Abstract B044: Engineering CAR NK cells for antigen-dependent autocrine expansion

Abstract

Abstract Given promising results with chimeric antigen receptor (CAR) T-cell therapy in hematologic malignancies attention has turned to whether CAR natural killer (NK) cells might have utility in cancer immunotherapy. NK cells are known to have potent cytolytic function and the ability to secrete interferons and cytokines, including GM-CSF and interferon-γ (IFNγ) upon stimulation. In pre-clinical models CAR NK cells have been shown to have efficacy and possibly some advantages over CAR T-cells. Several biotechs and pharmas are currently exploring this approach, but a major limitation of NK cells is their inability to produce autocrine growth factors to promote their own expansion and activation. In the context of CAR NK cell therapy, a major limitation is the inability of the infused CAR NK cells to expand in the absence of cytokine signals to initiate their proliferation and enhance their effector functions. IL-12 and IL-15 are essential for the clonal expansion of NK cells; however, recombinant IL-12 and IL-15 are quite toxic when administered systemically. Additionally, engineering NK cells to constitutively secrete IL-12 or IL-15 is not an attractive strategy as this may also result in off-target toxicity. Our goal is to engineer chimeric receptors with the intracellular signaling domains of IL-12 or IL-15 receptors fused to the extracellular domains of cytokine receptors. Consequently, self-secreted cytokines by activated NK cells or recognition of tumor cells will provide autocrine growth signal, permit NK clonal expansion and enhance NK effector functions. Citation Format: Avishai Shemesh, Kole T. Roybal, Lewis L. Lanier. Engineering CAR NK cells for antigen-dependent autocrine expansion [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B044.