T Cells Engineered against a Native Antigen Can Surmount Immunologic and Physical Barriers to Treat Pancreatic Ductal Adenocarcinoma

• Published in: Cancer cell Vol. 28; no. 5; pp. 638 - 652
• Main Authors: Stromnes, Ingunn M., Schmitt, Thomas M., Hulbert, Ayaka, Brockenbrough, J. Scott, Nguyen, Hieu N., Cuevas, Carlos, Dotson, Ashley M., Tan, Xiaoxia, Hotes, Jennifer L., Greenberg, Philip D., Hingorani, Sunil R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.11.2015
• Subjects: Animals; Antigens - immunology; Carcinoma, Pancreatic Ductal - immunology; Carcinoma, Pancreatic Ductal - pathology; Carcinoma, Pancreatic Ductal - therapy; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; GPI-Linked Proteins - genetics; GPI-Linked Proteins - immunology; GPI-Linked Proteins - metabolism; HEK293 Cells; Humans; Immunoblotting; Immunotherapy, Adoptive - methods; Jurkat Cells; Kaplan-Meier Estimate; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - therapy; Protein Engineering - methods; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - transplantation; Transfection; Tumor Cells, Cultured
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2015.09.022

Pancreatic ductal adenocarcinomas (PDAs) erect physical barriers to chemotherapy and induce multiple mechanisms of immune suppression, creating a sanctuary for unimpeded growth. We tested the ability of T cells engineered to express an affinity-enhanced T cell receptor (TCR) against a native antigen to overcome these barriers in a genetically engineered model of autochthonous PDA. Engineered T cells preferentially accumulate in PDA and induce tumor cell death and stromal remodeling. However, tumor-infiltrating T cells become progressively dysfunctional, a limitation successfully overcome by serial T cell infusions that resulted in a near-doubling of survival without overt toxicities. Similarly engineered human T cells lyse PDA cells in vitro, further supporting clinical advancement of this TCR-based strategy for the treatment of PDA. [Display omitted] •CD8 T cells with an enhanced affinity TCR readily infiltrate and accumulate in PDA•Mesothelin-targeted T cells induce tumor cell lysis and stromal involution•T cell therapy increases survival in KPC mice without chemotherapy or radiation•Analogously engineered T cells with mesothelin-specific TCR lyse human PDA cells Stromnes et al. show in preclinical models that T cells engineered to express affinity-enhanced T cell receptors against mesothelin overcome physical and immunologic barriers to treat pancreatic ductal adenocarcinoma. Serial adoptive transfers of these cells are safe and significantly increase overall survival.