Abstract I11: Targeting pancreatic cancer with TCR-engineered T cells
Authors: Greenberg Philip D. , Anderson Kristin G. , Egan Dan , Hingorani Sunil R. , Nezi Luigi , Manzo Teresa , Oda Shannon K. , Paulson Kelly G. , Perret Rachel , Schmidt Leah , Schmitt Tom M. , Stromnes Ingunn M. , Chapuis Aude G. 
Published: March 2020

Abstract
We have been exploring in preclinical models and clinical trials methods to reproducibly provide therapeutic T-cell responses by transfer of genetically engineered T cells. Our largest clinical experience has been in treating human acute myelogenous leukemia (AML), in which we have utilized a high-affinity TCR specific for WT1, a protein associated with promoting leukemic transformation that is overexpressed in human leukemic stem cells, to genetically engineer CD8 T cells. We recently reported a study (Chapuis et al., Nat Med 2019) in which we treated leukemia patients at high risk of relapse (after hematopoietic cell transplant) that demonstrated all treated patients remain alive and relapse free at a median of 48 months, compared to a relapse rate of ~35% in the concurrent matched cohort (p&lt;0.01). We have also been developing strategies to translate insights and technologies from this study to treatment of solid tumors. In a preclinical genetically engineered mouse model (KPC mice) of pancreatic cancer that faithfully replicates most aspects of human disease, we demonstrated (Stromnes et al., Cancer Cell 2015) that CD8 T cells engineered with a high-affinity TCR specific for mesothelin (Msln) can infiltrate pancreatic tumors, mediate antitumor activity, and provide therapeutic benefit. However, since the T cells are ultimately rendered dysfunctional in the tumor microenvironment (TME), prolonging survival has required repeated infusions of T cells to sustain antitumor activity. We have now isolated and validated a human high-affinity TCR specific for Msln for use in a planned clinical trial modeled after the approach successful in KPC mice. However, we would like to both enhance and sustain antitumor activity without requiring repeated infusions. In-depth analyses of the T cells, tumors, and the TME in treated KPC mice have illuminated strategies to potentially overcome the obstacles to tumor eradication, and we have been exploring molecular engineering approaches to achieve this. One approach has been to create synthetic immunomodulatory fusion proteins (IFPs) that have an ectodomain composed of the receptor for an inhibitory ligand encountered in the TME but, rather than the natural cytoplasmic tail that would deliver an inhibitory signal, the receptor has the tail of a costimulatory receptor and delivers an activation signal. Expression of such IFPs takes advantage of the inhibitory ligands commonly encountered in the TME by T cells by co-opting potential inhibitory signals and has resulted in enhanced T cell function, persistence/survival, and antitumor activity. Another major obstacle to sustained therapeutic activity appears to be the limited access in the TME to nutrients that effector T cells can utilize as an energy source. Analysis of the metabolites present in the TME and the transcriptional program in T cells has provided insights into genetic modifications that can be made to allow T cells to survive and function in the metabolically hostile TME. These and related studies will be discussed.
Citation Format: Philip D. Greenberg, Kristin G. Anderson, Dan Egan, Sunil R. Hingorani, Luigi Nezi, Teresa Manzo, Shannon K. Oda, Kelly G. Paulson, Rachel Perret, Leah Schmidt, Tom M. Schmitt, Ingunn M. Stromnes, Aude G. Chapuis. Targeting pancreatic cancer with TCR-engineered T cells [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I11.