IL-10 Expressing CD19 CAR-T Cells Induce Complete Remission and Improve Long-Term Protection in Relapsed or Refractory B-Cell Hematological Malignancies

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 due 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 animal models, resulting in robust tumor eradication and durable protection. To further evaluate both efficacy and safety, we have initiated an open-label, single-arm, investigator-initiated phase I trial (NCT06277011) of IL-10 expressing CD19 CAR-T cells, denoted as Meta10-19, targeting patients with relapsed or refractory B-cell hematological malignancies.

Objective:

The primary objective of this phase I trial is to assess the safety and tolerability of Meta10-19 among patients diagnosed with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and B-cell acute lymphoblastic leukemia (B-ALL). Secondary goals encompass investigating pharmacokinetics and gauging initial efficacy outcomes.

Methods:

From February 2023 to July 2024, we enrolled and treated a total of 20 eligible patients with elapsed or refractory B-cell hematological malignancies, including 10 patients with DLBCL and 10 patients with B-ALL. Patients received a single infusion of Meta10-19 across multiple dose level (DL) cohorts from 2.0×10⁴ cells/kg to 2.0×10⁵ cells/kg. 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:

As of July 16, 2024, Meta10-19 had been successfully infused into 20 eligible patients, who subsequently underwent comprehensive safety and preliminary efficacy evaluations. The median age of the cohort was 50 years (range 17-65). CAR-T cells reached their expansion peak at about 12 days for both DLBCL and B-ALL patients. Remarkably, the complete response (CR) rate for all 20 patients was 100% (20/20), sustained at 100% for 3 months (19/19), and maintained at 94.11% at 6 months (16/17) post-treatment, which is much higher than commercial products (approximately 50% at 6 months post-treatment). Notably, 5 patients have been surviving over 12 months, with the longest observed remission duration to date being 17 months. Treatment-related adverse events, predominantly neutropenia, thrombocytopenia, and anemia, were manageable and effectively resolved with standard and supportive care.

Summary:

This first-in-human trial of Meta10-19 has demonstrated encouraging preliminary efficacy and a manageable safety profile. Notably, Meta10-19 exhibited a significantly higher CR rate compared to commercial products. Additionally, it provided substantial long-term survival benefits for infused cancer patients, especially at 6 months post-treatment. Ongoing investigations with larger patient cohorts and extended follow-up periods aim to provide further insight into the efficacy and safety parameters.