Phase 1/2 study of anbalcabtagene autoleucel, novel anti-CD19 CAR-T cell therapy with dual silencing of PD-1 and TIGIT in relapsed or refractory large B-cell lymphoma.

7522 Background: Anbal-cel is a novel 2nd generation autologous CD19 CAR-T cell therapy which has been knock-downed for PD-1 and TIGIT using OVIS platform. Anbal-cel demonstrated the eradication of CD19 positive tumor cells in vitro and in vivo better than conventional CD19 CAR-T cells. The knock-down of PD-1 and TIGIT at CD19 CAR-T cells exerts the superior T-cell functionality by delaying the exhaustion of CAR-T cells. Methods: This phase 1 dose escalation part (NCT04836507) was evaluated the safety and preliminary efficacy in patients with r/r LBCL. Anbal-cel was manufactured at GMP facility with fresh leukapheresis product. Patient was administered as a single intravenous dose at dose level 1 (2x105 cells/kg), DL2 (7x105 cells/kg) or DL3 (2x106 cells/kg). Lymphodepletion with cyclophosphamide (500mg/m2) and fludarabine (30mg/m2) was performed for 3 days prior to Anbal-cel infusion. Results: As of Jan 17 2022, 9 patients with r/r DLBCL were infused with Anbal-cel; 4pts at DL1, 3pts at DL2 and 2pts at DL2. Median age was 54 (range 26-71); all patients received 2 or more prior lines of therapy and 44% (4/9) received ≥4 prior line of treatment before the study. 78% (7/9) patients were refractory to their last treatment. 67% (6/9) of patients were at IPI 3-4 and 44% (4/9) of patients had bulky disease. No patient experienced DLT during the study. Of the 9 patients, 5 (56%) experienced CRS; 4 (44%) were grade 1 or 2 and one patient experienced grade 3 CRS. Median time to onset of CRS was 7 days (range, 1-16) with median duration of 4 days (range, 0-18). One patient dosed at DL3 experienced grade 2 ICANS, time to onset of ICANS was 7 days and lasted for 13 days. This patient had prior CNS involvement history before the study. Most commonly reported grade 3/4 AEs were neutrophil count decrease (6/9, 67%), anemia (5/9, 56%), thrombocytopenia (2/9, 22%), platelet count decrease (2/9, 22%) and no infection was reported. Complete response rate (CRR) was 78% and complete responses were observed at the lowest dose level and from patients expressing less than 10% CD19 at IHC; 3 complete responses (CR) at DL1, 2 CRs at DL2 & DL3 respectively. Dose-dependent CRC01 expansion was observed; median Tmax was 15.4, 15.8, 11.0 days at DL1, DL2 & DL3 each; median Cmax was 18,003, 30,103, 53,688 copies/ug gDNA at DL1, DL2 & DL3 each; median AUC0-28day was 679,125, 1,110,108, 2,852,235 copies/ug gDNA at DL1, DL2 & DL3 respectively. Conclusions: Anbal-cel demonstrated promising efficacy and tolerable safety profile in this dose escalation study. Based on this phase 1 study, phase 2 patient enrollment will be commenced in Mar 2022 to evaluate the response rate, duration of response of CRC01 as well as safety. In addition, various biomarker studies are planned to investigate the differential mode of action of Anbal-cel during phase 2 study. Clinical trial information: NCT04836507.