Abstract LB236: Metabolically armed CD19 CAR-T cells for safe and effective treatment of relapsed or refractory CD19+ B cell hematological malignancies at extremely low doses
Authors: Yugang Guo, Qianwen Xu, Lei Xue, Erling Chen, Chonglin Liu, Min Gao, Youjia Li, Jingjing Ren, Jinping Li, Li Tang, Xingbing Wang
Journal: Cancer Research (2024)

Abstract Background: The undeniable success of CD19 CAR-T cell therapy in managing relapsed or refractory (r/r) B-cell hematological malignancies, such as diffuse large B-cell lymphoma (DLBCL) and B-cell acute lymphoblastic leukemia (B-ALL), underscores its significance. Despite the favorable complete remission (CR) rates of around 50% for r/r DLBCL and up to 90% for r/r B-ALL, a notable challenge persists as more than half of patients experiencing CR after CD19 CAR-T cells treatment encounter relapse within a year, attributed to inadequate CAR-T persistence in both indications. Urgent attention is required to devise innovative strategies to overcome these challenges. Recently, we developed metabolically armed CD19 CAR-T cells expressing IL-10 can enhance OXPHOS metabolism, proliferation, and persistence of CAR-T cells in vivo. Significantly, these IL-10-expressing CAR-T cells trigger stem-like memory responses in various lymphoid organs, leading to robust tumor eradication and durable protection. Motivated by these promising findings, an open-label, single arm, investigator-initiated trial (IIT, ClinicalTrials.gov identifier: NCT05715606, NCT05747157) was conducted to assess the safety and efficacy of newly developed metabolically armed IL-10-expressing CD19 CAR-T (product name: Meta10-19 infusion) for treating patients with r/r DLBCL or r/r B-ALL. Method: From Feb 2023 to Dec 2023, this IIT clinical trial evaluated Meta10-19 infusion in adult patients with r/r DLBCL or r/r B-ALL. The patients were recruited and treated at the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China. Patients in 3 dose cohorts (2.0 × 104, 5.0 × 104, or 1.0 × 105 CAR-T cells/kg, corresponding to 1%, 2.5%, or 5% doses of commercialized CAR-T infusion) underwent lymphodepleting chemotherapy with cyclophosphamide and fludarabine before Meta10-19 infusion. The primary endpoint was the incidence of dose-limiting toxicities. The secondary endpoint was the response and survival. Results: The treatment with Meta10-19 infusion has successfully induced CR in all 12 cases of r/r DLBCL (n=6) or r/r B-ALL (n=6), as evaluated by PET-CT scan, NMR spectroscopy or minimal residual disease assessment of bone marrow. No server cytokine storm syndrome or neurotoxicity was observed. All treated patients achieved CR at 3 months post treatment, with the first patient maintaining continuous remission up to 9 months until now. Notably, these metabolically armed CD19 CAR-T cells demonstrated efficacy even for patients with bulky mass (≥7.5 cm) of DLBCL at extremely low infusion dose (1~5% doses of commercialized CAR-T). Conclusion: Preliminary findings suggest that Meta10-19 infusion exhibits promising breakthrough efficacy and safety profile, and active enrollment is ongoing to validate the initial results. Citation Format: Yugang Guo, Qianwen Xu, Lei Xue, Erling Chen, Chonglin Liu, Min Gao, Youjia Li, Jingjing Ren, Jinping Li, Li Tang, Xingbing Wang. Metabolically armed CD19 CAR-T cells for safe and effective treatment of relapsed or refractory CD19+ B cell hematological malignancies at extremely low doses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB236.