Key Points

  • Memory-like NK cell differentiation and CAR engineering synergistically combine to enhance NK cell responses to resistant leukemia/lymphoma

  • CAR ML NK cells expand and control NK-resistant leukemia/lymphoma in vivo in xenograft models

NK cells are a promising cellular immunotherapy for cancer. Cytokine-induced memory-like (ML) NK cells differentiate after activation with IL-12, IL-15, and IL-18, exhibit potent anti-tumor responses, and safely induce complete remissions in patients with leukemia. However, many cancers are not fully recognized via NK cell receptors. Chimeric antigen receptors (CAR) have been utilized to enhance tumor-specific recognition by effector lymphocytes. We hypothesized that memory-like differentiation and CAR-engineering would result in complementary improvements in NK cell responses against NK-resistant cancers. To test this idea, peripheral blood ML NK cells were modified to express an anti-CD19 CAR (19-CAR-ML), which displayed significantly increased IFN-γ production, degranulation, and specific killing against NK-resistant lymphoma lines and primary targets, compared to non-specific control CAR-ML NK cells or conventional CAR NK cells. The 19-CAR and ML responses were synergistic, CAR-specific, and required ITAM signaling. Furthermore, 19-CAR-ML NK generated from lymphoma patients exhibited improved responses against their autologous lymphoma. 19-CAR-ML NK cells controlled lymphoma burden in vivo and improved survival in human xenograft models. Thus, CAR engineering of ML NK cells enhanced responses against resistant cancers and warrant further investigation, with the potential to broaden ML NK cell recognition against a variety of NK cell-resistant tumors.

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