ZIA BC 011220 (ZIA) | |||
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Title | Understanding T Cell Rapamycin Resistance | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Fowler, Daniel | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $224,566 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2013 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Bone Marrow Transplantation (40.0%) Cancer (100.0%) |
Hodgkins disease (10.0%) Kidney Cancer (20.0%) Kidney Disease (20.0%) Leukemia (40.0%) Non Hodgkins Lymphoma (30.0%) Urinary System (20.0%) |
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Research Type | |||
Systemic Therapies - Clinical Applications | |||
Abstract | |||
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. |