Durable Remissions With Humanized Cd19-Targeted Chimeric Antigen Receptor (Car)-Modified T Cells In Car-Naive And Car-Exposed Children And Young Adults With Relapsed/Refractory Acute Lymphoblastic Leukemia

Background Chimeric antigen receptor (CAR)-modified T cells targeting CD19 can induce potent and sustained responses in children with relapsed/refractory acute lymphoblastic leukemia (ALL). We previously demonstrated durable remissions with the CD19-targeted CAR T cell product CTL019; however, a subset of patients has limited persistence, which can increase the risk of relapse. Most CAR single chain variable fragment (scFv) domains, including that of CTL019, are of murine origin; therefore, anti-mouse reactivity is one potential cause of immune-mediated rejection that may be overcome by fully human or humanized CAR designs. We developed a humanized anti-CD19 scFv domain and now report on treatment with humanized CD19-directed CAR T cells (CTL119). Design A pilot/phase 1 study of CTL119 enrolled children and young adults with relapsed/refractory B-ALL or lymphoblastic lymphoma (B-LL) with or without prior exposure to a CAR T cell product in retreatment and CAR-naive cohorts, respectively. Patients in the retreatment cohort were eligible if they met 1 of 3 criteria: 1) CD19+ relapse 2) no response or 3) early B cell recovery indicating poor persistence of CAR T cells. Patient-derived T cells were transduced ex vivo with a lentiviral vector encoding the CAR composed of CD3z, 4-1BB, and humanized anti-CD19 scFv domains and activated/expanded with anti-CD3/CD28 beads. Patients received lymphodepletion with cyclophosphamide and fludarabine 1 week prior to infusion with CTL119. Results Thirty-eight children and young adults (2-24 yr) with B-ALL (n=37) and B-LL (n=1) were infused with CTL119 in 2 cohorts: CAR-naive (n=22) and retreatment (n=16). Indications included primary refractory disease (n=4), first relapse (n=9), second or greater relapse (n=25), relapse after prior allogeneic stem cell transplant (SCT, n=22), CNS disease (n=7), and other extramedullary disease (n=6). Sixteen patients with prior exposure to murine-derived CD19-specific CAR-modified T cells (CTL019, n=10; other, n=6) were retreated for B cell recovery (n=5), CD19+ relapse (n=10), or no response to prior CAR T cells (n=1). Two retreatment patients previously received 2 different CAR T cell products. At assessment 1 month after infusion, 22/22 (100%) CAR-naive patients were in complete remission. Multiparameter flow cytometry for minimal residual disease (MRD) was negative at a detection level of 0.01% in all responding patients. Four patients relapsed 3-9 months after infusion, 2 CD19+, 2 CD19-. Median follow-up was 14 mo. RFS in responding patients was 86% (95% CI: 63, 95) at 6 months and 82% (95% CI: 58, 93) at 12 months, with 3/22 (14%) proceeding to SCT in remission. In the retreatment cohort, 9/16 (56%) patients achieved a complete response (CR), defined as morphologic remission with B cell aplasia. Refractory disease showed reduced CD19 expression in 3 non-responding patients. MRD was negative in 7/9 responding patients and positive in 2 patients, who progressed to CD19+ relapse at 1.6 and 3 mo. Median follow-up was 13 months. Relapse-free survival (RFS) in responding patients was 67% (95% CI: 28, 88) at 6 months and 56% (95% CI: 20, 80) at 12 months. B cell aplasia, a functional marker of CD19-targeted CAR T cell persistence, continued for 6 months or more in 15/26 patients with adequate follow-up: 13/17 CAR-naive, 2/9 retreatment. Cytokine release syndrome (CRS) was observed in 34/38 patients and mild in most patients (grade 1, n=6; grade 2, n=23). Four patients experienced grade 3 CRS requiring supplemental oxygen and/or low-dose vasopressor support and 1 experienced grade 4 CRS requiring high-dose vasopressor and ventilatory support. Neurologic toxicity included encephalopathy (n=5) and seizure (n=5) and was fully reversible. Conclusion In the first study of humanized anti-CD19 CAR T cells, CTL119 induced CR in 100% of patients with no prior CAR T cell exposure, with a 12-mo RFS of 82%. In the retreatment setting, 56% of patients with poor or transient response to prior murine CD19-directed CAR T cells achieved CR. CTL119 can induce durable remissions without further therapy in children and young adults with relapsed/refractory B-ALL. Disclosures Maude: Novartis Pharmaceuticals: Consultancy, Other: Medical Advisory Boards. Brogdon: Novartis: Employment. Young: Novartis: Research Funding. Levine: Tmunity Therapeutics: Equity Ownership, Research Funding; Novartis Pharmaceuticals Corporation: Patents u0026 Royalties, Research Funding; Brammer Bio: Consultancy; GE Healthcare: Consultancy. Frey: Novartis: Research Funding. Porter: Genentech/Roche: Employment, Other: Family member employment, stock ownship - family member; Incyte: Honoraria; Immunovative Therapies: Other: Member DSMB; Servier: Honoraria, Other: Travel reimbursement; Novartis: Honoraria, Patents u0026 Royalties, Research Funding. Lacey: Novartis: Research Funding; Genentech: Honoraria. Melenhorst: Novartis: Research Funding. June: Novartis: Patents u0026 Royalties, Research Funding; Celldex: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Tmunity Therapeutics: Equity Ownership, Research Funding; WIRB/Copernicus Group: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Immune Design: Equity Ownership, Membership on an entity9s Board of Directors or advisory committees. Grupp: Adaptimmune: Consultancy; University of Pennsylvania: Patents u0026 Royalties; Jazz Pharmaceuticals: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Other: grant.