Abstract CT145: Phase I investigator-initiated clinical trial of BCMACAR -T cells secreting PD-1-targeted IL-21 in relapsed/refractory multiple myeloma

Abstract Background: Chimeric antigen receptor (CAR) T cell therapy has shown significant promise in treating hematologic malignancies, including multiple myeloma. Several BCMA-targeted CAR-T therapies have demonstrated remarkable efficacy, achieving high overall response rates (ORR) in heavily pretreated patients. However, challenges remain, including limited durability of response, antigen loss, and immune suppression within the tumor microenvironment. To address these issues, we developed a novel BCMACAR-T cell therapy engineered to secrete a fusion protein composed of an anti-PD-1 single-chain antibody and IL-21 (PD-1Ab21). This approach is designed to enhance the therapeutic effects of CAR-T cells by promoting their proliferation and memory differentiation. In this investigator-initiated clinical trial, we evaluated the safety and efficacy of this novel CAR-T therapy in patients with advanced relapsed/refractory multiple myeloma (RRMM). Methods: This is a single-arm, open-label, phase I clinical trial that has enrolled 10 patients with RRMM, with further patient enrollment ongoing. Patients received lymphodepleting chemotherapy followed by a single infusion of PD-1Ab21-BCMACAR-T cells at a dose range of 0.3×106 to 3×106 cells/kg. The primary endpoint was ORR, while secondary endpoints included complete response rate (CR), progression-free survival (PFS), and overall survival (OS). Safety assessments focused on the incidence and severity of cytokine release syndrome (CRS) and neurotoxicity. The expansion of CAR-T cells and lymphocytes were also monitored. Results: Ten patients were enrolled, with a median age of 57 years (range: 47-72). Six of these patients relapsed after autologous hematopoietic stem cell transplantation, and four patients had extramedullary plasmacytoma (EMP). The ORR was 90% (9/10), including 60% (6/10) achieving CR and 30% (3/10) achieving PR. The median time to CR was 6 months. Among the three patients with PR, further evaluation is ongoing, with some potentially achieving CR over time. CRS occurred in 70% (7/10) of patients, all of which were mild (grade ≤2). No treatment-related neurotoxicity or deaths were reported. Among the four patients with EMP, one achieved CR, two achieved PR, and one died from a non-treatment-related cerebral infarction. Once the expansion of CAR-T cells was detected, the proportion of CD8+ T cell in circulating CD3+ T cells increased dramatically, rapidly reaching above 75% and maintaining above 50% for an extended period in all treated patients. Conclusion: PD-1Ab21-secreting BCMACAR-T cells demonstrated promising safety and efficacy, with sustained and durable therapeutic responses in RRMM patients, including those with EMP. Our data also suggest that PD-1Ab21-secreting CAR-T therapy can activate endogenous anti-tumor CD8+ T cell responses. Further studies are needed to validate these findings and optimize this novel approach. Citation Format: Meng Li, Ying Li, Yu Jing, Shengjuan Zhang, Baocai Zhao, Yueyi An, Hang Li, Liping Dou, Shengdian Wang. Phase I investigator-initiated clinical trial of BCMACAR -T cells secreting PD-1-targeted IL-21 in relapsed/refractory multiple myeloma [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 CT145.