Chimeric Antigen Receptor-engineered NK-92 cells for adoptive immunotherapy of pancreatic cancer

Despite several advances in the understanding of its molecular pathophysiology, pancreatic cancer (PC) remains one of the most challenging tumors to treat with standard approaches. Recently, adoptive cell therapy (ACT) with Chimeric Antigen Receptor-engineered T cells (CAR-T) has emerged as a novel strategy to control the advanced stage of the disease by specifically targeting the tumor. This therapy has demonstrated clinical success in treating hematological malignancies but has not been effective against solid tumors thus far. Despite all the clinical breakthroughs in CAR-T-based immunotherapy, further development to enhance the efficacy, to reduce toxicity, and to reduce the costs of such strategies is essential. Hence, other immune effector cells have drawn increased attention as possible candidates for CAR-engineered cancer immunotherapy. In this study, we developed a novel therapeutic approach against PC based on engineering of IL-2-independent NK-92 MI cell line with a second-generation CAR recognizing the human Prostate Stem Cell Antigen (hPSCA), a glycoprotein overexpressed in pancreatic cancer from the early stages of malignant transformation. The preliminary results obtained have shown that, upon anti-hPSCA CAR transduction by lentiviral vector, CAR NK-92 MI cells produced cytokines and exerted a high and specific cytotoxic activity by engagement with PSCA-expressing pancreatic tumor cells, irrespective of 10 Gy γ-irradiation, a safety measure to prevent permanent engraftment, which did not impact on the phenotype and short-term functionality of the effectors. Overall, anti-hPSCA CAR-modified NK-92 MI cells could represent a valid, off-the-shelf, and cost-effective product as a new therapeutic approach for pancreatic cancer immunotherapy.