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
Authors: Chong Elise A. , Svoboda Jakub , Dwivedy Nasta Sunita , Landsburg Daniel J. , Winchell Nicole , Napier Ellen , Mato Anthony R. , Melenhorst J. Joseph , Ruella Marco , Lacey Simon F , June Carl H , Schuster Stephen J. 
Published: October 2019

Abstract
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:Regeneron: Research Funding; Kyowa: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; TG Therapeutics: Research Funding; KITE: Consultancy; Pharmacyclics: Consultancy, 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:Curis: Consultancy, Research Funding; Takeda: Consultancy. 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:University of Pennsylvania: Patents & Royalties. 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.