Pancreatic ductal adenocarcinoma (PDA) presents a formidable challenge for effective therapies given the robust desmoplasia, immunosuppressive elements and relatively few coding mutations characteristic of this disease. We demonstrate the safety and therapeutic activity of T cells engineered to express an affinity-enhanced T cell receptor (TCR) targeting the naturally overexpressed self/tumor antigen Mesothelin in an autochthonous, genetically engineered mouse model of PDA (KPC). Notably, despite the hostile tumor microenvironment surrounding PDA, the engineered T cells readily infiltrate the desmoplastic tumor, induce tumor cell lysis and remodel the tumor extracellular matrix without causing detectable toxicity in normal tissues. The transferred T cells persist in PDA, but antitumor activity is transient, as the tumor-infiltrating donor T cells upregulate a panel of inhibitory receptors and become progressively dysfunctional specifically in PDA that is due to both TCR-dependent and independent mechanisms of inhibition. This obstacle to sustained therapeutic activity can be overcome by serial T cell infusions, which mediate objective responses and a near doubling of KPC survival without overt toxicities. Similarly engineered human T cells recognize and lyse PDA cells in vitro, further supporting the clinical advancement of this TCR-based strategy for the treatment of human PDA.
Citation Format: Ingunn M. Stromnes, Thomas M. Schmitt, Scott J. Brockenbrough, Hieu Nguyen, Carlos Cuevas, Ayaka Hulbert, Jennifer Hotes, Ashley Dotson, Sunil R. Hingorani, Philip D. Greenberg. Engineered T cell-receptor based therapy of pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr IA38.
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