Abstract IA18: Building better T cells for targeting and eliminating tumors

Abstract

Abstract Effective cellular therapy for human malignancies requires first identifying and validating an appropriate antigenic target, and then establishing in each patient a tumor-reactive T cell response of high avidity and high magnitude that is not only safe but can infiltrate and retain function in the tumor microenvironment. We have used molecular expression profiling to detect antigens selectively or markedly over-expressed by tumors, and then used these antigens as stimuli to generate T cells from normal repertoires. We have developed a high throughput technology to identify those T cells that express high affinity TCRs, and to then isolate from these T cells the TCR genes, place them either directly or after affinity enhancement into shuttle vectors, and use these reagents to create recipient T cells with high avidity for tumor targets that can be administered in vivo. We have utilized in silico, in vitro, and preclinical mouse models to assess the safety and potential efficacy of T cells expressing such TCRs. We are currently pursuing targeting of 3 antigens that are expressed in both murine and human tumors and are pro-oncogenic, contributing to the malignant phenotype. This includes ongoing clinical trials that will be discussed in acute myelogenous leukemia and in non-small cell lung cancer or mesothelioma targeting WT1 with T cells transduced to express a high affinity TCR specific for WT1, as well as trials being designed to target Mesothelin (MSLN) with T cells transduced to express a high affinity TCR specific for MSLN in pancreatic and ovarian cancer that are anticipated to begin within 8-12 months. Our clinical results in treatment of AML and preclinical results in mouse models of pancreatic and ovarian cancer appear very promising. However, the composite clinical data, as well as the results in the preclinical mouse models that drive our clinical trials, demonstrate substantial obstacles to sustaining T cell function in vivo after transfer, particularly in the context of solid tumors. Engineered T cells with specificity for tumor antigens appear to have the capacity to infiltrate and accumulate in solid tumors, and to initially mediate anti-tumor activity, but frequently become dysfunctional in the tumor microenvironment. Studies are being pursued to identify the critical obstacles to maintaining T cell function and achieving more reproducible tumor eradication, including modulating the tumor microenvironment and engineering T cells to express immunomodulatory fusion proteins (IFP) that recognize ligands for inhibitory signals but deliver an activation/costimulatory signal. Our data suggest that engineering T cells to acquire novel properties not naturally found in unmanipulated T cells has the potential to create effective therapies for human cancers. Citation Format: Philip D. Greenberg, Aude Chapuis, Dan Egan, Ingunn Stromnes, Sunil Hingorani, Shannon Oda, Rachel Perret, Kristin Anderson, Tom Schmitt. Building better T cells for targeting and eliminating tumors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA18.