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253 The Intestinal Microbiota Correlates with Response and Toxicity after CAR T Cell Therapy in Patients with B-Cell Malignancies

Program: Oral and Poster Abstracts
Type: Oral
Session: 704. Cellular Immunotherapies: Cellular Therapies-Immune Interactions, Lineage Switching and CNS targets
Hematology Disease Topics & Pathways:
Biological, ALL, Lymphoid Leukemias, Lymphomas, Translational Research, Chimeric Antigen Receptor (CAR)-T Cell Therapies, B Cell Lymphoma, Diseases, Microbiome, Therapies, Lymphoid Malignancies, Biological Processes
Saturday, December 11, 2021: 2:00 PM

Melody Smith, MD, MS1, Anqi Dai, MS2*, Guido Ghilardi, MD3*, Kimberly Amelsberg3*, Sean M Devlin, PhD4*, Raymone Pajarillo, MS3*, John B Slingerland5,6*, Silvia Beghi7*, Pamela S Herrera8*, Paul A Giardina6*, Annelie Clurman, BA6*, Emmanuel A Dwomoh8*, Gabriel K Armijo8*, Antonio L.C. Gomes, PhD9*, Eric R Littmann, BA10*, Jonas Schluter11*, Emily Fontana, BA12*, Ying Taur, MD, MPH13*, Jae H Park, MD14, Maria Lia Palomba15, Elizabeth Halton16*, Josel D Ruiz, MPH17*, Tania Jain, MD18, Martina Pennisi, MD19*, Aishat Olaide Afuye, BA20*, Miguel-Angel Perales, MD21, Craig W. Freyer, PharmD22*, Alfred L Garfall, MD23, Shannon H Gier, BS3*, Sunita Nasta, MD24,25, Daniel J Landsburg, MD24, James N Gerson, MD24, Jakub Svoboda, MD24, Justin Cross, PhD26*, Elise A Chong, MD24, Sergio A Giralt, MD27, Saar Gill, MD, PhD28, Isabelle Rivière, PhD29*, David L Porter, MD30, Stephen J Schuster, MD31, Michel Sadelain, MD, PhD32, Noelle V Frey, MD, MS33, Renier J Brentjens, MD, PhD14, Carl H June, MD3,34, Eric G Pamer, MD10*, Jonathan U Peled, MD35, Marco Ruella, MD36, Marcel van den Brink, MD, PhD17 and Andrea Facciabene, PhD37*

1Adult Bone Marrow Transplant Service and Cellular Therapeutics Center, Memorial Sloan-Kettering Cancer Center, New York, NY
2MSKCC, New York, NY
3Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA
4Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
5MSKcc, New York
6Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, NY
7University of Pennsylvania, Philadelphia, PA
8Memorial Sloan Kettering Cancer Center, New York, NY
9Xbiome, New York
10The Duchossois Family Institute, University of Chicago, Chicago, IL
11Department of Microbiology, New York University School of Medicine, New York
12Sloan Kettering Institute, Lucille Castori Center for Microbes, Inflammation & Cancer, Memorial Sloan Kettering Cancer Center, New York, NY
13Infectious Disease Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
14Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
15Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY
16Cellular Therapeutics Service, Memorial Sloan Kettering Cancer Center, New York, NY
17Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY
18Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD
19Division of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
20Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
21Adult Allogeneic Bone Marrow Transplantation, Memorial Sloan-Kettering Cancer Center, New York, NY
22Department of Pharmacy, Hospital of the University of Pennsylvania, Philadelphia, PA
23Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
24Department of Medicine, Division of Hematology/Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA
25The University of Pennsylvania, Philadelphia, PA
26Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan-Kettering Cancer Center, New York, NY
27Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York
28Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
29Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY
30Division of Hematology-Oncology/Department of Medicine, University of Pennsylvania, Philadelphia, PA
31Division of Hematology/Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA
32Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY
33Abramson Cancer Center, University of Pennsylvania, Narberth, PA
34Center for Cellular Immunotherapies (CCI), The University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA
35Adult Bone Marrow Transplant Service, MSKCC, New York, NY
36Division of Hematology-Oncology and Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA
37Center for Cellular Immunotherrapy (CCI), University of Pennsylvania, Philadelphia, PA

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= <0.001). A subgroup analysis of the patients with NHL also demonstrated decreased OS associated with P-I-M exposure whether the costimulatory domain was CD28 or 4-1BB (data not shown). Next, we queried whether patients exposed to P-I-M had more aggressive disease. We evaluated potential confounders for the findings in uni- and multi-variable models. Importantly, exposure to P-I-M remained a strong predictor of decreased OS (HR, 2.58; 95% CI, 1.55 – 4.3; p= <0.001) (Table 1). Exposure to P-I-M was also associated with increased ICANS (p= 0.023) but not CRS (p= 0.058) in patients in the combined NHL and ALL cohort as well as in patients with NHL (CRS: p= 0.154, ICANS: p= 0.002) (data not shown).

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= <0.001, Fig 1C). Finally, linear discriminant analysis effect size (LEfSe) identified an increased abundance of Lachnospiraceae, Ruminococcaceae, and Bacteroidaceae in patients who achieved a Day 100 complete response (CR) and those who experienced CAR-mediated toxicity (data not shown).

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.

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: Syneos Health: Research Funding; CTI Biopharma: Research Funding; CareDx: Other: for advisory board participation; Bristol Myers Squibb: Other: for advisory board participation; Targeted Healthcare Communications: Consultancy. 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: Carisma Therapeutics: Current holder of stock options in a privately-held company, Research Funding; Novartis: Other: licensed intellectual property, Research Funding; Interius Biotherapeutics: 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: ASH: Membership on an entity's Board of Directors or advisory committees; DeCart: Membership on an entity's Board of Directors or advisory committees; Tmunity: Patents & Royalties; Wiley and Sons Publishing: Honoraria; Genentech: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: 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; 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; American Society for Transplantation and Cellular Therapy: Honoraria. 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: Kite Pharma: Consultancy; Sana Biotechnology: Consultancy; Syndax Pharmaceuticals: Consultancy; Novartis: Research Funding. Brentjens: sanofi: Patents & Royalties; Caribou: Patents & Royalties; Gracell Biotechnologies, Inc: Consultancy, Ended employment in the past 24 months; BMS: Consultancy, Patents & Royalties, Research Funding. 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: Tmunity: Patents & Royalties; AbClon: Consultancy, Research Funding; BMS, BAYER, GSK: Consultancy; Novartis: 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 .

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*signifies non-member of ASH