Project 462032

The treatment of cancers, especially blood cancers, with the transfer of genetically-engineered T cells has demonstrated great promise. Unfortunately, many barriers remain to be overcome to allow patients with multiple other types of tumors, including solid tumors, to benefit from these T cell therapies. One of the major problems is that the environment within tumors is depleted of many essential nutrients required for T cell function. For instance, the abundance of amino acids has been demonstrated to be low within tumors. This scarcity of amino acids, particularly arginine, is believed to curtail T cell function and promote tumor growth. To study this issue, we tested the effect of acute deprivation of arginine on activated T cells. Unexpectedly, our preliminary data indicates that this sudden metabolic perturbation does not decrease T cell function. In fact, we found the opposite, as arginine deprivation increased the function of T cells and also reprogrammed their metabolism. These arginine-deprived T cells performed better than control T cells in mouse models of T cell transfer therapy. Building on these results, we tested if halofuginone (Halo), a drug known to mimic amino acid deprivation, caused changes in T cells. Indeed, our early data indicates that treatment with Halo results in the same metabolic reprogramming of T cells and increase in effector function. Accordingly, the major objectives of this project are to first further characterize and identify all the metabolic and functional changes induced by Halo treatment. Second, we aim to optimize and integrate treatment with Halo into clinically-relevant, human T cell activation protocols to allow translation of Halo into the clinic. By accomplishing these goals we will gain valuable insight into the metabolic regulation of T cell function as well as develop a drug that has the potential to improve the efficacy of T cell transfer therapies for Canadians afflicted with cancer.