Preclinical Evaluation of an Allogeneic CD22 CAR-NK to Target B-Cell Hematologic Malignancies

Chimeric antigen receptor (CAR) immunotherapy targeting CD19 has shown remarkable responses and sustained remission in clinical trials for B cell malignancies. However, 30%-60% of patients relapse due to poor CAR-T persistence or CD19 antigen escape, necessitates the exploration of additional targets, with CD22 being an attractive candidate. CD22 is expressed from the pre-B cell stage through mature B cells and is present on most B cell hematologic malignancies. CAR therapy targeting CD22 alone is being investigated as a sequential treatment option to address CD19-negative relapse following CD19-targeted therapy.

We generated CD22 CAR-NK cells to evaluate their anti-tumor efficacy both in vitro and in vivo against CD22-expressing B cell lymphoma cells. Our cord blood-derived CD22 CAR-NK cells were designed to secrete IL-15, supporting NK cell survival and proliferation upon antigen stimulation. Ex-vivo expanded, cryopreserved CD22 CAR-NK cells showed a pure NK cell phenotype (>95%) with high CD22 CAR expression (>90%). These cells demonstrated target-specific cytotoxicity against CD22-positive tumor cells, with no significant cytotoxicity against CD22-negative tumor cells. In long-term cytotoxicity assays, they completely inhibited the growth of CD22-positive tumor cells. In the presence of CD22-positive tumor cells, CD22 CAR-NK cells exhibited substantial cytokine secretion, including IFN-γ and IL-15, indicating their therapeutic potential for CD22-positive B cell malignancies.

In the NALM-6 xenograft model, mice treated with CD22 CAR-NK cells exhibited a significant delay in tumor growth and prolonged survival, with high levels of CD22 CAR-NK cells detected in their peripheral blood. Our study demonstrates that CD22 CAR-NK cells play a crucial role in long-term persistence both in vitro and in vivo, indicating their potential therapeutic efficacy in B cell malignancies. These results highlight the potential of novel CD22 CAR-NK cell therapy as a promising treatment strategy for CD22-positive B cell malignancies and as an option for relapsed/refractory patients who experience antigen loss or failure with anti-CD19-related immunotherapy.

No relevant conflicts of interest to declare.