Previously Funded Research

Joshua Veatch, MD, PhD

Fred Hutchinson Cancer Research Center

Research Project:

Using CD4+ T cells to target the tumor microenvironment in non-small cell lung cancer

Summary:

“Helper” CD4 T cells coordinate the functions of other immune cells and are important for responses to immune therapies like PD-1 inhibitors in mouse models, but their functions in lung cancer are not well understood. We have recently found that we can identify the subset of CD4 T cells in melanoma patients that are specific for tumors based on a unique signature, and that the presence of these cells correlates with the activation of other immune cells like “Killer” CD8 T cells and macrophages. CD4 T cells with a similar signature exist in lung cancer, and we propose to see whether these cells are also specific for the tumor and whether they correlate with greater immune activation. The eventual goal is to use CD4 T cells targeting tumor antigens as a tool to activate immune cells within lung cancer to enhance other immune therapies including PD-1 inhibitors.

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Final report:
This project had to change aims because of similar work that was published by another group. The researcher has focused on isolation of potential T cell receptors for use in CD4 based T cell therapy. Two potential receptors have been identified that target the neoantigen of an EGFR L858 mutation from an actual patient. A model for preclinical testing is being built with the intention of doing a clinical trial to test CD4 T cell therapy in EGFR mutated NSCLC. The researcher is working with a mouse model using CD4 T cell therapy to understand the mechanism of CD4 T cell therapy and develop ways of targeting inflammatory signals to tumors with CD4 T cells in order to increase antitumor immunity. Targeting of IL-12 and IL-18 signals to tumors with CD4 T cells results in the activation of CD8 T cells and myeloid cells in the tumor microenvironment which has led a decrease in suppressive regulatory T cells and an increase in activated inflammatory monocytes.

Impact:
Cell therapy, specifically engineered T cells (immune cells), has been successful in the treatment of hematologic malignancies and melanoma. There has been a great deal of interest in establishing its use in other solid tumors. The researcher has identified 2 CD4 receptors that could represent viable targets for cellular therapy. This approach is being used to develop a model of a resistant EFGRmut+ NSCLC. Since the majority of patients with EGFRmut+ cancer are not cured by their treatment this could potentially open up a novel approach for therapy. The researcher is at the Fred Hutchenson Cancer Center which has long been known for their clinical trials using cellular therapy. If successful with his research, the scientist feels confident that this approach could lead to a clinical trial.