Human natural killer cells: Advancing biology and clinical applications

PROJECT SUMMARY The current R35 competitive renewal is revised from 2023 (Score 15). The Panel and Reviewers raised 5 “minor” (the word used in the Summary Statement) weaknesses that I addressed. I have studied the basic biology of human natural killer (NK) cells and their clinical application for cancer treatment over the past 33 years. Basic discoveries from my lab have brought chimeric antigen receptor (CAR) NK cells into the clinic, yet their development for cancer treatment requires improvement. This proposal is built upon our body of work that has been accomplished during the past seven-plus years of this R35 award. We investigated how NK cells develop, survive, kill, and what cell-extrinsic or cell-intrinsic modifications are engaged to enhance these and other properties to improve their clinical efficacy for cancer treatment. This resulted in over 50 publications, including senior authorships in high-profile journals such as Cell, Nature Biotechnology, Nature Immunology (3), Nature Cancer, Immunity (3), Science Immunology, and Cancer Discovery (2). Importantly, we successfully translated our findings into the clinic to treat cancer patients. We now propose to address the key challenges in the field and to improve CAR NK cell therapy. We will: (1) determine the biomarkers and mechanisms that will define NK cell exhaustion, including in vivo models, to reduce or eliminate this effect; (2) investigate whether NK cells possess memory of tumors and if tumors possess memory of NK cells. We will employ novel approaches to define this at the molecular level; (3) elucidate mechanisms by which CAR NK cells traffic into solid tumors; (4) optimize CAR constructs of NK cells for effective anti-tumor activity: and (5) perform IND-enabling studies on CAR NK cells expressing IL-15 to then translate our discoveries into the clinic. This will be exemplified by the proposed IND-enabling studies to translate our published work on anti-PSCA CAR NK cells expressing soluble IL-15 from the past funding cycle (Teng et al., Gastroenterology, 2022) into the clinic to treat pancreatic cancer (PC) patients via institutional funding sources. PC has a 5-year survival rate of 9% and is the 3rd leading cause of cancer-related death. We believe our proposed studies for the next funding cycle will lead to innovative, cost effective, allogeneic, “off-the-shelf”, and safe CAR NK cell therapies to benefit a broader group of cancer patients.