Targeting off-the-shelf iPSC-derived natural killer cells against solid tumors

During the last 2.5 decades, I have led clinical efforts to develop novel NK cell immunotherapy strategies to treat cancer by advancing lab-based discoveries in the areas of natural killer (NK) cell and IL-15 biology. This work has been supported by a continuously funded and recently renewed NCI P01 (CA111412) grant, now in its 21st year of funding (through 2026). This P01 will serve as the clinical output for the translational work proposed in this R35 application. An R35 award will allow me to further pivot my research program to focus on solid tumors. I started a long-standing NK Cell Program at the University of Minnesota that now includes a team of basic and translational scientists interested in NK cell immunotherapy. My research group has found that exposure to cytomegalovirus (CMV) induces a population of NK cells with potent immune and anti-tumor function that are marked by the expression of the NKG2C activating receptor that recognizes HLA-E, which is overexpressed on many solid tumor cancers. Our highest impact research during the past 5 years is based on an induced pluripotent stem cell (iPSC)-derived NK cell platform designed with attributes of naturally occurring CMV-induced adaptive NK cells. This iPSC platform allows an unlimited number of iPSC gene edits to be performed at the clonal level for mechanistic studies that will be translated into clinical trials. I have used my expertise in NK cell development to help develop methods for directed differentiation of iPSCs to the NK cell lineage (termed iNK) at clinical scale to generate fully functional NK cells for immunotherapy. These iNK cells will be multiplex engineered to enhance tumor-specific activity and persistence in a hostile “cold” tumor environment. My team, who pioneered adoptive transfer of allogeneic NK cells in 2005, has the most experience worldwide, having infused >400 haploidentical NK cell products to treat patients with cancer. We have now made a complete transition away from individual donor blood cell products because of their variability, barriers to gene editing, high cost, and difficulty exporting to the cancer community. The overarching goal of this R35 OIA is to develop novel strategies to specifically target solid tumor malignancies by testing new iPSC edits that facilitate homing and migration, overcome hypoxia, and promote survival after adoptive transfer in patients with solid tumor malignancies. To enhance the specificity and anti-tumoral activity of our iNK cells, we have developed a camelid nanobody specific for B7-H3 that serves as the engager of a novel chimeric antigen receptor (CAR). We have chosen to further study the anti-tumor function of these new CAR iNK cells against two solid tumors (glioblastoma and prostate cancer) that demonstrate oncogenic dependence on the expression of B7-H3. B7-H3 is not expressed at the protein level in normal tissues. We will also compare these CAR iNK cells using the same CAR edited into an iPSC-derived T cell (termed iT). The impact of these investigations is to develop novel off-the- shelf immune cell therapies with potential to change standards of cancer care.