It is estimated by the National Cancer Institute at NIH that in 2022 more than 23,000 people in the U.S. will die from leukemia. Recent development of immunotherapies, and especially chimeric antigen receptor (CAR)-modified cell therapies, have benefitted many patients with B-cell leukemia in which they can induce remissions and even cure the disease. Unfortunately, patients with T-cell leukemia do not have such options, owing to a number of difficulties in developing engineered cell therapies for this disease. In fact, there have been little progress in treating T-cell leukemia in the past two decades, and the patients still rely on chemotherapy and bone marrow transplants, which are very t...

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It is estimated by the National Cancer Institute at NIH that in 2022 more than 23,000 people in the U.S. will die from leukemia. Recent development of immunotherapies, and especially chimeric antigen receptor (CAR)-modified cell therapies, have benefitted many patients with B-cell leukemia in which they can induce remissions and even cure the disease. Unfortunately, patients with T-cell leukemia do not have such options, owing to a number of difficulties in developing engineered cell therapies for this disease. In fact, there have been little progress in treating T-cell leukemia in the past two decades, and the patients still rely on chemotherapy and bone marrow transplants, which are very toxic and not always curative. As a result, only 1 out of 4 children (25%) and less than 1 out of 10 adults (10%) who do not respond to conventional treatment will survive for 5 years or longer. In past years, we developed and tested in the clinic the first-in-class CAR T-cell therapy for T-cell leukemia. This therapy was very safe and did not induce immunosuppression, which was a major risk of this approach. At the same time, CAR T-cells produced remarkable responses, including complete elimination of treatment-resistant leukemia in some patients. These responses were particularly robust when we added certain pharmacologic agents during cell manufacturing pointing at an important role of these drugs in shaping an optimal T-cell product. Based on the extensive data collected on this trial, we identified several mechanisms that may regulate the activity of CAR T-cells. In this proposal, we will determine factors that control the activity of CAR T-cells against leukemia and normal cells and will utilize this knowledge to develop a next-generation targeted CAR T-cell therapy for T-cell leukemia. These studies are aimed at understanding key mechanisms that regulate safety and anti-leukemic activity of CAR T-cells to ultimately improve outcomes in patients with this deadly disease.

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