Pancreatic cancer (PC) is one of the most lethal forms of cancer with a 5-year overall survival rate of 9%, routinely presenting as a late-stage incurable cancer that responds only modestly to standard chemotherapy. It is the third leading cause of cancer-related deaths. Approximately 60-80% of PC express prostate stem cell antigen (PSCA), as do gastric, bladder, prostate and some lung cancers. We therefore developed a chimeric antigen receptor (CAR) directed against PSCA for transduction into human natural killer (NK) cells. NK cells spontaneously kill both liquid and solid tumors without regards to expression of MHC self-antigens. In vivo, human NK cells utilize endogenous IL-15 to develop, survive, expand and activate against tumor cells. We therefore incorporated a soluble (s), secretable form of IL-15 into the PSCA CAR construct itself, followed by transduction into human NK cells obtained from umbilical cord blood with ~50% transduction efficiency. Transduced NK cells expressed the CAR directed against PSCA and secreted measurable amounts of human IL-15 protein in vitro. The PSCA CAR NK cells could be expanded ex vivo over 1,000-fold in approximately 16 days and retain their expression and their capacity to specificity kill PSCA(+) tumor cell targets in vitro. Indeed, when directed against the PSCA(+) human pancreatic tumor cell line (Capan-1), PSCA CAR NK cells produced significantly greater TNFα (P < 0.0001), IFNγ (P < 0.0001), and CD107a (P < 0.05), when compared to PSCA CAR NK cells against the PSCA(-) human pancreatic tumor cell line PANC-1. Moreover, we showed that the co-expression of sIL-15 with PSCA CAR NK cells significantly enhances their cytotoxic function against pancreatic tumor cells compared to PSCA CAR NK cells without expression of sIL-15 (P < 0.01) determined by a real-time cytolysis assay (RTCA) over 3.5 days. Encouraged by these in vitro data, we developed a model of metastatic human pancreatic cancer in immunodeficient mice using the PSCA(+) Capan-1 cell line. Compared to NK cells only expressing sIL-15, repeated infusions of human PSCA CAR NK cells from a viably frozen source resulted in a significantly prolonged survival (P < 0.001), including clearance of metastatic disease. In summary, our in vitro and in vivo studies utilizing viably frozen human PSCA CAR NK cells co-expressing sIL-15 demonstrate significant efficacy in prolonging survival against a human pancreatic tumor cell line without evidence of systemic toxicity, providing a rationale to move this novel form of cell therapy into the clinic for PSCA(+) solid tumors.
Citation Format: Kun-Yu Teng, Anthony Mansour, Zhu Zheng, Lei Tien, Yi Zheng, Zhiyao Li, Jianying Zhang, Saul J. Priceman, Michael A. Caligiuri, Jianhua Yu. A potent human CAR NK cell therapy directed against pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB154.