Context: Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment landscape of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). However, challenges such as suboptimal durability of complete responses and high relapse rates remain. Preclinical studies have shown that engineering CAR-T cells to secrete IL-10 can enhance their metabolic fitness and antitumor activity (Guo et al., Nat. Immunol. 2021; Zhao et al., Nat. Biotechnol. 2024). To evaluate the clinical safety and efficacy of this strategy, we initiated an open-label, single-arm, investigator-initiated Phase I trial (NCT06120166) of IL-10-expressing CD19 CAR-T cells, designated Meta10-19, in patients with R/R DLBCL.
Objective: The primary objective of this phase I trial is to evaluate the safety and tolerability of Meta10-19 in patients with R/R DLBCL. Secondary objectives include assessment of pharmacokinetics and gauging initial efficacy outcomes.
Methods: This Phase I trial evaluated the safety and preliminary efficacy of IL-10-expressing CD19 CAR-T cells (Meta10-19) in R/R DLBCL. Autologous whole blood was collected for cell manufacturing. Following lymphodepletion with fludarabine and cyclophosphamide, patients received Meta10-19 infusion at 3 dose levels: 2×103, 5×103, or 2×104 CAR-T cells/kg (corresponding to 1‰ ~ 1% of conventional CAR-T regimens). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to Lee 2014 and ASTCT 2019 guidelines, respectively. Adverse events (AEs) were assessed based on CTCAE 5.0 criteria.
Results: From November 16, 2023 to October 20, 2024, 12 patients were enrolled, of whom 11 received treatment, and 10 evaluable for efficacy, with 1 succumbing before efficacy evaluation. Among these evaluable patients, the objective responses rate was 100%, comprising 9 CR (90%) and 1 partial response (PR, 10%), suggesting a potent initial antitumor activity even at ultra-low doses. Cytokine release syndrome was observed in 10 patients (Grade 1: 6; Grade 2: 3; Grade 3: 1), while immune effector cell-associated neurotoxicity syndrome occurred in 2 patients (Grade 1: 1; Grade 2: 1). All participants exhibited robust CAR-T cell expansion (average peak: 2437.4 cells/μL), with an increase in serum IL-10 (average peak: 2056.4 pg/mL). Single-cell RNA sequencing (scRNA-seq) further revealed that IL-10 signaling may drive robust expansion of effector CAR-T cells and induce the generation of stem cell-like memory T cells, potentially supporting robust effector response and long-term antitumor immunity.
Summary:This IIT clinical trial of Meta10-19 demonstrated promising efficacy at ultra-low cell doses (1‰ of commercial CD19 CAR-T) with robust in vivo expansion and a favorable safety profile. The strong expansion capacity and high complete remission rates underscore the therapeutic potential of Meta10-19. Ongoing studies with extended follo
