Lung Cancer Immunotherapy using new generation of TCR-engineered CD4 + T cells

Abstract Lung cancer is the leading cause of death among men and women in the U.S and world. The majority of non- small cell lung cancer (NSCLC) is diagnosed at an advanced stage. Lung cancer treatment has made tremendous progress in the past decade with advances in targeted therapies for EGFR, ALK, ROS1, MET exon 14 skip mutation, RET, NTRK, and most recently KRAS G12C along with immune checkpoint blockade (ICB) therapy, which shows 20% clinical response rate in lung cancer. Despite these advances, most patients will ultimately die of the disease. Thus, lung cancer remains an unmet medical need for development of novel therapeutics. The rationale for this application is that clinical responses to immune checkpoint therapy rely on the presence of tumor- infiltrating and antigen-specific T cells. Thus, development of tumor-specific T cell receptor-engineered-T cell immunotherapy is key to the success of immunotherapy in lung cancer. Because of the nature of tumor heterogeneity, antigen loss or negative tumor variants represents a key mechanism to develop resistance to immunotherapy. To address this issue, we recently developed academic (University of Southern California) - industrial (Immunova Therapeutics LLC) partnership to facilitate translational development of CT83-specific TCR- engineered CD4+ T cell product. CT83 is a cancer-testis antigen and is highly expressed in 40-60% of NSCLC. Furthermore, MHC-II molecules have been documented to express in lung cancer samples. To further improve its therapeutic potential, we generated an affinity-enhanced TCRM50A along with incorporation of three key technologies to reduce potential risk of TCR-mispairing, increase the pools of stem-like memory T cells and resist to T cell exhaustion and immune suppression. We named the final product as MHC-II-restricted CT83-specific CD4-dependent (MIIC4) TCRM50A-STEM2 T cells (or IMT-423) and demonstrated its robust antitumor activity in vitro and in vivo. Based on these solid data, we propose to determine the mechanisms by which MIIC4 TCRM50A- STEM2 T cells eliminate lung cancer cells (Aim 1); produce good manufacturing practice (GMP) grade master cell bank and viral particles and develop scale-up process of TCRM50A-STEM2 T cell manufacturing (Aim 2); and finally, we will determine the biodistribution and toxicity of TCRM50A-STEM2 T cells, prepare and submit an IND (investigational new drug) application to Food and Drug Administration (FDA) (Aim 3). The positive outcomes will advance the development of TCR-T cell immunotherapy for lung cancer patients, and perhaps spur for the development of immunotherapy for other CT83-positive cancers.