CAR NK Cell Immunotherapy

Natural Killer (NK) cells are innate cytotoxic lymphocytes that rapidly identify tumor cells through expression of multiple NK cell activating receptors, contain premade granules with perforin and granzyme B for cell lysis, and secrete inflammatory cytokines to amplify the immune response. NK cell function is tightly regulated by a balance of activating and inhibitory receptors. Robust cytotoxicity is dependent on the activation of several activating receptors and is driven by cytosolic signaling of immunoreceptor tyrosine-based activation motifs (ITAMs).

Engineering NK cells to express chimeric antigen receptors (CARs) may increase antigen-specific cytotoxicity. The CAR construct includes an extracellular antibody fragment linked to a transmembrane domain and several intracellular signaling domains commonly used by NK cell activating receptors. CAR NK cells are targeted to the tumor through interactions between the antibody fragment and target antigen which enhance tumor specific cytotoxicity and amplification of the immune response. Unlike CAR T cells, CAR NK cells have multiple mechanisms of killing. They retain expression of their native activating receptors and CAR-initiated attachment to the tumor cells may promote further NK cell stimulation through these receptors. Several preclinical models show improved efficacy and targeting of hematological and solid malignancies using CAR-modified NK cells.

We are evaluating several CAR NK cells targeted to different antigens specific to metastatic prostate cancer using a variety of interdisciplinary techniques. Flow cytometry, in vitro cytotoxicity assays, ELISA, tumor xenograft models, in vivo fluorescence and bioluminescence imaging.