Phase I study to evaluate the safety and efficacy of switchable CAR-T cell therapy with FY001 and CART001 in patients with refractory CD20-positive B-cell non-Hodgkin lymphoma (EPOC1803).

7031 Background: CD19-targeted CAR-T cell therapy has shown remarkable efficacy against relapsed/refractory B-cell non-Hodgkin lymphoma (r/r B-NHL). However, clinical challenges persist, including relapse due to CD19 antigen loss and severe immune-related adverse events such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). We developed a combination therapy using FITC-labeled rituximab (FY001) with FITC-recognizing CAR-T cells (CART001). FY001 binds to CD20 on lymphoma cells, and CART001 activation occurs exclusively through FY001, enabling fine-tuning of anti-tumor activity while minimizing adverse events. This switchable CAR-T can be applied to broader r/r B-NHL cases, including elderly or frail patients. In addition, for patients with target antigen loss, FITC-labeled antibodies targeting different antigens can activate residual CART001 to combat relapsed lymphoma cells. We conducted a phase I trial to assess the safety and efficacy of the switchable CAR-T. Methods: This investigator-initiated phase I trial enrolled patients with r/r B-NHL, to evaluate adverse event, including dose-limiting toxicities (DLTs), as the primary endpoint. The trial design specified evaluating DLTs in 3 initial participants; zero DLTs prompted the addition of 3 expansion cohort participants; one DLT necessitated 3 additional participants for DLT evaluation; two or more DLTs led to enrollment discontinuation. Participants underwent lymphocyte-depleting chemotherapy (LDC) until the day before FY001 administration. Following LDC, participants received intravenous FY001 administration at 2 mg/kg, and CART001 infusion at 1×10 6 cells/kg on the subsequent day. Results: Between March 2020 and March 2022, 6 participants received FY001 and CART001 treatment, in DLT evaluation (n=3) and expansion (n=3) cohorts. Participant ages ranged from 68-79 years, with 2-8 prior therapy lines; five had diffuse large B-cell lymphoma and one had follicular lymphoma. In all cases, no DLTs occurred. Observed adverse events, none of which were determined to be causally related to FY001 or CART001, included 1 case of Grade 4 blood creatine phosphokinase elevation (16.7%) and 1 case of Grade 3 anemia (16.7%). Notably, no CRS or ICANS cases were reported. The best overall response rate reached 100% (95% CI: 54.1%-100%), comprising 4 complete responses (CR) and 2 partial responses (PR). As of January 2025, 2 patients continue maintaining CR (57 and 47 months). Conclusions: The switchable CAR-T demonstrated excellent tolerability and 100% response rate with long-term remission in r/r B-NHL patients. These promising results warrant further clinical development of this therapy. Clinical trial information: jRCT1080224690 .