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4198 Sequential Anti-CD19 Directed Chimeric Antigen Receptor Modified T-Cell Therapy (CART19) and PD-1 Blockade with Pembrolizumab in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphomas

Program: Oral and Poster Abstracts
Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials: Poster III
Hematology Disease Topics & Pathways:
Biological, Diseases, Therapies, CAR-Ts, Non-Hodgkin Lymphoma, checkpoint inhibitors, Technology and Procedures, B-Cell Lymphoma, gene therapy, cell expansion, immunotherapy, Lymphoid Malignancies, Clinically relevant
Monday, December 3, 2018, 6:00 PM-8:00 PM
Hall GH (San Diego Convention Center)

Elise A. Chong, MD1, Jakub Svoboda, MD1, Sunita Dwivedy Nasta, MD1, Daniel J. Landsburg, MD1, Nicole Winchell1*, Ellen Napier, NP1*, Anthony R. Mato, MD MSCE2, J. Joseph Melenhorst, PhD3, Marco Ruella, MD3,4, Simon F Lacey, PhD, BS3, Carl H June, MD5 and Stephen J. Schuster, MD1

1Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
2CLL Program, Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY
3Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA
4Center for Cellular Immunotherapies and Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA
5Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

Introduction: Chimeric antigen receptor modified T cells directed against CD19 (CART19) achieve durable remissions in about 30-40% of relapsed or refractory (r/r) diffuse large B cell lymphoma (DLBCL); this led to recent FDA approvals of tisagenlecleucel (Schuster NEJM 2017, Schuster ASH 2017) and axicabtagene ciloleucel (Neelapu NEJM 2017). Despite this, about two-thirds of pts will not achieve a durable remission and there remains a need for effective therapies for these pts. CAR T cell exhaustion and an immunosuppressive tumor-microenvironment are considered possible causes of CAR T cell failure. Pembrolizumab, an anti-PD1 immune checkpoint inhibitor, is an attractive option following CAR T-cell therapy to reverse T cell exhaustion (Chong, Blood 2017). In this trial, pembrolizumab was administered to pts with B-cell lymphomas (NHL) with progressive or relapsed disease at various points in time after CART19, including during early progression (non-responders) or late relapse after CART19. Thus, this study provides important insights into the timing and ability of pembrolizumab to stimulate CAR T cells.

Methods: This prospective single-institution trial enrolled pts with progressive or relapsed NHL after treatment with CART19 expressing either a murine (CTL019) or a humanized (CTL119) CD19-specific single chain antibody fragment fused in tandem with 4-1BB and CD3ζ costimulatory / activation domains (NCT02650999). Pts who received intervening therapy between CART19 infusion and screening were excluded. Pts received fixed dose pembrolizumab 200mg IV every 3 weeks until progression of disease, therapy limiting-toxicity, or elective protocol discontinuation. The primary endpoint was safety. Secondary endpoints included clinical outcomes.

Results: From June 1, 2016 to June 4, 2018, 12 pts who received CART19 for r/r NHL on other clinical trials (NCT02030834; NCT02445248) were enrolled with progressive disease (N=8) or relapse (N=4) following CART19. 11 pts had DLBCL [4 germinal center (3 “double/triple hit”), 4 non-germinal center;1 T-cell rich DLBCL; 1 transformed FL; 1 primary mediastinal B-cell lymphoma] and 1 pt had follicular lymphoma (FL). Median age was 58 years (range: 30-78 years). Median number of prior therapies was 4 (range 3-8). Median PFS after CART19 was 2.2 months (range: 0.4-3.2 months); median time to first pembrolizumab dose was 3.3 months (range: 0.4-42.8 months). After pembrolizumab, adverse events (CTCAE 4.0) per patient at least possibly related were: neutropenia (grade 3/4; N=3), cytokine release syndrome (grade 3 on Penn scale; N=1), infusion reaction (grade 2; N=1), fever (grade 1/2; N=2), fatigue (grade 1/2; N=2), pleural effusion (grade 1, N=1), arthralgia (grade 1; N=1). One patient developed CMV infection (unrelated; grade 4) resulting in discontinuation of protocol therapy. Eleven pts are evaluable for response. Best ORR after pembrolizumab was 27% [1 complete response (CR); 2 partial response (PR)]; 1 pt had stable disease, and 7 pts had progressive disease. One patient with germinal center DLBCL continues in CR at 20 months; one patient with T-cell rich DLBCL in PR was removed from study because of CMV pneumonitis. 9/12 pts showed a re-expansion peak in peripheral blood CART19 cells (CART19 transgene copy number) after the first pembrolizumab dose between days 2 and 14 (median 3 days). Maximum CAR transgene copy number during therapy did not correlate with response; however, responding pts had more than one re-expansion peak during pembrolizumab while non-responding pts had only a single re-expansion peak or no expansion following the initial dose of pembrolizumab. Of the 3 pts without CART19 post-pembrolizumab expansion, 2 pts had relapsed disease after sustained CR following CART19 and 1 pt was CART19 refractory.

Conclusions: PD1 blockade with pembrolizumab appears safe and results in clinical responses in a subset of pts with progression of NHL after anti-CD19 directed CART cell therapy. Analysis of the pharmacokinetics of CAR T-cells in pts treated with pembrolizumab appears to identify responding pts and supports the hypothesis that, in some pts, CAR T cells expand following PD1 blockade. Additional studies examining the immunophenotype of CAR T cells in detail are in progress and will be presented.

Disclosures: Chong: Novartis: Consultancy. Svoboda: Seattle Genetics: Consultancy, Research Funding; Kyowa: Consultancy; TG Therapeutics: Research Funding; KITE: Consultancy; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Regeneron: Research Funding. Dwivedy Nasta: Debiopharm: Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding; Rafael/WF: Research Funding; Takeda/Millenium: Research Funding; Roche: Research Funding; Merck: Other: DSMC; Aileron: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Landsburg: Triphase: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Curis, INC: Consultancy, Research Funding. Mato: TG Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Acerta: Research Funding; AstraZeneca: Consultancy; Portola: Research Funding; Regeneron: Research Funding; Medscape: Honoraria; AbbVie: Consultancy, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; Prime Oncology: Honoraria; Johnson & Johnson: Consultancy. Melenhorst: Incyte: Research Funding; Parker Institute for Cancer Immunotherapy: Research Funding; Shanghai UNICAR Therapy, Inc: Consultancy; novartis: Patents & Royalties, Research Funding; Casi Pharmaceuticals: Consultancy. Ruella: Tmunity: Research Funding; Novartis: Research Funding; University of Pennsylvania: Patents & Royalties; Nanostring: Consultancy. Lacey: Parker Foundation: Research Funding; Tmunity: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding; Novartis Pharmaceuticals Corporation: Patents & Royalties. June: Celldex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Immune Design: Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Immune Design: Membership on an entity's Board of Directors or advisory committees. Schuster: Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Consultancy, Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH