1‰ Regular Dose of Metabolically Armored CD19 CAR-T Cells Induces Robust In Vivo Expansion and Complete Remission in Relapsed or Refractory Diffuse Large B-Cell Lymphoma Patients

Context:

Despite the undeniable success of CAR-T therapy in treating hematological malignancies, persistent challenges such as ineffectiveness and relapse after remission are observed, often contributed to CAR-T cell exhaustion and dysfunction. To address these issues, metabolically armored CAR-T cells expressing IL-10 have demonstrated significant improvements in the proliferation and persistence of CAR-T cells in vivo. These engineered cells exhibit remarkable resistance to exhaustion and elicit stem-like memory responses in diverse animal models, resulting in robust tumor eradication and enduring protection (Guo et al., Nat. Immunol. 2021；Zhao et al., Nat. Biotechnol. 2024). To further evaluate both efficacy and safety, we have initiated an open-label, single-arm, investigator-initiated phase I trial (NCT06120166) of IL-10 expressing CD19 CAR-T cells, denoted as Meta10-19, targeting patients with relapsed/refractory (R/R) diffused large B cell lymphoma (DLBCL).

Objective:

The first aim of this phase I trial is to assess the safety and tolerability of Meta10-19 among patients diagnosed with R/R DLBCL. Secondary goals encompass investigating pharmacokinetics and gauging initial efficacy outcomes.

Methods:

From December 2023 to July 2024, 6 eligible patients with R/R DLBCL were enrolled in this phase I trial and treated with Meta10-19. Patients received a single infusion of Meta10-19 across 2 dose level (DL) cohorts: DL1 at 2.0×10⁴ cells/kg (1% regular dose, n=3) and DL2 at 2.0×10³ cells/kg (1‰ regular dose, n=3). The administration followed a standard lymphodepletion regimen involving 30 mg/m²/day fludarabine for 3 days, and 300 mg/m²/day cyclophosphamide for 3 days. 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:

By July 31, 2024, Meta10-19 had been successfully infused into 6 eligible patients, who subsequently underwent comprehensive safety and preliminary efficacy evaluations. The median age of the cohort was 62.5 years (range from 45 years to 69 years). Notably, 4 patients maintained a complete response, while the remaining patients are being monitored for further response. All 6 patients demonstrated a robust capacity for in vivo expansion, with an average peak level up to 86.42% of peripheral blood T cells being CAR-T cells (range from 77.90% to 97.30%). The median peak level of CAR-T cells was 1018/μL (range from 518/μL to 10090/μL), with average 96.17% of these CAR-T cells being CD8⁺ CAR-T cells. The serum IL-10 median peak level was 1437.00 pg/mL (range from 995.06 pg/mL to 5213.15 pg/mL). Five patients suffered from grade 2 CRS and 1 suffered from grade 3 CRS. One patient suffered from grade 2 ICANS. CRS and ICANS were all controllable. Moreover, treatment-related AEs, predominantly neutropenia, thrombocytopenia, and anemia, were significantly alleviated with the 1‰ regular dose of IL-10 expressing CD19 CAR-T cells, and these AEs were effectively resolved with standard and supportive care.

Summary:

This clinical trial of Meta10-19 has shown encouraging preliminary efficacy even at super tiny doses (1‰ doses of commercial products) with remarkable in vivo expansion ability. These low doses further reduced hematological toxicity in treated patients, significantly improving safety profiles. Ongoing investigations with larger patient cohorts and extended follow-up periods aim to provide further insight into the efficacy and safety parameters.