In cancer, the immune system fails to clear tumor cells. A major cause is T cell exhaustion, a dysfunctional state of T cells caused by chronic exposure to tumor antigens. Over the last decade, adoptive T cell therapy such as chimeric antigen receptor (CAR) T cell therapy have achieved remarkable successes in treating some types of cancers. However, T cell exhaustion limits the ability of therapeutic T cells to induce sustained tumor control in a larger population of cancer patients, especially those with solid tumor. Thus, there is an unmet need to develop therapeutic T cells that resist exhaustion and induce long-term tumor control. A T cell population resembles stem cells and can both sel...

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In cancer, the immune system fails to clear tumor cells. A major cause is T cell exhaustion, a dysfunctional state of T cells caused by chronic exposure to tumor antigens. Over the last decade, adoptive T cell therapy such as chimeric antigen receptor (CAR) T cell therapy have achieved remarkable successes in treating some types of cancers. However, T cell exhaustion limits the ability of therapeutic T cells to induce sustained tumor control in a larger population of cancer patients, especially those with solid tumor. Thus, there is an unmet need to develop therapeutic T cells that resist exhaustion and induce long-term tumor control. A T cell population resembles stem cells and can both self-renew and replenish other T cell subsets. Importantly, stem-like T cells induce strong and persistent immunity during adoptive cell therapy including CAR T cell therapy. Our published studies have shown that stem-like properties in T cells can be programmed by certain transcription factors. Our unpublished data reveal potential mechanism of how T cells maintain stemness despite persistent stimulation through antigen receptor. In addition, we engineered T cells in which the molecular program of stem-like T cells can be induced by a small molecule drug. In this study, we will dissect the molecular program required for stem-like properties and resistance of exhaustion in antitumor T cells and evaluate strategy to chemically control T cell differentiation to enhance the efficacy of CAR T cells against solid tumor. The result from this study will shed light on the molecular program controlling T cell stemness versus exhaustion and form the scientific foundation for future immunotherapies that allow dynamic control of T cell immune response to exert greater tumor control in a larger population of cancer patients.

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