Timing of PD-L1 Blockade with Durvalumab May Affect Outcomes of CD19 CAR-T Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma

Introduction CD19-targeted chimeric antigen receptor T (CAR-T) cell therapy has shown high overall response rates (ORRs) in patients (pts) with relapsed/refractory (R/R) large B-cell lymphoma (LBCL); however, CD19 CAR-T cells fail to elicit a complete response (CR) in a considerable proportion of pts. PD-L1 expression in the tumor microenvironment could impair the efficacy of CAR-T cell therapy. PD-1/PD-L1 pathway blockade may enhance the function and antitumor activity of CAR-T cells. Here, we report the analysis of a phase I dose-finding study (NCT02706405) of combination therapy with CD19-targeted 4-1BB-costimulated CAR-T cells (JCAR014) and escalating doses of durvalumab (durva), an anti-PD-L1 monoclonal antibody, in adults with R/R LBCL.

Methods Pts were treated in 1 of 2 groups. All pts received lymphodepletion (LD) with cyclophosphamide (Cy) and fludarabine (Flu) followed by JCAR014 infusion. Pts in group 1 (Grp 1) received the first dose of durva (225 mg or 750 mg) after JCAR014 infusion. Pts in group 2 (Grp 2) received the first dose of durva (7.5 mg, 22.5 mg, 75 mg, 225 mg, or 750 mg) 1 day prior to JCAR014 infusion. Up to 10 doses of durva were administered at 4-week intervals after JCAR014 at the highest identified safe dose until toxicity or disease progression. Adverse events (AEs) were graded by CTCAE 4.03, except for cytokine release syndrome (CRS), which was graded according to Lee 2014 consensus criteria. Response was reported according to PET/CT 2014 Lugano criteria.

Results Between 01/23/2017 and 07/02/2020, 34 pts were screened, 32 underwent leukapheresis, and 29 were enrolled and received LD and JCAR014. Eleven pts were treated in Grp 1 and 18 in Grp 2 (Table 1). All pts received 2 x 10⁶ JCAR014 cells/kg, except for the first 2 pts treated on the study who received 7 x 10⁵ cells/kg. The most common AEs of any grade related to LD and JCAR014 with or without durva were CRS (41%), neutropenia (21%), neurotoxicity (17%), and hypogammaglobulinemia (17%). The incidences of any grade and grade ≥ 3 CRS and neurotoxicity were similar between Grp 1 and Grp 2 (Table 2A). Patients in Grp 2 had later onset of CRS after JCAR014 infusion compared with Grp 1 (median of 6 vs. 4 days, P = .05) and shorter duration of CRS (median of 3 vs. 8 days, P = .08). Among the 27 pts evaluable for dose-limiting toxicity (DLT), 2 (7%) had DLT: 1 pt with grade 4 CRS in Grp 2 (durva 225 mg) and 1 pt with prolonged grade 3 neurotoxicity in Grp 2 (durva 750 mg). No maximum-tolerated dose of durva was identified.

In pts evaluable for response (n = 26), the ORR and the CR rate at 3 months were 35% (95% CI, 17-56) and 27% (95% CI, 14-46). We retrospectively compared the response rates of LBCL pts treated with JCAR014 in combination with durva (NCT02706405) with LBCL pts who received the same Cy/Flu lymphodepletion regimen and JCAR014 dose (2 x 10⁶ cells/kg) without durva (JCAR014 alone cohort) on our previous phase I/II clinical trial (NCT01865617). There was a trend towards lower ORR (P = .08) and CR rate (P = .09) in pts treated with JCAR014 in combination with durva compared with those treated in the JCAR014 alone cohort (Table 2B). There were no significant differences in ORR and CR rate between patients in Grp 1 and those who received JCAR014 alone. However, despite a trend towards lower tumor burden, pts in Grp 2 (first durva before JCAR014) had lower ORR (P = .07) and CR rate (P = .03) compared with those treated in the JCAR014 alone cohort, and a trend towards lower CR rate compared with those treated in Grp 1 (first durva after JCAR014; P = .16). Patients treated with JCAR014 alone had significantly shorter time to CAR-T cell peak counts in blood compared with patients treated with JCAR014 in combination with durva (median of 8 vs. 14 days, P = .01). We did not observe significant differences in peak CAR-T cell expansion, area under the curve (AUC) from day 0 to 28 after JCAR014 infusion, and day 28 CAR-T cell counts by qPCR between the cohorts.

Conclusion The combination of JCAR014 with durva for the treatment of adult pts with LBCL was safe. Our findings suggest that the timing of initiation of durva therapy is a key variable that may affect outcomes. To our knowledge, this is the first report suggesting that PD-L1 blockade may impact toxicity and antitumor response in pts with LBCL undergoing CD19 CAR-T cell therapy. Additional studies will be required to determine the optimal approach for combining CD19 CAR-T cell therapy with PD-1/PD-L1 pathway blockade in LBCL.

Vinaud Hirayama:Nektar Therapeutics: Research Funding; Juno Therapeutics, a BMS Company: Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Fiorenza:Bristol Myers Squibb: Patents & Royalties, Research Funding. Gauthier:Celgene (A BMS Company): Research Funding; Multerra Bio: Consultancy; Kite Pharma: Consultancy; Sobi: Research Funding; Legend Biotech: Consultancy; Juno Therapeutics - A BMS Company: Research Funding. Kimble:Juno Therapeutics, a BMS company: Research Funding. Cassaday:Autolus: Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company: Consultancy, Research Funding; Merck: Research Funding; Servier: Research Funding; Vanda: Research Funding; Pepromene Bio: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Seagen: Current Employment, Current equity holder in private company, Other: Spouse employment with Seagen; stock or other ownership in Seagen.; Jazz: Consultancy. Chapuis:Juno Therapeutics, a BMS company: Patents & Royalties, Research Funding; Adaptive Biotechnologies Corporation: Patents & Royalties. Green:SpringWorks Therapeutics: Research Funding; Neoleukin Theraeutics: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Patents & Royalties, Research Funding; Janssen Biotech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Cellectar Biosciences: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Legend Biotech: Consultancy; GSK: Membership on an entity's Board of Directors or advisory committees. Kiem:Rocket Pharmaceuticals: Consultancy; Homology Medicines: Consultancy; VOR Biopharma: Consultancy; Ensoma: Consultancy. Shadman:Epizyme: Consultancy; Morphosys/Incyte: Consultancy, Research Funding; Regeneron: Consultancy; MEI Pharma: Consultancy; Fate Therapeutics: Consultancy; Merck: Consultancy; Mustang Bio: Consultancy, Research Funding; Adaptimmune: Consultancy; Epi Lilly: Consultancy; Adaptive Biotechnologies: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Sound Biologics: Consultancy; Kite Pharma: Consultancy; Innate Pharma: Consultancy; TG Therapeutics: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Atara Biotherapeutic: Consultancy, Research Funding; Celgene, a BMS Company: Research Funding; Gilead: Research Funding; Sunesis: Research Funding; Genmab: Research Funding. Till:BMS/Celgene: Research Funding; Proteios Technology: Consultancy; Mustang Bio: Consultancy, Patents & Royalties, Research Funding. Riddell:Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Lyell Immunopharma: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Other: Founder, Patents & Royalties; Nohla: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics, a BMS Company: Current equity holder in publicly-traded company, Patents & Royalties. Maloney:A2 Biotherapeutics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Data Safety Monitory Board , Research Funding; Genentech: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Legand Biotech: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Mustang Bio: Consultancy, Honoraria; Navan Technologies: Consultancy, Current holder of stock options in a privately-held company, Honoraria; Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Umoja: Consultancy, Honoraria; Bioline Rx: Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitory Board ; Fred Hutch: Patents & Royalties: For Patients licensed to Juno ; A2 Biotherapeutics: Current holder of stock options in a privately-held company. Turtle:Kite Pharma, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Caribou Bioscience: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Eureka Therapeutics: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Precision Bioscience: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Decheng Capital: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics, a BMS Company: Patents & Royalties, Research Funding; T-CURX: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Century Therapeutics: Membership on an entity's Board of Directors or advisory committees; Arsenal Bio: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Myeloid Therapeutics: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Expert Connect: Consultancy; Allogene: Membership on an entity's Board of Directors or advisory committees; Prescient Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Anti-PD-L1 monoclonal antibody durvalumab in combination with CD19 CAR-T cells.