Abstract PO079: Effects of the lung tumor microenvironment on T cell therapy
Authors: Schmidt Leah M. , Tran Oanh , Oda Shannon , Inman Quintin , Tan Sasha , Jenkins Cody , Greenberg Philip 
Published: February 2021

Abstract
Immune checkpoint therapy (ICT) is a front-line treatment for lung cancer; however, low mutational burden and ‘non-T cell inflamed’ signatures predict poor responses to ICT in ~50% of patients. Adoptive cellular therapy (ACT) with T cells engineered to express T cell receptors (TCRs) specific for tumor-associated antigens (TAAs; native proteins that are overexpressed by cancers) is an approach that circumvents the need for endogenous T cell responses. TCR-ACT has been effective against hematologic cancers, but ACT against solid tumors is still in the early stages of exploration. A deeper understanding of the complex interaction between therapeutic T cells and the tumor microenvironment (TME) will be important for identifying successful strategies to enhance function and mitigate toxicity. Genetically engineered mouse models (GEMMs) achieve in situ tumor development alongside competent immune systems, recapitulating the native TME over the full spectrum of disease progression in a preclinical setting. Targeting TAAs naturally overexpressed by GEMM tumors, and expressed at native levels in healthy adult tissues, allows for study of the factors dictating the efficacy and toxicity of TCR-ACT in experimentally tractable systems. GEMM lung tumors driven by oncogenic Kras and deletion of the tumor suppressor p53 (KP) harbor few mutations, are poorly infiltrated by T cells, and are refractory to ICT, modeling treatment-recalcitrant patient disease. Using CD8+ T cells transduced with a TCR against the mesothelin (msln) protein, a TAA commonly overexpressed across many cancer types, including lung cancers, we showed that TAA-specific T cells recognize KP lung cancer cells and efficiently home to tumors. However, therapeutic T cells rapidly lose function in the lung TME compared to those recovered from the spleen, or from KP pancreatic tumors, which bear similar driver mutations and also overexpress the msln TAA. Repetitive TCR-ACT can extend survival of animals with lung tumors, dependent on treatment timing, but animals eventually succumb to disease. These results show promise for TCR-ACT against lung cancer but highlight the presence of tissue-specific obstacles that must be overcome to enhance efficacy. For example, TAA-specific T cells accumulate less efficiently in KP tumors engineered to express strong model T cell antigens, indicating acquired immune suppressive TME phenotypes. Preliminary studies indicate that engineered therapeutic CD8+ T cells modified to express costimulatory immunomodulatory fusion proteins (IFPs) or accompanied by engineered TAA-specific CD4+ helper T cells exhibit increased function in lung tumors, indicating that increased costimulation signaling or T cell help might partially overcome T cell suppression in the lung TME. As we continue to leverage these models to advance our understanding of tissue-specific effects on therapeutic outcomes, these findings offer inroads to uncovering more effective therapies, with the ultimate goal of benefitting cancer patients.
Citation Format: Leah M. Schmidt, Oanh Tran, Shannon Oda, Quintin Inman, Sasha Tan, Cody Jenkins, Philip Greenberg. Effects of the lung tumor microenvironment on T cell therapy [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO079.