Abstract CT144: Phase I investigator-initiated clinical trial of CD19CAR -T cells secreting PD-1-targeted IL-21 in relapsed/refractory B-cell non-Hodgkin lymphoma

Abstract Background: Chimeric antigen receptor (CAR) T cell therapy has demonstrated exceptional efficacy in treating hematologic malignancies. However, clinical outcomes can be limited by factors such as suboptimal expansion and persistence of adoptively transferred CAR-T cells, antigen-negative relapses, and the immunosuppressive tumor microenvironment. In our previous work, we engineered CD19CAR-T cells to secrete a PD-1Ab21 fusion protein, which combines an anti-PD-1 single-chain antibody with IL-21 (PD-1Ab21-CD19CAR-T). This investigator-initiated clinical trial aims to evaluate the safety and therapeutic potential of these novel CAR-T cells in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (r/r B-NHL). Methods: The study has recruited 9 patients with r/r B-NHL, with additional patient enrollment ongoing. All patients received fludarabine and cyclophosphamide before a single infusion of PD-1Ab21-CD19CAR-T cells, with escalating dose ranging from 0.3×106 to 3×106 cells/kg. Patients were monitored for adverse events, clinical responses, and immune cell kinetics, including the expansion of CAR-T cells and CD8+ T cells. Results: Nine patients were enrolled, with a median age of 61 years (range: 38-73). One patient had follicular lymphoma (FL), and the remaining eight were diagnosed with diffuse large B-cell lymphoma (DLBCL), two of whom had bone marrow involvement. The overall response rate (ORR) was 77.8% (7/9), with 66.7% (6/9) achieving complete remission (CR). Cytokine release syndrome (CRS) occurred in 55.6% (5/9) of patients, but all cases were very mild (grade ≤1). No treatment-related neurotoxicity or deaths were reported. The first patient, diagnosed with DLBCL and presenting with paraplegia, achieved CR three months after CAR-T infusion, which has been sustained for over two years, resulting in a progression-free survival (PFS) greater than two years. After CAR-T infusion, we observed a rapid increase in CAR-CD8+ T cell proportion, which remained above 50% even after the decline of CAR-T cells. Conclusion: These preliminary findings suggest that PD-1Ab21-CD19CAR-T cells have promising clinical efficacy in r/r B-NHL, with a high ORR and sustained CR. The mild nature of CRS (grade ≤1) indicates that this treatment can be well tolerated. Further studies are necessary to confirm these results and assess long-term outcomes. Citation Format: Yu Jing, Ying Li, Meng Li, Shengjuan Zhang, Baocai Zhao, Yueyi An, Hang Li, Jitao Zhao, Liping Dou, Shengdian Wang. Phase I investigator-initiated clinical trial of CD19CAR -T cells secreting PD-1-targeted IL-21 in relapsed/refractory B-cell non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT144.