Edward E. Lemmens, Takahiro Tsujikawa, Sushil Kumar, Lisa M. Coussens, Aimee L. Murphy, Dirk G. Brockstedt, Sven D. Koch, Martin Sebastian, Christian Weiss, Martin Früh, Miklos Pless, Richard Cathomas, Wolfgang Hilbe, Georg Pall, Thomas Wehler, Jürgen Alt, Helge Bischoff, Michael Geissler, Frank Griesinger, Jens Kollmeier, Alexandros Papachristofilou, Fatma Doener, Mariola Fotin-Mleczek, Madeleine Hipp, Henoch S. Hong, Karl-Josef Kallen, Ute Klinkhardt, Claudia Stosnach, Birgit Scheel, Andreas Schroeder, Tobias Seibel, Ulrike Gnad-Vogt, Alfred Zippelius, Ha-Ram Park, Yong-Oon Ahn, Tae Min Kim, Soyeon Kim, Seulki Kim, Yu Soo Lee, Bhumsuk Keam, Dong-Wan Kim, Dae Seog Heo, Shari Pilon-Thomas, Amy Weber, Jennifer Morse, Krithika Kodumudi, Hao Liu, John Mullinax, Amod A. Sarnaik, Luke Pike, Andrew Bang, Tracy Balboni, Allison Taylor, Alexander Spektor, Tyler Wilhite, Monica Krishnan, Daniel Cagney, Brian Alexander, Ayal Aizer, Elizabeth Buchbinder, Mark Awad, Leena Ghandi, Jonathan Schoenfeld, Elizabeth Lessey-Morillon, Lisa Ridnour, Neil H. Segal, Manish Sharma, Dung T. Le, Robert L. Ferris, Andrew D. Zelenetz, Ronald Levy, Izidore S. Lossos, Caron Jacobson, Radhakrishnan Ramchandren, John Godwin, A. Dimitrios Colevas, Roland Meier, Suba Krishnan, Xuemin Gu, Jaclyn Neely, John Timmerman, Claire I. Vanpouille-Box, Silvia C. Formenti, Sandra Demaria, Erik Wennerberg, Aranzazu Mediero, Bruce N. Cronstein, Michael P. Gustafson, AriCeli DiCostanzo, Courtney Wheatley, Chul-Ho Kim, Svetlana Bornschlegl, Dennis A. Gastineau, Bruce D. Johnson, Allan B. Dietz, Cameron MacDonald, Mark Bucsek, Guanxi Qiao, Bonnie Hylander, Elizabeth Repasky, William J. Turbitt, Yitong Xu, Andrea Mastro, Connie J. Rogers, Sita Withers, Ziming Wang, Lam T. Khuat, Cordelia Dunai, Bruce R. Blazar, Dan Longo, Robert Rebhun, Steven K. Grossenbacher, Arta Monjazeb, William J. Murphy, Scott Rowlinson, Giulia Agnello, Susan Alters, David Lowe, Nicole Scharping, Ashley V. Menk, Ryan Whetstone, Xue Zeng, Greg M. Delgoffe, Patricia M. Santos, Jian Shi, Greg Delgoffe, Misako Nagasaka, Ammar Sukari, Miranda Byrne-Steele, Wenjing Pan, Xiaohong Hou, Brittany Brown, Mary Eisenhower, Jian Han, Natalie Collins, Robert Manguso, Hans Pope, Yashaswi Shrestha, Jesse Boehm, W. Nicholas Haining, Kyle R. Cron, Ayelet Sivan, Keston Aquino-Michaels, Marco Orecchioni, Davide Bedognetti, Wouter Hendrickx, Claudia Fuoco, Filomena Spada, Francesco Sgarrella, Gianni Cesareni, Francesco Marincola, Kostas Kostarelos, Alberto Bianco, Lucia Delogu, Jessica Roelands, Sabri Boughorbel, Julie Decock, Scott Presnell, Ena Wang, Franco M. Marincola, Peter Kuppen, Michele Ceccarelli, Darawan Rinchai, Damien Chaussabel, Lance Miller, Andrew Nguyen, J. Zachary Sanborn, Charles Vaske, Shahrooz Rabizadeh, Kayvan Niazi, Steven Benz, Shashank Patel, Nicholas Restifo, James White, Sam Angiuoli, Mark Sausen, Sian Jones, Maria Sevdali, John Simmons, Victor Velculescu, Luis Diaz, Theresa Zhang, Jennifer S. Sims, Sunjay M. Barton, Angela Kadenhe-Chiweshe, Filemon Dela Cruz, Andrew T. Turk, Christopher F. Mazzeo, Andrew L. Kung, Jeffrey N. Bruce, Darrell J. Yamashiro, Eileen P. Connolly, Jason Baird, Marka Crittenden, David Friedman, Hong Xiao, Rom Leidner, Bryan Bell, Kristina Young, Michael Gough, Zhen Bian, Koby Kidder, Yuan Liu, Emily Curran, Xiufen Chen, Leticia P. Corrales, Justin Kline, Ethan G. Aguilar, Jennifer Guerriero, Alaba Sotayo, Holly Ponichtera, Alexandra Pourzia, Sara Schad, Ruben Carrasco, Suzan Lazo, Roderick Bronson, Anthony Letai, Richard S. Kornbluth, Sachin Gupta, James Termini, Elizabeth Guirado, Geoffrey W. Stone, Christina Meyer, Laura Helming, Nicholas Wilson, Robert Hofmeister, Natalie J. Neubert, Laure Tillé, David Barras, Charlotte Soneson, Petra Baumgaertner, Donata Rimoldi, David Gfeller, Mauro Delorenzi, Silvia A. Fuertes Marraco, Daniel E. Speiser, Tara S. Abraham, Bo Xiang, Michael S. Magee, Scott A. Waldman, Adam E. Snook, Wojciech Blogowski, Ewa Zuba-Surma, Marta Budkowska, Daria Salata, Barbara Dolegowska, Teresa Starzynska, Leo Chan, Srinivas Somanchi, Kelsey McCulley, Dean Lee, Nico Buettner, Feng Shi, Paisley T. Myers, Stuart Curbishley, Sarah A. Penny, Lora Steadman, David Millar, Ellen Speers, Nicola Ruth, Gabriel Wong, Robert Thimme, David Adams, Mark Cobbold, Remy Thomas, Mariam Al-Muftah, Michael KK Wong, Michael Morse, Joseph I. Clark, Howard L. Kaufman, Gregory A. Daniels, Hong Hua, Tharak Rao, Janice P. Dutcher, Kai Kang, Yogen Saunthararajah, Vamsidhar Velcheti, Vikas Kumar, Firoz Anwar, Amita Verma, Zinal Chheda, Gary Kohanbash, John Sidney, Kaori Okada, Shruti Shrivastav, Diego A. Carrera, Shuming Liu, Naznin Jahan, Sabine Mueller, Ian F. Pollack, Angel M. Carcaboso, Alessandro Sette, Yafei Hou, Hideho Okada, Jessica J. Field, Weiping Zeng, Vincent FS Shih, Che-Leung Law, Peter D. Senter, Shyra J. Gardai, Nicole M. Okeley, Jennifer G. Abelin, Abu Z. Saeed, Stacy A. Malaker, Jeffrey Shabanowitz, Stephen T. Ward, Donald F. Hunt, Pam Profusek, Laura Wood, Dale Shepard, Petros Grivas, Kerstin Kapp, Barbara Volz, Detlef Oswald, Burghardt Wittig, Manuel Schmidt, Julian P. Sefrin, Lars Hillringhaus, Valeria Lifke, Alexander Lifke, Anna Skaletskaya, Jose Ponte, Thomas Chittenden, Yulius Setiady, Eva Sivado, Vincent Thomas, Meddy El Alaoui, Sébastien Papot, Charles Dumontet, Mike Dyson, John McCafferty, Said El Alaoui, Praveen K. Bommareddy, Andrew Zloza, Frederick Kohlhapp, Ann W. Silk, Sachin Jhawar, Tomas Paneque, Jenna Newman, Pedro Beltran, Felicia Cao, Bang-Xing Hong, Tania Rodriguez-Cruz, Xiao-Tong Song, Stephen Gottschalk, Hugo Calderon, Sam Illingworth, Alice Brown, Kerry Fisher, Len Seymour, Brian Champion, Emma Eriksson, Jessica Wenthe, Ann-Charlotte Hellström, Gabriella Paul-Wetterberg, Angelica Loskog, Ioanna Milenova, Magnus Ståhle, Justyna Jarblad-Leja, Gustav Ullenhag, Anna Dimberg, Rafael Moreno, Ramon Alemany, Sharad Goyal, Ann Silk, Janice Mehnert, Nashat Gabrail, Jennifer Bryan, Daniel Medina, Leah Mitchell, Kader Yagiz, Fernando Lopez, Daniel Mendoza, Anthony Munday, Harry Gruber, Douglas Jolly, Steven Fuhrmann, Sasa Radoja, Wei Tan, Aldo Pourchet, Alan Frey, Ian Mohr, Matthew Mulvey, Robert H. I. Andtbacka, Merrick Ross, Sanjiv Agarwala, Kenneth Grossmann, Matthew Taylor, John Vetto, Rogerio Neves, Adil Daud, Hung Khong, Stephanie M. Meek, Richard Ungerleider, Scott Welden, Maki Tanaka, Matthew Williams, Sigrun Hallmeyer, Bernard Fox, Zipei Feng, Christopher Paustian, Carlo Bifulco, Sadia Zafar, Otto Hemminki, Simona Bramante, Lotta Vassilev, Hongjie Wang, Andre Lieber, Silvio Hemmi, Tanja de Gruijl, Anna Kanerva, Tameem Ansari, Srividya Sundararaman, Diana Roen, Paul Lehmann, Anja C. Bloom, Lewis H. Bender, Ian B. Walters, Jay A. Berzofsky, Fanny Chapelin, Eric T. Ahrens, Jeff DeFalco, Michael Harbell, Amy Manning-Bog, Alexander Scholz, Danhui Zhang, Gilson Baia, Yann Chong Tan, Jeremy Sokolove, Dongkyoon Kim, Kevin Williamson, Xiaomu Chen, Jillian Colrain, Gregg Espiritu Santo, Ngan Nguyen, Wayne Volkmuth, Norman Greenberg, William Robinson, Daniel Emerling, Charles G. Drake, Daniel P. Petrylak, Emmanuel S. Antonarakis, Adam S. Kibel, Nancy N. Chang, Tuyen Vu, Dwayne Campogan, Heather Haynes, James B. Trager, Nadeem A. Sheikh, David I. Quinn, Peter Kirk, Murali Addepalli, Thomas Chang, Ping Zhang, Marina Konakova, Katsunobu Hagihara, Steven Pai, Laurie VanderVeen, Palakshi Obalapur, Peiwen Kuo, Phi Quach, Lawrence Fong, Deborah H. Charych, Jonathan Zalevsky, John L. Langowski, Yolanda Kirksey, Ravi Nutakki, Shalini Kolarkar, Rhoneil Pena, Ute Hoch, Stephen K. Doberstein, John Cha, Zach Mallon, Myra Perez, Amanda McDaniel, Snjezana Anand, Darrin Uecker, Richard Nuccitelli, Eva Wieckowski, Ravikumar Muthuswamy, Roshni Ravindranathan, Ariana N. Renrick, Menaka Thounaojam, Portia Thomas, Samuel Pellom, Anil Shanker, Duafalia Dudimah, Alan Brooks, Yu-Lin Su, Tomasz Adamus, Qifang Zhang, Sergey Nechaev, Marcin Kortylewski, Spencer Wei, Clark Anderson, Chad Tang, Jonathan Schoenhals, Efrosini Tsouko, John Heymach, Patricia de Groot, Joe Chang, Kenneth R. Hess, Adi Diab, Padmanee Sharma, David Hong, James Welsh, Andrea J. Parsons, Jardin Leleux, Stephane Ascarateil, Marie Eve Koziol, Dina Bai, Peihong Dai, Weiyi Wang, Ning Yang, Stewart Shuman, Liang Deng, Patrick Dillon, Gina Petroni, David Brenin, Kim Bullock, Walter Olson, Mark E. Smolkin, Kelly Smith, Carmel Nail, Craig L. Slingluff, Meenu Sharma, Faisal Fa’ak, Louise Janssen, Hiep Khong, Zhilan Xiao, Yared Hailemichael, Manisha Singh, Christina Vianden, Willem W. Overwijk, Andrea Facciabene, Pierini Stefano, Fang Chongyung, Stavros Rafail, Michael Nielsen, Peter Vanderslice, Darren G. Woodside, Robert V. Market, Ronald J. Biediger, Upendra K. Marathi, Kevin Hollevoet, Nick Geukens, Paul Declerck, Nathalie Joly, Laura McIntosh, Eustache Paramithiotis, Magnus Rizell, Malin Sternby, Bengt Andersson, Alex Karlsson-Parra, Rui Kuai, Lukasz Ochyl, Anna Schwendeman, James Moon, Weiwen Deng, Thomas E. Hudson, Bill Hanson, Chris S. Rae, Joel Burrill, Justin Skoble, George Katibah, Michele deVries, Peter Lauer, Thomas W. Dubensky, Xin Chen, Li Zhou, Xiubao Ren, Charu Aggarwal, Drishty Mangrolia, Roger Cohen, Gregory Weinstein, Matthew Morrow, Joshua Bauml, Kim Kraynyak, Jean Boyer, Jian Yan, Jessica Lee, Laurent Humeau, Sandra Oyola, Susan Duff, David Weiner, Zane Yang, Mark Bagarazzi, Douglas G. McNeel, Jens Eickhoff, Robert Jeraj, Mary Jane Staab, Jane Straus, Brian Rekoske, Glenn Liu, Marit Melssen, William Grosh, Nikole Varhegyi, Nadejda Galeassi, Donna H. Deacon, Elizabeth Gaughan, Maurizio Ghisoli, Minal Barve, Robert Mennel, Gladice Wallraven, Luisa Manning, Neil Senzer, John Nemunaitis, Masahiro Ogasawara, Shuichi Ota, Kaitlin M. Peace, Diane F. Hale, Timothy J. Vreeland, Doreen O. Jackson, John S. Berry, Alfred F. Trappey, Garth S. Herbert, Guy T. Clifton, Mark O. Hardin, Anne Toms, Na Qiao, Jennifer Litton, George E. Peoples, Elizabeth A. Mittendorf, Lila Ghamsari, Emilio Flano, Judy Jacques, Biao Liu, Jonathan Havel, Vladimir Makarov, Timothy A. Chan, Jessica B. Flechtner, John Facciponte, Stefano Ugel, Francesco De Sanctis, George Coukos, Sébastien Paris, Agnes Pottier, Laurent Levy, Bo Lu, Federica Cappuccini, Emily Pollock, Richard Bryant, Freddie Hamdy, Adrian Hill, Irina Redchenko, Hussein Sultan, Takumi Kumai, Valentyna Fesenkova, Esteban Celis, Ingrid Fernando, Claudia Palena, Justin M. David, Elizabeth Gabitzsch, Frank Jones, James L. Gulley, Mireia Uribe Herranz, Hiroshi Wada, Atsushi Shimizu, Toshihiro Osada, Satoshi Fukaya, Eiji Sasaki, Milad Abolhalaj, David Askmyr, Kristina Lundberg, Ann-Sofie Albrekt, Lennart Greiff, Malin Lindstedt, Dallas B. Flies, Tomoe Higuchi, Wojciech Ornatowski, Jaryse Harris, Sarah F. Adams, Todd Aguilera, Marjan Rafat, Laura Castellini, Hussein Shehade, Mihalis Kariolis, Dadi Jang, Rie vonEbyen, Edward Graves, Lesley Ellies, Erinn Rankin, Albert Koong, Amato Giaccia, Reham Ajina, Shangzi Wang, Jill Smith, Mariaelena Pierobon, Sandra Jablonski, Emanuel Petricoin, Louis M. Weiner, Lorcan Sherry, John Waller, Mark Anderson, Alison Bigley, Chantale Bernatchez, Cara Haymaker, Harriet Kluger, Michael Tetzlaff, Natalie Jackson, Ivan Gergel, Mary Tagliaferri, Patrick Hwu, Mario Snzol, Michael Hurwitz, Theresa Barberi, Allison Martin, Rahul Suresh, David Barakat, Sarah Harris-Bookman, Charles Drake, Alan Friedman, Sara Berkey, Stephanie Downs-Canner, Robert P. Edwards, Tyler Curiel, Kunle Odunsi, Tullia C. Bruno, Brandon Moore, Olivia Squalls, Peggy Ebner, Katherine Waugh, John Mitchell, Wilbur Franklin, Daniel Merrick, Martin McCarter, Brent Palmer, Jeffrey Kern, Dario Vignali, Jill Slansky, Anissa S. H. Chan, Xiaohong Qiu, Kathryn Fraser, Adria Jonas, Nadine Ottoson, Keith Gordon, Takashi O. Kangas, Steven Leonardo, Kathleen Ertelt, Richard Walsh, Mark Uhlik, Jeremy Graff, Nandita Bose, Ravi Gupta, Nitin Mandloi, Kiran Paul, Ashwini Patil, Rekha Sathian, Aparna Mohan, Malini Manoharan, Amitabha Chaudhuri, Yu Chen, Jing Lin, Yun-bin Ye, Chun-wei Xu, Gang Chen, Zeng-qing Guo, Andrey Komarov, Alex Chenchik, Michael Makhanov, Costa Frangou, Yi Zheng, Carla Coltharp, Darryn Unfricht, Ryan Dilworth, Leticia Fridman, Linying Liu, Milind Rajopadhye, Peter Miller, Fernando Concha-Benavente, Julie Bauman, Sumita Trivedi, Raghvendra Srivastava, James Ohr, Dwight Heron, Uma Duvvuri, Seungwon Kim, Heather Torrey, Toshi Mera, Yoshiaki Okubo, Eva Vanamee, Rosemary Foster, Denise Faustman, Edward Stack, Daisuke Izaki, Kristen Beck, Dan Tong Jia, Paul Armenta, Ashley White-Stern, Douglas Marks, Bret Taback, Basil Horst, Laura Hix Glickman, David B. Kanne, Kelsey S. Gauthier, Anthony L. Desbien, Brian Francica, Justin L. Leong, Leonard Sung, Ken Metchette, Shailaja Kasibhatla, Anne Marie Pferdekamper, Lianxing Zheng, Charles Cho, Yan Feng, Jeffery M. McKenna, John Tallarico, Steven Bender, Chudi Ndubaku, Sarah M. McWhirter, Elena Gonzalez Gugel, Charles J. M. Bell, Adiel Munk, Luciana Muniz, Nina Bhardwaj, Fei Zhao, Kathy Evans, Christine Xiao, Alisha Holtzhausen, Brent A. Hanks, Nathalie Scholler, Catherine Yin, Pien Van der Meijs, Andrew M. Prantner, Cecile M. Krejsa, Leia Smith, Brian Johnson, Daniel Branstetter, Paul L. Stein, Juan C. Jaen, Joanne BL Tan, Ada Chen, Timothy Park, Jay P. Powers, Holly Sexton, Guifen Xu, Steve W. Young, Ulrike Schindler, Wentao Deng, David John Klinke, Hannah M. Komar, Gregory Serpa, Omar Elnaggar, Philip Hart, Carl Schmidt, Mary Dillhoff, Ming Jin, Michael C. Ostrowski, Madhuri Koti, Katrina Au, Nichole Peterson, Peter Truesdell, Gillian Reid-Schachter, Charles Graham, Andrew Craig, Julie-Ann Francis, Beatrix Kotlan, Timea Balatoni, Emil Farkas, Laszlo Toth, Mihaly Ujhelyi, Akos Savolt, Zoltan Doleschall, Szabolcs Horvath, Klara Eles, Judit Olasz, Orsolya Csuka, Miklos Kasler, Gabriella Liszkay, Eytan Barnea, Collin Blakely, Patrick Flynn, Reid Goodman, Raphael Bueno, David Sugarbaker, David Jablons, V. Courtney Broaddus, Brian West, Paul R. Kunk, Joseph M. Obeid, Kevin Winters, Patcharin Pramoonjago, Edward B. Stelow, Todd W. Bauer, Osama E. Rahma, Adam Lamble, Yoko Kosaka, Fei Huang, Kate A. Saser, Homer Adams, Christina E. Tognon, Ted Laderas, Shannon McWeeney, Marc Loriaux, Jeffery W. Tyner, Brian J. Druker, Evan F. Lind, Zhuqing Liu, Shanhong Lu, Lawrence P. Kane, Gulidanna Shayan, Julia Femel, Ryan Lane, Jamie Booth, Amanda W. Lund, Anthony Rodriguez, Victor H. Engelhard, Alessandra Metelli, Bill X. Wu, Caroline W. Fugle, Rachidi Saleh, Shaoli Sun, Jennifer Wu, Bei Liu, Zihai Li, Zachary S. Morris, Emily I. Guy, Clinton Heinze, Jasdeep Kler, Monica M. Gressett, Lauryn R. Werner, Stephen D. Gillies, Alan J. Korman, Hans Loibner, Jacquelyn A. Hank, Alexander L. Rakhmilevich, Paul M. Harari, Paul M. Sondel, Erica Huelsmann, Joseph Broucek, Dorothee Brech, Tobias Straub, Martin Irmler, Johannes Beckers, Florian Buettner, Elke Schaeffeler, Matthias Schwab, Elfriede Noessner, Alison Wolfreys, Andre Da Costa, John Silva, Andrea Crosby, Ludovicus Staelens, Graham Craggs, Annick Cauvin, Sean Mason, Alison M. Paterson, Andrew C. Lake, Caroline M. Armet, Rachel W. O’Connor, Jonathan A. Hill, Emmanuel Normant, Ammar Adam, Detlev M. Biniszkiewicz, Scott C. Chappel, Vito J. Palombella, Pamela M. Holland, Annette Becker, Manmohan R. Leleti, Eric Newcomb, Joanne B. L. Tan, Suthee Rapisuwon, Arash Radfar, Kellie Gardner, Geoffrey Gibney, Michael Atkins, Keith R. Rennier, Robert Crowder, Ping Wang, Russell K. Pachynski, Rosa M. Santana Carrero, Sarai Rivas, Figen Beceren-Braun, Scott Anthony, Kimberly S. Schluns, Deepali Sawant, Maria Chikina, Hiroshi Yano, Creg Workman, Elise Salerno, Ileana Mauldin, Donna Deacon, Sofia Shea, Joel Pinczewski, Thomas Gajewski, Stefani Spranger, Brendan Horton, Akiko Suzuki, Pamela Leland, Bharat H. Joshi, Raj K. Puri, Randy F. Sweis, Riyue Bao, Jason Luke, Marie-Nicole Theodoraki, Frances-Mary Mogundo, Haejung Won, Dayson Moreira, Chan Gao, Xingli Zhao, Priyanka Duttagupta, Jeremy Jones, Massimo D’Apuzzo, and Sumanta Pal

Subjects
0301 basic medicine, Pharmacology, Cancer Research, medicine.medical_specialty, business.industry, medicine.medical_treatment, Immunology, Cancer, Immunotherapy, medicine.disease, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Family medicine, Molecular Medicine, Immunology and Allergy, Medicine, business
Abstract

O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells #### Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1

Published
2016
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39. T-Regulatory Cells: Key Players in Tumor Immune Escape and Angiogenesis

Author

George Coukos, Andrea Facciabene, and Gregory T. Motz

Subjects
Tumor angiogenesis, Cancer Research, Neovascularization, Pathologic, Antitumor immunity, Extramural, Angiogenesis, Tumor Immune Escape, Cancer, hemic and immune systems, chemical and pharmacologic phenomena, Biology, medicine.disease, T-Lymphocytes, Regulatory, Article, Neovascularization, Immune system, Oncology, Neoplasms, Immunology, medicine, Animals, Humans, Tumor Escape, medicine.symptom
Abstract

T-regulatory cells (Tregs) are found infiltrating tumors in a vast array of tumor types, and tumor-infiltrating Tregs are often associated with a poor clinical outcome. Tregs are potent immunosuppressive cells of the immune system that promote progression of cancer through their ability to limit antitumor immunity and promote angiogenesis. Here, we discuss the ways in which Tregs suppress the antitumor immune response and elaborate on our recent discovery that Tregs make significant direct contributions to tumor angiogenesis. Further, we highlight several current therapies aimed at eliminating Tregs in cancer patients. Given the multifaceted role of Tregs in cancer, a greater understanding of their functions will ultimately strengthen future therapies. Cancer Res; 72(9); 2162–71. ©2012 AACR.

Published
2012
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40. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells

Author

Andrea Facciabene, Li-Ping Wang, Xiaohui Peng, Phyllis A. Gimotty, C. Blake Gilks, George Coukos, Andrea Barchetti, Lin Zhang, Priti Lal, Klara Balint, and Ian S. Hagemann

Subjects
Vascular Endothelial Growth Factor A, Chemokine, Angiogenesis, Receptors, CCR10, medicine.disease_cause, T-Lymphocytes, Regulatory, Immune tolerance, Neovascularization, Mice, Immune system, Cell Line, Tumor, Immune Tolerance, medicine, Animals, Humans, Ovarian Neoplasms, Multidisciplinary, Neovascularization, Pathologic, biology, Hypoxia (medical), Cell Hypoxia, Gene Expression Regulation, Neoplastic, Mice, Inbred C57BL, Chemokines, CC, Culture Media, Conditioned, Immunology, Disease Progression, biology.protein, Cancer research, CCL28, Female, medicine.symptom, Carcinogenesis
Abstract

Although immune mechanisms can suppress tumour growth, tumours establish potent, overlapping mechanisms that mediate immune evasion. Emerging evidence suggests a link between angiogenesis and the tolerance of tumours to immune mechanisms. Hypoxia, a condition that is known to drive angiogenesis in tumours, results in the release of damage-associated pattern molecules, which can trigger the rejection of tumours by the immune system. Thus, the counter-activation of tolerance mechanisms at the site of tumour hypoxia would be a crucial condition for maintaining the immunological escape of tumours. However, a direct link between tumour hypoxia and tolerance through the recruitment of regulatory cells has not been established. We proposed that tumour hypoxia induces the expression of chemotactic factors that promote tolerance. Here we show that tumour hypoxia promotes the recruitment of regulatory T (T(reg)) cells through induction of expression of the chemokine CC-chemokine ligand 28 (CCL28), which, in turn, promotes tumour tolerance and angiogenesis. Thus, peripheral immune tolerance and angiogenesis programs are closely connected and cooperate to sustain tumour growth.

Published
2011
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41. CTL-based immunotherapy (PP-109)

Author

E. Stronen, J. Walia, Patrizia Castellani, X. Liu, A. Facciabene, K. J. Adams, X. Shang, L. Wu, Y. Zhang, T. Sugiyama, T. Felizardo, S. Wälchli, M. Toebes, S. Schmucker, J. Johansen, S. E. Church, T. Nishimura, T. Waks, N. Liddy, A. Marcus, Roberto S. Accolla, N. J. Pumphrey, J. A. Medin, M. Schmück, A. Mackiewicz, M. Kagabu, A. Richter, T. M. Mahon, Y. Wu, V. Salerno, H. Ikeda, K. M. Friedman, A. Fischer, L. Fallang, T. Takeshima, A. Labbe, E. Aleksaite, E. Morris, M. Yamane, A. Vuidepot, A. Römhild, Xue-Feng Bai, K. Takeda, A. Gedvilaite, N. M. Lissin, Barbara Carnemolla, S. M. Jensen, D. W. Kowalczyk, Laura Borsi, H. van den Poel, Lorenzo Mortara, C. J. Shu, D. Wakita, Y. Li, B. K. Jakobsen, N. Liu, K. Chamoto, F. Lund-Johansen, Y. Maekawa, John P. Hagan, K. Oosterhuis, K. Yasutomo, Y. Cai, N. J. Hassan, J. Olweus, I. Tawara, G. Brestrich, Hani Y. El-Omrani, C. J. Paige, U. Blohm, T. Ohkuri, Pramod S. Joshi, Y. Chu, I. C. Chua, C. B. Bifulco, Z. Rose, D. Xu, G. Coukos, C. Linnemann, H. Shirato, B. A. Fox, H. Shiku, E. P. Kwiatkowska, I. Weum Abrahamsen, S. Hans, A. Holler, D. D. Williams, R. Ashfield, K. Mori, H. Volk, J. Gavarret, Z. Eshhar, F. Luo, L. Wang, D. Soncini, C. Furlonger, P. Reinke, P. E. Molloy, H. Kitamura, M. E. Nelles, G. M. Bendle, Enrica Balza, C. Liu, S. Kumari, N. Imai, Y. Xiao, R. Hoppes, H. Ovaa, U. O. Kazimierczak, S. Luu, A. Kaiser, A. K. Sewell, G. Bossi, T. N. M. Schumacher, and Jin-Qing Liu

Subjects
CTL, business.industry, medicine.medical_treatment, Immunology, medicine, Immunology and Allergy, General Medicine, Immunotherapy, business
Published
2010
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42. Regulatory T cells (PP-045)

Author

E. Tasaki, Y. Okuno, E. M. Bertram, H. Isaka, S. Delbauve, T. Nakashima, K. A. Newell, J. C. Antvorskov, H. Fan, S. Kawashima, G. Ying, D. Horwitz, T. Thomas, M. Feuerer, Akihiko Yoshimura, C. Elly, K. Wang, T. Kanzaki, K. Buschard, T. P. Arstila, T. Huenig, F. Mair, N. Perdue, J. Sprent, L. Lu, L. Akahira, Y. Yoshida, H. Feng, W. Wang, Howard L. Weiner, Thorsten Buch, T. Laurinolli, D. Lim, F. X. Qin, X. Cao, J. Bártová, Y. m. Cao, I. R. van Driel, S. Hong, C. Tsao, L. M. Kastner, E. M. Ross, J. Wang, T. Honda, S. Park, Y. Chung, S. Schwele, R. Haque, B. Li, T. Yoshikawa, Matthew C. Cook, B. H. Hahn, M. G. Netea, Aleksandar Bulog, I. Iwamoto, J. Liu, P. Fundova, M. Kibata, Y. Lee, C. C. Goodnow, F. Conti, J. S. LeMasurier, Jeffrey A. Bluestone, J. Kie, K. Soejima, N. Erfani, X. R. Zhou, R. J. Steptoe, I. Kim, M. A. Fernandez, C. S. Constantinescu, S. Bauchiero, X. Jin, D. S. Y. Tan, Holly A. Bolton, S. Hu, L. R. Wedderburn, V. Flamand, Z. Liu, K. Sugimura, S. Kunkel, J. M. Rolland, Takatoku Oida, T. Ho, Tobias Bopp, L. Zheng, Y. Li, S. Shen, K. Michishita, M. Shin, R. Germain, Y. Tang, S. Klein-Hessling, Q. h. Wang, X. P. Peng, S. Nakamura, Daniel J. Campbell, Irma Joosten, X. Jiang, M. Braitch, Z. Yao, Masahide Hamaguchi, V. Pancre, H. Lee, Y. Zheng, Y. Cui, W. Müller, R. White, H. Yue, Ai Harashima, J. Perheentupa, M. Tomura, A. T. Endharti, S. Gattenloehner, Kenji Kabashima, M. Goldman, Z. Sarraf, Mihoko Shibuya, T. Sasaki, Y. Kanno, M. Yamamoto, J. Lee, G. Y. Zhou, A. M. Fischer, Y. Kwon, Christophe Benoist, Z. Chen, M. Nakatsugawa, Y. Liu, Y. Park, K. Yamamoto, Dirk H. Busch, C. S. Constantinecsu, T. Hamamoto, A. Carpentier, Y. Zhou, Hans-Dieter Volk, Tomohisa Okamura, J. Tsukada, K. Webster, E. Rabellino, I. Debock, F. Lin, Vladimir Mićović, T. Wakayama, Josef Bodor, H. Bae, G. Metzner, A. Kwan, Ari Waisman, C. Pecli, C. Wu, J. Song, S. Imoto, S. Han, H. Tanizaki, M. Mariotti-Ferrandiz, J. Paik, S. M. Salonen, K. Kawahata, B. Adams, M. H. Nyirenda, C. L. Hardy, K. Isobe, L. M. Lu, J. R. Killebrew, O. Morales, D. P. Funda, A. R. Kendal, A. McNally, R. A. DePinho, Ryuji Iida, N. Sasaki, S. Kim, N. Yang, L. H. Rossi, G. Brestrich, L. Hsu, N. Wada, C. Lu, C. B. Schmidt-Weber, V. Seyfert-Margolis, A. J. van der ven, T. Nakatsura, V. Nikolaev, H. Collins, A. R. Kitching, Carla Jones, B. Yen, Z. J. Jiao, C. Chan, T. Nakagaki, M. Takeuchi, Hirofumi Shoda, G. Lee, G. Wang, T. V. Hogan, M. Plebanski, F. Stenard, F. Liu, A. Suto, T. Otani, K. Tsuji-Takayama, D. E. Furst, Y. Takasaki, Tim Sparwasser, A. Tanaka, M. Asakawa, J. H. Louie, D. Brand, D. W. Dwyer, S. Nakano, A. Okamoto, M. Imamura, L. Chi, C. Zhu, J. Zhu, P. Roubal, S. Dharancy, M. Dohi, E. Kekäläinen, S. I. Alexander, H. Kojima, Dong Han, Q. Wang, N. Delhem, K. Takahashi, D. M. Heery, J. Sun, N. Sakemura, B. Gran, T. Toraya, A. Feng, X. Shen, C. A. Garcia Santana, H. Itoh, S. Zheng, N. MacDonald, U. Behn, A. Facciabene, B. Chiang, W. Kastenmuller, M. W. Leung, Shuji Sumitomo, X. Qu, S. Huang, R. Molinaro, A. Kokešová, M. Bozza, S. Z. Josefowicz, K. Bourcier, D. Bourges, K. Hirose, S. Rahimifar, F. Yamasaki, K. Nistala, E. Serfling, E. Schmitt, Friederike Berberich-Siebelt, Y. Wang, G. Coukos, F. Gross, I. Drexler, L. Yang, T. Gogishvili, S. Kagami, Y. Harada, H. Nakajima, E. Market, Y. Chen, A. Sledzinska, Lin Tian, Amy L. Putnam, F. Cunha, Anthony E.J. Dubois, M. I. Greene, S. Kamei, J. J. Lafaille, D. Kolodin, P. A. Gleeson, Ranjeny Thomas, W. Bolton, Xiao-Sen Li, I. Osawa, C. Miroux, Y. Kang, J. Drbohlav, A. Chaudhry, C. F. Benjamim, C. Kang, A. Ghaderi, G. Zhang, R. P. Singh, M. Hong, S. R. Holdsworth, L. Sanvito, L. Wang, J. j. Wu, T. Kobata, M. Kuo, B. Kim, M. Michels, A. I. Kokaji, Z. Li, W. Shi, J. Yao, X. Xia, W. Chang, S. Choi, R. Nakagawa, Y. y. Pan, M. Vaeth, C. Canetti, F. Lei, P. Hsu, J. Alves-Filho, S. Hori, A. Šalaková, B. L. Wang, J. Wilkinson, P. Zdziarski, M. Fairhurst, Keishi Fujio, X. Zheng, H. Suzuki, R. K. Dinesh, Shimon Sakaguchi, Z. Jiang, S. Hemmers, B Fazekas de St Groth, M. Zelman-Femiak, H. Moncrieffe, L. Han, J. Park, M. Suzuki, S. Eaton, D. Sakurai, T. Inoue, F. Lhommé, S. Nishimoto, Ines Mrakovčić-Šutić, R. Mohamud, Matthias Klein, S. D'Costa, R. E. O'Hehir, N. Morishima, J. Cha, M. Schmueck, M. Uchiyama, K. Imi, H. Hase, E. Boleslowski, A. Liston, C. Park, P. Reinke, C. Shen, H. Wakashin, D. A. Horwitz, Ohkura Naganari, Herman Waldmann, A. Okochi, A. Khoo, I. Kubajewska, J. Seoh, A. Roemhild, Alexander Y. Rudensky, Diane Mathis, J. A. Altin, C. Liu, M. Lohse, T. Shimada, B. Yang, W. Liu, L. Turka, M. Kweon, G. Gasteiger, Hans J. P. M. Koenen, Y. Kim, S. Okuda, Burkhard Becher, and Osami Kanagawa

Subjects
Immunology, Immunology and Allergy, General Medicine
Published
2010
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43. Abstract 3798: Gut microbiota modulates adoptive cell therapy via CD8α dendritic cells

Author

Andrea Facciabene, Kyle Bittinger, Sonia Guedan, Mark A. Morgan, Mireia Uribe-Herranz, Ceylan Tanes, Stefano Pierini, Janos Tany, Saar Gill, Carl H. June, Frederic D. Bushman, and Stavros Rafail

Subjects
Cell therapy, Cancer Research, Oncology, Immunology, Biology, Gut flora, biology.organism_classification
Abstract

Adoptive T-Cell therapy (ACT) is a promising new modality for malignancies. Here, we report that adoptive T-cell efficacy in tumor-bearing mice is significantly affected by differences in the native composition of the gut microbiome, treatment with antibiotics or by heterologous fecal transfer. Depletion of bacteria with vancomycin, decreased the rate of tumor growth in mice receiving ACT, whereas treatment with neomycin and metronidazole had no effect, indicating the role of specific bacteria in host response. Vancomycin treatment induced an increase in systemic CD8α+ dendritic cells, which mediated a sustained systemic expansion of adoptively transferred antitumor T cells in an IL-12-dependent manner. In subjects undergoing allogeneic hematopoietic cell transplantation, we found that oral vancomycin also increased IL-12 levels. Collectively, our findings demonstrate an important role played by the gut microbiota in the antitumor effectiveness of ACT and suggest new avenues to improve response to ACT by altering the gut microbiota. Citation Format: Mireia Uribe-Herranz, Kyle Bittinger, Stavros Rafail, Sonia Guedan, Stefano Pierini, Ceylan Tanes, Saar A. Gill, Janos Tany, Mark A. Morgan, Frederic D. Bushman, Carl H. June, Andrea Facciabene. Gut microbiota modulates adoptive cell therapy via CD8α dendritic cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3798.

Published
2018
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44. Abstract 666: Gut microbiota SCFA modulates DCs antigen presentation and impacts tumor response to radiotherapy

Author

Stefano Pierini, Stavros Rafail, Kyle Bittinger, Luis Gil de Gomez, Andrea Facciabene, and Mireia Uribe-Herranz

Subjects
0301 basic medicine, Cancer Research, biology, business.industry, T cell, Antigen presentation, Cancer, Butyrate, Gut flora, biology.organism_classification, medicine.disease, 03 medical and health sciences, 030104 developmental biology, Immune system, medicine.anatomical_structure, Oncology, Antigen, Cancer research, Medicine, business, CD8
Abstract

Alterations in gut microbiota modulate host physiologic functions, including immune responses, and they play a role in the pathophysiology of several diseases, including cancer. Radiotherapy (RT), an established curative and palliative cancer treatment, exerts potent immune modulatory effects, inducing tumor-associated antigen (TAA) cross-priming with antitumor CD8+ T cell elicitation and abscopal effects. Herein, we tested whether the gut microbiota modulates antitumor immune response following RT. Vancomycin, an antibiotic that acts mainly on gram-positive bacteria and is restricted to the gut, potentiated the RT-induced antitumor immune response and tumor growth inhibition. This synergy was dependent on tumor-associated antigen cross-presentation enanchement, cytolytic CD8+ T cells and on IFN-g. Notably, butyrate, a metabolite produced by the vancomycin-depleted gut bacteria, abrogated the vancomycin effect. In conclusion, gram-positive bacteria depletion by vancomycin enhances the antitumor activity of RT, which has important clinical ramifications. Citation Format: Andrea Facciabene, Stavros Rafail, Luis Gil de Gomez, Stefano Pierini, Mireia Uribe-Herranz, Kyle Bittinger. Gut microbiota SCFA modulates DCs antigen presentation and impacts tumor response to radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 666.

Published
2018
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45. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part two

Author

Ager, Casey, Reilley, Matthew, Nicholas, Courtney, Bartkowiak, Todd, Jaiswal, Ashvin, Curran, Michael, Albershardt, Tina C., Bajaj, Anshika, Archer, Jacob F., Reeves, Rebecca S., Ngo, Lisa Y., Berglund, Peter, ter Meulen, Jan, Denis, Caroline, Ghadially, Hormas, Arnoux, Thomas, Chanuc, Fabien, Fuseri, Nicolas, Wilkinson, Robert W., Wagtmann, Nicolai, Morel, Yannis, Andre, Pascale, Atkins, Michael B., Carlino, Matteo S., Ribas, Antoni, Thompson, John A., Choueiri, Toni K., Hodi, F. Stephen, Hwu, Wen-Jen, McDermott, David F., Atkinson, Victoria, Cebon, Jonathan S., Fitzharris, Bernie, Jameson, Michael B., McNeil, Catriona, Hill, Andrew G., Mangin, Eric, Ahamadi, Malidi, van Vugt, Marianne, van Zutphen, Mariëlle, Ibrahim, Nageatte, Long, Georgina V., Gartrell, Robyn, Blake, Zoe, Simoes, Ines, Fu, Yichun, Saito, Takuro, Qian, Yingzhi, Lu, Yan, Saenger, Yvonne M., Budhu, Sadna, De Henau, Olivier, Zappasodi, Roberta, Schlunegger, Kyle, Freimark, Bruce, Hutchins, Jeff, Barker, Christopher A., Wolchok, Jedd D., Merghoub, Taha, Burova, Elena, Allbritton, Omaira, Hong, Peter, Dai, Jie, Pei, Jerry, Liu, Matt, Kantrowitz, Joel, Lai, Venus, Poueymirou, William, MacDonald, Douglas, Ioffe, Ella, Mohrs, Markus, Olson, William, Thurston, Gavin, Capasso, Cristian, Frascaro, Federica, Carpi, Sara, Tähtinen, Siri, Feola, Sara, Fusciello, Manlio, Peltonen, Karita, Martins, Beatriz, Sjöberg, Madeleine, Pesonen, Sari, Ranki, Tuuli, Kyruk, Lukasz, Ylösmäki, Erkko, Cerullo, Vincenzo, Cerignoli, Fabio, Xi, Biao, Guenther, Garret, Yu, Naichen, Muir, Lincoln, Zhao, Leyna, Abassi, Yama, Cervera-Carrascón, Víctor, Siurala, Mikko, Santos, João, Havunen, Riikka, Parviainen, Suvi, Hemminki, Akseli, Dalgleish, Angus, Mudan, Satvinder, DeBenedette, Mark, Plachco, Ana, Gamble, Alicia, Grogan, Elizabeth W., Krisko, John, Tcherepanova, Irina, Nicolette, Charles, Dhupkar, Pooja, Yu, Ling, Kleinerman, Eugenie S., Gordon, Nancy, Grenga, Italia, Lepone, Lauren, Gameiro, Sofia, Knudson, Karin M., Fantini, Massimo, Tsang, Kwong, Hodge, James, Donahue, Renee, Schlom, Jeffrey, Evans, Elizabeth, Bussler, Holm, Mallow, Crystal, Reilly, Christine, Torno, Sebold, Scrivens, Maria, Foster, Cathie, Howell, Alan, Balch, Leslie, Knapp, Alyssa, Leonard, John E., Paris, Mark, Fisher, Terry, Hu-Lieskovan, Siwen, Smith, Ernest, Zauderer, Maurice, Fogler, William, Franklin, Marilyn, Thayer, Matt, Saims, Dan, Magnani, John L., Gong, Jian, Gray, Michael, Fromm, George, de Silva, Suresh, Giffin, Louise, Xu, Xin, Rose, Jason, Schreiber, Taylor H., Gameiro, Sofia R., Clavijo, Paul E., Allen, Clint T., Hodge, James W., Tsang, Kwong Y., Grogan, Jane, Manieri, Nicholas, Chiang, Eugene, Caplazi, Patrick, Yadav, Mahesh, Hagner, Patrick, Chiu, Hsiling, Waldman, Michelle, Klippel, Anke, Thakurta, Anjan, Pourdehnad, Michael, Gandhi, Anita, Henrich, Ian, Quick, Laura, Young, Rob, Chou, Margaret, Hotson, Andrew, Willingham, Stephen, Ho, Po, Choy, Carmen, Laport, Ginna, McCaffery, Ian, Miller, Richard, Tipton, Kimberly A., Wong, Kenneth R., Singson, Victoria, Wong, Chihunt, Chan, Chanty, Huang, Yuanhiu, Liu, Shouchun, Richardson, Jennifer H., Kavanaugh, W. Michael, West, James, Irving, Bryan A., Jaini, Ritika, Loya, Matthew, Eng, Charis, Johnson, Melissa L., Adjei, Alex A., Opyrchal, Mateusz, Ramalingam, Suresh, Janne, Pasi A., Dominguez, George, Gabrilovich, Dmitry, de Leon, Laura, Hasapidis, Jeannette, Diede, Scott J., Ordentlich, Peter, Cruickshank, Scott, Meyers, Michael L., Hellmann, Matthew D., Kalinski, Pawel, Zureikat, Amer, Edwards, Robert, Muthuswamy, Ravi, Obermajer, Nataša, Urban, Julie, Butterfield, Lisa H., Gooding, William, Zeh, Herbert, Bartlett, David, Zubkova, Olga, Agapova, Larissa, Kapralova, Marina, Krasovskaia, Liudmila, Ovsepyan, Armen, Lykov, Maxim, Eremeev, Artem, Bokovanov, Vladimir, Grigoryeva, Olga, Karpov, Andrey, Ruchko, Sergey, Shuster, Alexandr, Khalil, Danny N., Campesato, Luis Felipe, Li, Yanyun, Lazorchak, Adam S., Patterson, Troy D., Ding, Yueyun, Sasikumar, Pottayil, Sudarshan, Naremaddepalli, Gowda, Nagaraj, Ramachandra, Raghuveer, Samiulla, Dodheri, Giri, Sanjeev, Eswarappa, Rajesh, Ramachandra, Murali, Tuck, David, Wyant, Timothy, Leshem, Jasmin, Liu, Xiu-fen, Bera, Tapan, Terabe, Masaki, Bossenmaier, Birgit, Niederfellner, Gerhard, Reiter, Yoram, Pastan, Ira, Xia, Leiming, Xia, Yang, Hu, Yangyang, Wang, Yi, Bao, Yangyi, Dai, Fu, Huang, Shiang, Hurt, Elaine, Hollingsworth, Robert E., Lum, Lawrence G., Chang, Alfred E., Wicha, Max S., Li, Qiao, Mace, Thomas, Makhijani, Neil, Talbert, Erin, Young, Gregory, Guttridge, Denis, Conwell, Darwin, Lesinski, Gregory B., Gonzales, Rodney JM Macedo, Huffman, Austin P., Wang, Ximi K., Reshef, Ran, MacKinnon, Andy, Chen, Jason, Gross, Matt, Marguier, Gisele, Shwonek, Peter, Sotirovska, Natalija, Steggerda, Susanne, Parlati, Francesco, Makkouk, Amani, Bennett, Mark K., Emberley, Ethan, Huang, Tony, Li, Weiqun, Neou, Silinda, Pan, Alison, Zhang, Jing, Zhang, Winter, Marshall, Netonia, Marron, Thomas U., Agudo, Judith, Brown, Brian, Brody, Joshua, McQuinn, Christopher, Farren, Matthew, Komar, Hannah, Shakya, Reena, Ludwug, Thomas, Morillon, Y. 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Chris S., Burrill, Joel, Skoble, Justin, Katibah, George, deVries, Michele, Lauer, Peter, Dubensky, Thomas W., Chen, Xin, Zhou, Li, Ren, Xiubao, Aggarwal, Charu, Mangrolia, Drishty, Cohen, Roger, Weinstein, Gregory, Morrow, Matthew, Bauml, Joshua, Kraynyak, Kim, Boyer, Jean, Yan, Jian, Lee, Jessica, Humeau, Laurent, Oyola, Sandra, Duff, Susan, Weiner, David, Yang, Zane, Bagarazzi, Mark, McNeel, Douglas G., Eickhoff, Jens, Jeraj, Robert, Staab, Mary Jane, Straus, Jane, Rekoske, Brian, Liu, Glenn, Melssen, Marit, Grosh, William, Varhegyi, Nikole, Galeassi, Nadejda, Deacon, Donna H., Gaughan, Elizabeth, Ghisoli, Maurizio, Barve, Minal, Mennel, Robert, Wallraven, Gladice, Manning, Luisa, Senzer, Neil, Nemunaitis, John, Ogasawara, Masahiro, Ota, Shuichi, Peace, Kaitlin M., Hale, Diane F., Vreeland, Timothy J., Jackson, Doreen O., Berry, John S., Trappey, Alfred F., Herbert, Garth S., Clifton, Guy T., Hardin, Mark O., Toms, Anne, Qiao, Na, Litton, Jennifer, Peoples, George E., Mittendorf, Elizabeth A., Ghamsari, Lila, Flano, Emilio, Jacques, Judy, Liu, Biao, Havel, Jonathan, Makarov, Vladimir, Chan, Timothy A., Flechtner, Jessica B., Facciponte, John, Ugel, Stefano, De Sanctis, Francesco, Coukos, George, Paris, Sébastien, Pottier, Agnes, Levy, Laurent, Lu, Bo, Cappuccini, Federica, Pollock, Emily, Bryant, Richard, Hamdy, Freddie, Hill, Adrian, Redchenko, Irina, Sultan, Hussein, Kumai, Takumi, Fesenkova, Valentyna, Celis, Esteban, Fernando, Ingrid, Palena, Claudia, David, Justin M., Gabitzsch, Elizabeth, Jones, Frank, Gulley, James L., Herranz, Mireia Uribe, Wada, Hiroshi, Shimizu, Atsushi, Osada, Toshihiro, Fukaya, Satoshi, Sasaki, Eiji, Abolhalaj, Milad, Askmyr, David, Lundberg, Kristina, Albrekt, Ann-Sofie, Greiff, Lennart, Lindstedt, Malin, Flies, Dallas B., Higuchi, Tomoe, Ornatowski, Wojciech, Harris, Jaryse, Adams, Sarah F., Aguilera, Todd, Rafat, Marjan, Castellini, Laura, Shehade, Hussein, Kariolis, Mihalis, Jang, Dadi, vonEbyen, Rie, Graves, Edward, Ellies, Lesley, Rankin, Erinn, Koong, Albert, Giaccia, Amato, Ajina, Reham, Wang, Shangzi, Smith, Jill, Pierobon, Mariaelena, Jablonski, Sandra, Petricoin, Emanuel, Weiner, Louis M., Sherry, Lorcan, Waller, John, Anderson, Mark, Bigley, Alison, Bernatchez, Chantale, Haymaker, Cara, Kluger, Harriet, Tetzlaff, Michael, Jackson, Natalie, Gergel, Ivan, Tagliaferri, Mary, Hwu, Patrick, Snzol, Mario, Hurwitz, Michael, Barberi, Theresa, Martin, Allison, Suresh, Rahul, Barakat, David, Harris-Bookman, Sarah, Drake, Charles, Friedman, Alan, Berkey, Sara, Downs-Canner, Stephanie, Edwards, Robert P., Curiel, Tyler, Odunsi, Kunle, Bruno, Tullia C., Moore, Brandon, Squalls, Olivia, Ebner, Peggy, Waugh, Katherine, Mitchell, John, Franklin, Wilbur, Merrick, Daniel, McCarter, Martin, Palmer, Brent, Kern, Jeffrey, Vignali, Dario, Slansky, Jill, Chan, Anissa S. H., Qiu, Xiaohong, Fraser, Kathryn, Jonas, Adria, Ottoson, Nadine, Gordon, Keith, Kangas, Takashi O., Leonardo, Steven, Ertelt, Kathleen, Walsh, Richard, Uhlik, Mark, Graff, Jeremy, Bose, Nandita, Gupta, Ravi, Mandloi, Nitin, Paul, Kiran, Patil, Ashwini, Sathian, Rekha, Mohan, Aparna, Manoharan, Malini, Chaudhuri, Amitabha, Chen, Yu, Lin, Jing, Ye, Yun-bin, Xu, Chun-wei, Chen, Gang, Guo, Zeng-qing, Komarov, Andrey, Chenchik, Alex, Makhanov, Michael, Frangou, Costa, Zheng, Yi, Coltharp, Carla, Unfricht, Darryn, Dilworth, Ryan, Fridman, Leticia, Liu, Linying, Rajopadhye, Milind, Miller, Peter, Concha-Benavente, Fernando, Bauman, Julie, Trivedi, Sumita, Srivastava, Raghvendra, Ohr, James, Heron, Dwight, Duvvuri, Uma, Kim, Seungwon, Torrey, Heather, Mera, Toshi, Okubo, Yoshiaki, Vanamee, Eva, Foster, Rosemary, Faustman, Denise, Stack, Edward, Izaki, Daisuke, Beck, Kristen, Jia, Dan Tong, Armenta, Paul, White-Stern, Ashley, Marks, Douglas, Taback, Bret, Horst, Basil, Glickman, Laura Hix, Kanne, David B., Gauthier, Kelsey S., Desbien, Anthony L., Francica, Brian, Leong, Justin L., Sung, Leonard, Metchette, Ken, Kasibhatla, Shailaja, Pferdekamper, Anne Marie, Zheng, Lianxing, Cho, Charles, Feng, Yan, McKenna, Jeffery M., Tallarico, John, Bender, Steven, Ndubaku, Chudi, McWhirter, Sarah M., Gugel, Elena Gonzalez, Bell, Charles J. M., Munk, Adiel, Muniz, Luciana, Bhardwaj, Nina, Zhao, Fei, Evans, Kathy, Xiao, Christine, Holtzhausen, Alisha, Hanks, Brent A., Scholler, Nathalie, Yin, Catherine, Van der Meijs, Pien, Prantner, Andrew M., Krejsa, Cecile M., Smith, Leia, Johnson, Brian, Branstetter, Daniel, Stein, Paul L., Jaen, Juan C., Tan, Joanne BL, Chen, Ada, Park, Timothy, Powers, Jay P., Sexton, Holly, Xu, Guifen, Young, Steve W., Schindler, Ulrike, Deng, Wentao, Klinke, David John, Komar, Hannah M., Serpa, Gregory, Elnaggar, Omar, Hart, Philip, Schmidt, Carl, Dillhoff, Mary, Jin, Ming, Ostrowski, Michael C., Koti, Madhuri, Au, Katrina, Peterson, Nichole, Truesdell, Peter, Reid-Schachter, Gillian, Graham, Charles, Craig, Andrew, Francis, Julie-Ann, Kotlan, Beatrix, Balatoni, Timea, Farkas, Emil, Toth, Laszlo, Ujhelyi, Mihaly, Savolt, Akos, Doleschall, Zoltan, Horvath, Szabolcs, Eles, Klara, Olasz, Judit, Csuka, Orsolya, Kasler, Miklos, Liszkay, Gabriella, Barnea, Eytan, Blakely, Collin, Flynn, Patrick, Goodman, Reid, Bueno, Raphael, Sugarbaker, David, Jablons, David, Broaddus, V. Courtney, West, Brian, Kunk, Paul R., Obeid, Joseph M., Winters, Kevin, Pramoonjago, Patcharin, Stelow, Edward B., Bauer, Todd W., Rahma, Osama E., Lamble, Adam, Kosaka, Yoko, Huang, Fei, Saser, Kate A., Adams, Homer, Tognon, Christina E., Laderas, Ted, McWeeney, Shannon, Loriaux, Marc, Tyner, Jeffery W., Druker, Brian J., Lind, Evan F., Liu, Zhuqing, Lu, Shanhong, Kane, Lawrence P., Shayan, Gulidanna, Femel, Julia, Lane, Ryan, Booth, Jamie, Lund, Amanda W., Rodriguez, Anthony, Engelhard, Victor H., Metelli, Alessandra, Wu, Bill X., Fugle, Caroline W., Saleh, Rachidi, Sun, Shaoli, Wu, Jennifer, Liu, Bei, Li, Zihai, Morris, Zachary S., Guy, Emily I., Heinze, Clinton, Kler, Jasdeep, Gressett, Monica M., Werner, Lauryn R., Gillies, Stephen D., Korman, Alan J., Loibner, Hans, Hank, Jacquelyn A., Rakhmilevich, Alexander L., Harari, Paul M., Sondel, Paul M., Huelsmann, Erica, Broucek, Joseph, Brech, Dorothee, Straub, Tobias, Irmler, Martin, Beckers, Johannes, Buettner, Florian, Schaeffeler, Elke, Schwab, Matthias, Noessner, Elfriede, Wolfreys, Alison, Da Costa, Andre, Silva, John, Crosby, Andrea, Staelens, Ludovicus, Craggs, Graham, Cauvin, Annick, Mason, Sean, Paterson, Alison M., Lake, Andrew C., Armet, Caroline M., O’Connor, Rachel W., Hill, Jonathan A., Normant, Emmanuel, Adam, Ammar, Biniszkiewicz, Detlev M., Chappel, Scott C., Palombella, Vito J., Holland, Pamela M., Becker, Annette, Leleti, Manmohan R., Newcomb, Eric, Tan, Joanne B. L., Rapisuwon, Suthee, Radfar, Arash, Gardner, Kellie, Gibney, Geoffrey, Atkins, Michael, Rennier, Keith R., Crowder, Robert, Wang, Ping, Pachynski, Russell K., Carrero, Rosa M. Santana, Rivas, Sarai, Beceren-Braun, Figen, Anthony, Scott, Schluns, Kimberly S., Sawant, Deepali, Chikina, Maria, Yano, Hiroshi, Workman, Creg, Salerno, Elise, Mauldin, Ileana, Deacon, Donna, Shea, Sofia, Pinczewski, Joel, Gajewski, Thomas, Spranger, Stefani, Horton, Brendan, Suzuki, Akiko, Leland, Pamela, Joshi, Bharat H., Puri, Raj K., Sweis, Randy F., Bao, Riyue, Luke, Jason, Theodoraki, Marie-Nicole, Mogundo, Frances-Mary, Won, Haejung, Moreira, Dayson, Gao, Chan, Zhao, Xingli, Duttagupta, Priyanka, Jones, Jeremy, D’Apuzzo, Massimo, and Pal, Sumanta

Subjects
Meeting Abstracts
Published
2016

46. Individual mouse analysis of the cellular immune response to tumor antigens in peripheral blood by intracellular staining for cytokines

Author

Nicola La Monica, Patrizia Giannetti, Luigi Aurisicchio, and Andrea Facciabene

Subjects
Genetically modified mouse, Cellular immunity, T-Lymphocytes, Immunology, Enzyme-Linked Immunosorbent Assay, Mice, Transgenic, Spleen, Biology, Sensitivity and Specificity, Immune tolerance, Interferon-gamma, Mice, Immune system, Antigen, medicine, Animals, Immunology and Allergy, education, Mice, Inbred BALB C, education.field_of_study, Staining and Labeling, Tumor Necrosis Factor-alpha, Reproducibility of Results, Flow Cytometry, Animal euthanasia, Carcinoembryonic Antigen, Mice, Inbred C57BL, Lymphatic system, medicine.anatomical_structure, Interleukin-2, Fluorescein-5-isothiocyanate
Abstract

Among the experimental animal models, mice remain the most widely used for the evaluation of immunotherapeutic strategies. Vaccines against parasites and viral antigens are commonly administered to the appropriate mouse strain which also allows testing of the therapeutic effect. Similarly, in mice transgenic for human tumor associated antigens (TAA), cancer vaccines must lead to breakage of immune tolerance to elicit a significant effect on the tumor. However, one of the major drawbacks in the monitoring of cellular immune responses induced by vaccination is that functional immunological assays require suppression of the animals to collect the spleen or lymph nodes for analysis. Here, we report the application of a rapid intracellular staining (ICS) method to quantify antigen-specific T cells responses in small volumes of murine blood. Genetic vaccination with plasmid DNA followed by electroporation (DNA-EP) and the use of adenoviral vectors (Ad) encoding CEA as a model target antigen were applied to different strains of mice. Optimal blood volume, number of lymphocytes, sensitivity and reproducibility of intracellular staining for IFN-gamma were determined both in non-tolerant/wild type mice as well as in tolerant CEA transgenic mice upon restimulation of PBMCs with CEA peptides. Groups of vaccinated mice were then sacrificed and PBMCs and splenocytes from individual animals were compared for intracytoplasmic detection of IFN-gamma and TNF-alpha. A significant correlation was observed between splenic and blood immune responses. Finally, the cellular immune response was followed over time in groups of vaccinated mice. The kinetics of IFN-gamma producing effectors were measured after priming and successive boosting with adenoviral vectors. We show that intracellular staining for mouse PBMCs is a rapid and simple method to measure antigen-specific immune responses. It does not require animal euthanasia and mirrors the response observed in lymphoid organs such as the spleen.

Published
2006
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47. A Tumor Mitochondria Vaccine Protects against Experimental Renal Cell Carcinoma

Author

Janos L. Tanyi, Jialing Huang, Mireia Uribe-Herranz, Chongyun Fang, Stavros Rafail, Francesco De Sanctis, Andrea Facciabene, Stefano Pierini, John G. Facciponte, and Mark A. Morgan

Subjects
Mitochondrial DNA, Somatic cell, medicine.medical_treatment, Immunology, Mitochondrion, Biology, Cancer Vaccines, Mitochondrial Proteins, Experimental, Mice, Immune system, Cancer immunotherapy, Antigen, Antigens, Neoplasm, Neoplasms, medicine, Immunology and Allergy, Cytotoxic T cell, Animals, Antigens, Carcinoma, Renal Cell, Inbred BALB C, Cyclooxygenase 1, Kidney Neoplasms, Membrane Proteins, Mice, Inbred BALB C, NADH Dehydrogenase, Neoplasms, Experimental, Carcinoma, Renal Cell, Dendritic cell, Molecular biology, Cancer research, Neoplasm
Abstract

Mitochondria provide energy for cells via oxidative phosphorylation. Reactive oxygen species, a byproduct of this mitochondrial respiration, can damage mitochondrial DNA (mtDNA), and somatic mtDNA mutations have been found in all colorectal, ovarian, breast, urinary bladder, kidney, lung, and pancreatic tumors studied. The resulting altered mitochondrial proteins or tumor-associated mitochondrial Ags (TAMAs) are potentially immunogenic, suggesting that they may be targetable Ags for cancer immunotherapy. In this article, we show that the RENCA tumor cell line harbors TAMAs that can drive an antitumor immune response. We generated a cellular tumor vaccine by pulsing dendritic cells with enriched mitochondrial proteins from RENCA cells. Our dendritic cell–based RENCA mitochondrial lysate vaccine elicited a cytotoxic T cell response in vivo and conferred durable protection against challenge with RENCA cells when used in a prophylactic or therapeutic setting. By sequencing mtDNA from RENCA cells, we identified two mutated molecules: COX1 and ND5. Peptide vaccines generated from mitochondrial-encoded COX1 but not from ND5 had therapeutic properties similar to RENCA mitochondrial protein preparation. Thus, TAMAs can elicit effective antitumor immune responses, potentially providing a new immunotherapeutic strategy to treat cancer.

Published
2015

48. Maternal CD8+T-cell depletion alleviates intrauterine inflammation-induced perinatal brain injury

Author

Nader Alhejaily, Irina Burd, Jason M. Rosenzweig, Wael Alshehri, Christopher M. Novak, Hongxi Zhao, Jun Lei, Julia L. Clemens, Andrea Facciabene, Candice Gard, Li Xie, Maide Ozen, Mia C. Feller, Michael W. McLane, and Yahya Shabi

Subjects
0301 basic medicine, Lipopolysaccharide, Offspring, Immunology, CCL5, Andrology, 03 medical and health sciences, chemistry.chemical_compound, symbols.namesake, 0302 clinical medicine, Immune system, Placenta, medicine, Immunology and Allergy, Cytotoxic T cell, 030219 obstetrics & reproductive medicine, business.industry, Obstetrics and Gynecology, respiratory system, 030104 developmental biology, medicine.anatomical_structure, Reproductive Medicine, chemistry, Nissl body, symbols, business, CD8
Abstract

We investigated the mechanisms by which CD8+ T-cell trafficking in placenta contributes to perinatal brain injury by studying effects of maternal CD8+ T-cell depletion (DEP) in a mouse model of intrauterine inflammation (IUI). Maternal CD8+ T cells were depleted with anti-CD8+ antibodies. IUI was induced with lipopolysaccharide (LPS). DEP was confirmed using flow cytometry. Preterm birth rate was evaluated. Offspring neurologic sequelae were assessed by Nissl staining, immune arrays, confirmatory individual TaqMan® gene assays, and neurobehavioral tests. DEP did not significantly prevent LPS-induced preterm birth but improved neurobehavioral performance (P

Published
2017
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49. Abstract LB-178: The impact of the gut microbiome on the antitumor effects of radiotherapy

Author

Costas Koumenis, Stefano Pierini, Andrea Facciabene, Iannis Verginadis, Amit Maity, Stavros Rafail, Kile Bittinger, and Mireia Uribe-Herranz

Subjects
0301 basic medicine, Cancer Research, T cell, medicine.medical_treatment, Antigen presentation, Cancer, Immunotherapy, Biology, medicine.disease, 03 medical and health sciences, 030104 developmental biology, medicine.anatomical_structure, Immune system, Oncology, Immunology, medicine, Cytotoxic T cell, Lung cancer, CD8
Abstract

The sheer enormity of the microbial biomass in the human intestinal tract, the co-evolution between humans and the microbiota, and the established function of the gut microbes in regulating normal host physiologic functions, are all consistent with the idea that alterations in gut microbial ecology play a role in the pathophysiology of several conditions including cancer. Radiotherapy (RT) is an established curative and palliative cancer treatment regimen, with approximately half of cancer patients with solid tumors receiving RT some time during their disease. Mounting evidence also suggests that high-dose (hypofractionated) radiation exerts potent immune modulatory effects, prompting immunological active tumor cell death inducing tumor associated antigen (TAA) cross priming with elicitation of anti-tumor CD8+ T cells, and abscopal effects. Although there have been groundbreaking responses to immunotherapy in certain malignancies such as lung cancer and melanomas, so far, immunotherapy is effective only in a portion of patients19. This raises the issue of whether there are additional important regulators of T cell function that are relevant to tumor control and could be harnessed to enhance radiotherapy. In support of this hypothesis, we have generated preliminary results demonstrating that: a) Treatment with vancomycin, an antibiotic with action in the gut mostly against Gram+ bacteria, significantly increased the presence of overall tumor infiltrating T cells or cytotoxic CD8+ cells in tumors from mice treated with RT/vancomycin combination compared to RT alone; b) vancomycin caused a significant enhancement of the tumor inhibitory effect of targeted radiation. c) Vancomycin enhanced the ability of RT to increase the expression of IFN-g in CD8+ infiltrating T cells and antigen presentation in the tumor draining lymph nodes and d) the observed synergy between vancomycin and RT in eliciting an anti-tumor immune response and inhibiting tumor growth was abrogated in IFN-g KO animals or by CD8+ cell depletion. Citation Format: Andrea Facciabene, Stavros Rafail, Mireia Uribe-Herranz, Stefano Pierini, Kile Bittinger, Iannis Verginadis, Costas Koumenis, Amit Maity. The impact of the gut microbiome on the antitumor effects of radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-178. doi:10.1158/1538-7445.AM2017-LB-178

Published
2017
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50. A Protocol to Guide Development of a Sensitive ELISA for Canine Erythropoietin

Author

Andrea Facciabene, Carmela Mennuni, and Saverio Giampaoli

Subjects
medicine.drug_class, Enzyme-Linked Immunosorbent Assay, Gene electrotransfer, Cross Reactions, Monoclonal antibody, Sensitivity and Specificity, Antibodies, law.invention, HeLa, Mice, Dogs, Antigen, law, hemic and lymphatic diseases, medicine, Animals, Humans, Dog Diseases, Erythropoietin, General Veterinary, biology, business.industry, Gene Transfer Techniques, Antibodies, Monoclonal, biology.organism_classification, Molecular biology, Polyclonal antibodies, Recombinant DNA, biology.protein, Kidney Failure, Chronic, Rabbits, Antibody, business, HeLa Cells, medicine.drug
Abstract

Background: The determination of canine erythropoietin (EPO) concentration is crucial for monitoring the effect of human recombinant (hr) EPO therapy in dogs with chronic renal failure. Current assays are not specific for canine EPO and not sensitive enough to detect physiologic EPO levels in dogs. Objective: The objective of this study was to develop a simple and sensitive ELISA for canine EPO that could serve as a starting point for developing a commercially available assay. Methods: The ELISA was based on a mouse monoclonal antibody (mAb) and a rabbit polyclonal antibody (pAb) using 2 different immunization techniques: gene electrotransfer (GET) to generate the pAb and multiple antigen peptides (MAPs) to generate the mAb. The ELISA was performed using both EPO obtained from HeLa cells transfected with an expression plasmid encoding canine EPO and canine plasma with known concentrations of EPO. Results: The ELISA standard curve was linear for canine EPO concentrations of 7–66 mU/ml. Coefficients of variation were about 10%. No cross-reactivity between canine EPO and hrEPO was detected. Conclusions: Using novel GET and MAP technology, we developed a sensitive and specific ELISA for canine EPO that can be used to guide future clinical applications for EPO detection and monitoring in dogs.

Published
2003
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