Muc16CD is a novel CAR T cell target antigen for the treatment of pancreatic cancer

• Published in: Molecular Therapy: Oncology 2024-12, Vol.32 (4), p.200868, Article 200868
• Main Authors: Lin, Heather K., Blake, Dejah A., Liu, Tongrui, Freeman, Ruby, Lesinski, Gregory B., Yang, Lily, Rafiq, Sarwish
• Format: Article
• Language: English
• Subjects: adoptive cellular therapy; CAR T cells; cellular immunotherapy; MT: Regular Issue; Muc16; pancreatic cancer; tumor-associated antigens
• ISSN: 2950-3299; 2950-3299
• DOI: 10.1016/j.omton.2024.200868

Pancreatic cancer is an aggressive malignancy with a 5-year survival rate of 13% that remains refractory to current immunotherapies, such as chimeric antigen receptor (CAR) T cells. These engineered cells can produce robust anti-tumor responses but require a reliable tumor-associated antigen (TAA) target. Here, we describe the retained ectodomain of Muc16, Muc16CD, as a novel TAA for targeting by CAR T cell therapy in pancreatic cancer. We establish clinically relevant, endogenous Muc16 and Muc16CD expression in pancreatic tumor tissues for CAR T cell targeting. Muc16CD-directed CAR T cells can both recognize and activate in a polyfunctional manner in response to patient-derived pancreatic tumor cells. Last, we demonstrate that Muc16CD-directed CAR T cells can elicit an anti-tumor response in vivo with significantly enhanced tumor control and survival benefits in a pancreatic tumor model. Overall, these findings demonstrate the utility of Muc16CD-targeted CAR T cell therapy in the novel setting of pancreatic cancer. [Display omitted] Pancreatic cancer is an aggressive malignancy that is predicted to become the second leading cause of cancer-related deaths. Rafiq and colleagues describe the retained ectodomain of Muc16, Muc16CD, as a novel TAA for targeting by chimeric antigen receptor (CAR) T cell therapy in pancreatic cancer.