NK cells, their receptors and cancer therapy

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Recent high-profile advances have reinvigorated enthusiasm for immunologic and cell-based therapies for cancer. While the first 15 years of this Program focused on related donor sourced products and defining the immunogenetics of NK cell contributions to allotransplantation, the adoptive transfer of single donor products is limited to specialty centers because of high cost, difficulty in exporting, and inability to test multi-dosing strategies. We have formed new strategic partnerships to shift from single donor products to off-the-shelf approaches. This approach is simpler for protein-based NK cell immune engagers, as they are readily druggable, but more challenging for cell products. Therefore, our overall goal is to develop off-the-shelf NK cell products to be used alone or in combination with novel immune engagers. We have assembled a team of Minnesota and international experts to lead the Projects and Cores. In Project 1, we discovered that NKG2C+ adaptive NK cells induced by CMV have properties of immune memory, exhibit a unique methylation signature similar to CD8+ T cells, and are primed for anti-tumor activity. Our group also published the 1st clinical link between adaptive NK cells and reduced rates of leukemia relapse in 2016. We will now conduct a multi-institutional phase I/II trial of allogeneic KIR-HLA mismatched adaptive NK cell infusions to treat patients with AML/MDS. We will also perform preclinical testing of off-the-shelf NK cell products and novel immune engagers called tri-specific killer engagers (TriKEs). TriKEs contain 3 arms: an arm that engages the CD16 activating receptor on NK cells; an arm that specifically engages a tumor antigen on cancer cells; and an IL-15 linker. In the current funding, we discovered that IL-15 is superior to IL-2 in promoting in vivo NK persistence and expansion; however, it also stimulates host CD8+ T cells in many subjects, and we will test whether IL-15’s targeted delivery via TriKE minimizes bystander T cell activation. Project 2 will focus on NHL and clinically test a dual-targeted strategy using an off-the-shelf, iPSC- derived NK (iNK) cell product containing a CAR against CD19, a CD16 receptor, and membrane bound IL-15. Preclinically, we will test whether targeting NK cell metabolism can improve in vivo NK cell performance. Project 3 will extend off-the-shelf iNK cell therapies into a solid tumor setting. Initial testing of adaptive NK cells in ovarian cancer showed that the intraperitoneal ( IP) space is immune privileged and allows for NK cell persistence. We will conduct a phase I clinical trial to determine whether IP delivery of off-the-shelf iNK cells expressing a non- cleavable CD16 (FT516) improves outcomes among patients with ovarian cancer. Preclinically, we will test novel immune engagers (TriKEs) in combination with FT516 and a new iNK cell product expressing a chimeric CD64/16A receptor capable of multi-antibody targeting. Projects will be supported by the Administration & Clinical Research Support (Core A), Biostatistics (Core B), and Immune Monitoring & Tissue Analysis (Core C) resources. This Program will build upon our success in establishing a signal of clinical efficacy with single-donor NK cells by moving from individually sourced related donor products to multi-dosed, off-the-shelf strategies.