In this project, we have found that immune T cells that are expanded ex vivo in the presence of rapamycin can develop resistance to rapamycin provided that necessary co-stimulation and cytokine signals are provided. Importantly, we have shown that a great variety of functional T cell subsets can be generated in rapamycin, including the Th1, Th2, Tc1, Tc2, and regulatory T cell subsets. Of significance, we have found that T cells that acquire rapamycin-resistance also attain an apoptosis resistance phenotype;this biology has functional significance because upon adoptive T cell transfer, such rapamycin- and apoptosis-resistant T cell have increased in vivo survival and therefore mediate more potent immune T cell reactions relative to control T cells. We have recently found that rapamycin causes polarized T cells to undergo a process known as autophagy;the anti-apoptotic phenotype of rapamycin-generated T cells is dependent upon autophagy. We have observed that this biology occurs with both murine T cells and human T cells. Given this understanding, we have initiated pilot clinical trials at the NIH Clinical Center using rapamycin-resistant T cells for the therapy of leukemia, lymphoma, and renal cell carcinoma.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
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National Cancer Institute Division of Basic Sciences
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Castiello, Luciano; Mossoba, Miriam; Viterbo, Antonella et al. (2013) Differential gene expression profile of first-generation and second-generation rapamycin-resistant allogeneic T cells. Cytotherapy 15:598-609
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