Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy that employs numerous mechanisms of immune suppression. Here we demonstrate the therapeutic activity and safety of an affinity-enhanced T cell receptor (TCR)-based therapy targeting a naturally overexpressed self/tumor antigen in an autochthonous, genetically engineered mouse model of PDA (KPC). T cells engineered to recognize Mesothelin infiltrated the desmoplastic tumor, induced tumor cell lysis and remodeled the extracellular matrix without apparent toxicities to normal tissues. However, this anti-tumor activity was transient despite T cell persistence in PDA. Donor T cells progressively upregulated inhibitory receptors and became dysfunctional specifically in the tumor microenvironment, indicating selective immunosuppression at the tumor site. However, the T cell dysfunction in PDA also was, in part, independent of antigen specificity and the observed upregulation of inhibitory receptors. Nevertheless, a second infusion of engineered T cells still preferentially accumulated in PDA and increased tumor epithelial cell death indicating that PDA remains susceptible to the effects of serial T cell infusions. Finally, we demonstrate that serial T cell infusions significantly increased survival in KPC mice enrolled with invasive PDA indicating that the observed anti-tumor activity can be associated with therapeutic benefits to the host. These results support the clinical advancement of TCR-based therapies for treatment of PDA.
This abstract is also presented as Poster B20.
Citation Format: Ingunn M. Stromnes, Scott J. Brockenbrough, Thomas M. Schmitt, Sunil R. Hingorani, Philip D. Greenberg. Enhanced affinity T cell receptor based therapy can surmount immune and physical barriers to treat pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr PR08.
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