Development of an IL-21 based TriKE for in vivo NK cell expansion and cytotoxicity against solid tumors 4799

Description Natural Killer (NK) cells are a promising adoptive cell therapy given their ability to target tumors in an antigen independent manner. NK cells can be expanded ex vivo using membrane bound IL-21 (mbIL-21) feeder cells enhancing their anti-tumor activity. We have also shown that expanded NK cells are metabolically reprogrammed, allowing them to withstand the metabolically hostile tumor microenvironment. While this approach to expand NK cells has demonstrated promising results in preclinical models and early clinical trials, ex vivo expansion requires resources and GMP-grade manufacturing facilities, increasing the cost and accessibility of this treatment. To overcome these challenges, we are developing a tri-specific killer engagers (TriKE) to activate and expand NK cells directly in cancer patients. Our TriKE consists of a HER-2 protein binding domain, an NKp30 binding domain, and an activating cytokine, IL-21 to induce NK activation and cytotoxicity against HER-2+ cancers. We demonstrate that in vitro, the TriKE elicits robust STAT-3 mediated signaling. Additionally, in a mouse model for HER-2 positive ovarian cancer, following adoptive transfer of human NK cells, mice treated with the TriKE showed increased NK cell accumulation in the peritoneum compared to untreated mice. Overall, we provide evidence that our TriKE is a promising strategy to expand NK cells in vivo to target solid tumors.