Expression of recombinant Fc receptors by engineered NK cells to enhance cancer cell killing

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Abstract. Natural killer (NK) cells are innate lymphocytes that can be targeted to multiple tumor antigens with exquisite specificity by anti-tumor antibodies, resulting in antibody-dependent cell-mediated cytotoxicity (ADCC). This is a key mechanism of action by several clinically successful monoclonal antibody (mAbs) therapies; however, most patients exhibit or acquire resistance to this immunotherapy. ADCC by human NK cells is exclusively mediated by CD16A (FcγRIIIA), a low affinity IgG Fc receptor. Patient data indicates that increasing the binding affinity between CD16A and antibodies augments the clinical response to therapeutic mAbs. Therefore, we generated a recombinant FcγR consisting of the extracellular region of CD64 (FcγRI), the only high affinity IgG Fc receptor, and the transmembrane and cytoplasmic regions of CD16A, a potent activating receptor. NK cells derived from induced pluripotent stem cells (iPSCs) engineered to express CD64/16A mediated robust ADCC. Moreover, CD64/16A could function as a docking platform for anti-tumor mAbs, arming NK cells with switchable and mixable tumor targeting elements. Our goal is to generate an optimized recombinant CD64 expressed by iPSC-derived NK cells (iNK cells). A compelling scientific premise is provided to support our hypothesis that recombinant CD64 expressed by iNK cells can modulate their activation and enhance their binding to tumor targeting mAbs and cancer cells. Our study will focus on epithelial ovarian cancer, the most lethal gynecologic malignancy, as strategies to enhance ADCC have yet to be carefully investigated. Our hypothesis will be tested by three specific aims: 1) Determination of the in vitro and in vivo ADCC efficacy of iNK cells expressing recombinant CD64; 2) optimization of recombinant CD64 signaling in iNK cells to enhance ADCC and their in vivo durability; and 3) evaluation of the “off-the-shelf” use of iNK cells expressing recombinant CD64 in a preclinical ovarian cancer model, including a high grade serous ovarian cancer patient- derived xenograft. The impact of our study is that it investigates an innovative engineered NK cell platform to express a novel recombinant FcγR to be used in combination with mAb therapies for universal tumor antigen targeting. Our study involves a diverse team of experts with a track record of progressing basic research to the clinic for cancer immunotherapy.