Autologous chimeric antigen receptor (CAR) T-cells have greatly changed the therapeutic landscape for the treatment of hematological malignancies. Nevertheless, the use of allogeneic CAR natural killer (NK) cells offers several advantages over CAR-T cells, including the potential as an off-the-shelf product with broad clinical applications, reduced cost, lower risks of graft-versus-host disease (GvHD) and less toxicity, especially with respect to cytokine-release syndrome (CRS) and neurotoxicity. A limited number of clinical studies have demonstrated the safety and efficacy of CAR-NK therapy. However, it remains unclear, to date, whether CAR-NK cells can induce sustained, durable remissions. Here, we generated anti-CD19 CAR-modified NK cells (CD19-BBz CAR-NK) by transduction of cord blood-derived NK cells and demonstrated their anti-lymphoma activity in a preclinical study. Additionally, we performed a phase 1 dose trial involving repetitive administration of CD19-BBz CAR-NK cells in patients with relapsed or refractory (R/R) large B-cell lymphoma (NCT05472558). Importantly, none of the 9 treated patients experienced CRS, neurotoxicity, or GvHD. The overall response rate at day 30 was 66.7% (6 of 9), with 5 patients (55.6%) achieving complete response. At a median follow-up time of 12 months from the time of CAR-NK infusion, the median progression-free survival was 9 months and estimated the overall survival rate was 58.33% at the end of the study. Single-cell RNA sequencing (scRNA-seq) of CAR-NK products revealed molecular features of CAR-NK cells associated with therapeutic efficacy. Moreover, scRNA-seq of patients' peripheral blood mono-nuclear cells (PBMC) post-treatment demonstrated efficacy-related immune cell interaction networks. In conclusion, CD19-BBz CAR-NK cells were feasible and safe, capable of inducing durable remission in R/R large B-cell lymphoma patients.

Disclosures

No relevant conflicts of interest to declare.

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2024
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