CAR T-Cell Therapy for Relapsed or Refractory Large B-Cell Lymphoma Using a Fully Human CD19-Targeted Single Chain Variable Fragment: Results of a First-in-Human Phase I/II Study

Background T cells engineered with a CD19-targeted chimeric antigen receptor (CD19 CAR T cells) achieve high response rates in patients (pts) with relapsed or refractory (R/R) large B-cell lymphoma (LBCL). However, durable responses are only achieved in 30-40% of pts. Since we previously found CAR T cell rejection is associated with CD8+ T-cell responses directed against epitopes in the murine single chain variable fragment (scFv) of the CAR, we hypothesized a fully human scFv may enable better in vivo CAR T cell kinetics and lead to superior clinical outcomes. We report the results of 23 R/R LBCL pts treated with a first-in-human CAR T-cell therapy product comprising a fully human CD19-targeted scFv (JCAR021).

Methods Pts with R/R LBCL were enrolled between 2018 and 2022 on a phase I/II study (NCT03103971) at our institution. Pts who had previously received CD19 CAR T cell therapy were excluded. All patients received lymphodepletion (LD) with cyclophosphamide 300 mg/m²/d and fludarabine 30 mg/m²/d for 3 days, followed by JCAR021 infusion. Disease response was evaluated at day 28 after JCAR021 infusion per PET-CT Lugano criteria 2014. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to the Lee 2014 consensus criteria and the NCI CTCAE v4.03 criteria, respectively.

Results Twenty-three pts received JCAR021 at one of 3 dose levels (dose level [DL] 1, 7x10⁵ CAR T cells/kg, n=4; DL2, 2x10⁶ CAR T cells/kg, n=4; DL3, 7x10⁶ CAR T cells/kg, n=15). LBCL histologies included diffuse large B-cell lymphoma, not otherwise specified (n=11, 48%); double-hit high-grade B-cell lymphoma (n=2, 8%), transformed LBCL from indolent histology (n=7, 31%), other (n=3, 13%). Prior to LD, median LDH was 185UI/L (range: 102-1670), the median cross-sectional tumor area was 3210mm² (range 162-18090), 19 pts (83%) had extra-nodal disease, and 11 (48%) had bulky disease (largest lesion ≥5cm). Median prior lines of therapy (excluding hematopoietic cell transplant [HCT]) was 3 (range: 2-7). Four (17%) pts had received prior autologous HCT and 1 an allogenic HCT.

In the toxicity-evaluable set (n=22), we observed CRS in 17 (77%; grade 3, 4%) and ICANS in 16 pts (72%; grade 3, 45%). ICANS had fully resolved by day 28 in all but 1 pt, who had the only dose-limiting toxicity in the study (spinal cord edema and paraplegia).

In the efficacy-evaluable set (n=23), the overall (OR) and complete response (CR) rates at day 28 were 74% and 52%, respectively. After a median follow-up of 15 months, the 12-month progression-free survival (PFS) and overall survival (OS) were 43% and 86%, respectively. In pts in CR at day 28, the 12-month PFS was 71% (Figure A). In responders with subsequent disease progression, CD19 expression was confirmed in 3 of 3 of pts with available data (100%).

In pts treated at the recommended phase 2 dose [RP2D] (DL3, n=15), the OR and CR rates were 87% and 67%, respectively; this was superior to the response rates observed at lower CAR T cell doses (DL1, ORR, 50%; CR, 25%; DL2, ORR, 50%; CR, 25%). The 12-month PFS and OS in pts treated at the RP2D were 47% and 86%, respectively (PFS in CR pts at the RP2D, 64%).

With advances in toxicity management, a higher RP2D was reached for JCAR021 (7x10⁶ CAR T cells/kg) in NCT03103971 compared to JCAR014 (2x10⁶ CAR T cells/kg), a murine scFv-containing CD19 CAR T cell product used in a previous trial (NCT01865617) at our institution. We compared the 15 pts treated at the JCAR021 RP2D with 17 pts treated at the JCAR014 RP2D with the same LD. Consistent with the higher JCAR021 RP2D compared to JCAR014, we observed after JCAR021 better OR (87% versus 59%, respectively), CR rates (67% versus 53%, respectively), and PFS (12-month PFS, 47% versus 25%; CR pts, 64% versus 37%, respectively; Figure B). Rates of CRS and ICANS (any grade CRS, 93% versus 29%; any grade ICANS, 80% versus 29%, respectively) and in vivo peak CAR-T counts were higher after JCAR021 (Figure C). No difference in CAR-T persistence was observed.

Conclusion JCAR021, a fully-human scFv CD19-targeted CAR T-cell product, was dose-escalated to the RP2D with manageable toxicities in pts with R/R LBCL. At the RP2D, high rates of durable responses were observed. A new cohort with pts in relapse after murine scFv-containing CD19 CAR T cell therapy is currently enrolling.

Fiorenza:Bristol Myers Squibb: Patents & Royalties, Research Funding. Kimble:Juno Therapeutics, a BMS company: Research Funding. Vinaud Hirayama:Nektar Therapeutics: Research Funding; Novartis: Honoraria; Juno Therapeutics, a BMS Company: Research Funding; Bristol Myers Squibb: Honoraria. Till:BMS/Celgene: Research Funding; Proteios Technology: Consultancy; Mustang Bio: Consultancy, Patents & Royalties, Research Funding. Shadman:Merck: Consultancy; Regeneron: Consultancy; Epi Lilly: Consultancy; Kite Pharma: Consultancy; Innate Pharma: Consultancy; TG Therapeutics: Consultancy, Research Funding; Adaptimmune: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Sound Biologics: Consultancy; Morphosys/Incyte: Consultancy, Research Funding; Fate Therapeutics: Consultancy; Beigene: Consultancy, Research Funding; Epizyme: Consultancy; Pharmacyclics: Consultancy, Research Funding; Mustang Bio: Consultancy, Research Funding; MEI Pharma: Consultancy; Atara Biotherapeutic: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Celgene, a BMS Company: Research Funding; Gilead: Research Funding; Sunesis: Research Funding; Genmab: 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:Legand Biotech: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Data Safety Monitory Board , Research Funding; Genentech: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Fred Hutch: Patents & Royalties: For Patients licensed to Juno ; Umoja: Consultancy, Honoraria; Bioline Rx: Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitory Board ; Mustang Bio: Consultancy, Honoraria; Navan Technologies: Consultancy, Current holder of stock options in a privately-held company, Honoraria; A2 Biotherapeutics: Current holder of stock options in a privately-held company; Amgen: Consultancy, Honoraria; A2 Biotherapeutics: Consultancy, Honoraria. Turtle:Century Therapeutics: 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; T-CURX: Membership on an entity's Board of Directors or advisory committees; 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; Decheng Capital: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: 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; Juno Therapeutics, a BMS Company: Patents & Royalties, Research Funding; Nektar Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Arsenal Bio: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Expert Connect: Consultancy; Kite Pharma, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; 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. Gauthier:Legend Biotech: Consultancy; Kite Pharma: Consultancy; Celgene (A BMS Company): Research Funding; Multerra Bio: Consultancy; Juno Therapeutics - A BMS Company: Research Funding; Sobi: Research Funding.