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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011220-05
Application #
8763410
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2013
Total Cost
$313,579
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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
Fowler, Daniel H; Mossoba, Miriam E; Steinberg, Seth M et al. (2013) Phase 2 clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after low-intensity allogeneic hematopoietic cell transplantation. Blood 121:2864-74
Floisand, Y; Brinch, L; Gedde-Dahl, T et al. (2012) Ultra-short course sirolimus contributes to effective GVHD prophylaxis after reduced-intensity allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 47:1552-7
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Mossoba, Miriam E; Onda, Masanori; Taylor, Justin et al. (2011) Pentostatin plus cyclophosphamide safely and effectively prevents immunotoxin immunogenicity in murine hosts. Clin Cancer Res 17:3697-705
Amarnath, Shoba; Chen, Hao; Foley, Jason E et al. (2011) Host-based Th2 cell therapy for prolongation of cardiac allograft viability. PLoS One 6:e18885
Amarnath, Shoba; Flomerfelt, Francis A; Costanzo, Carliann M et al. (2010) Rapamycin generates anti-apoptotic human Th1/Tc1 cells via autophagy for induction of xenogeneic GVHD. Autophagy 6:523-41
Amarnath, Shoba; Costanzo, Carliann M; Mariotti, Jacopo et al. (2010) Regulatory T cells and human myeloid dendritic cells promote tolerance via programmed death ligand-1. PLoS Biol 8:e1000302
Granville, Courtney A; Memmott, Regan M; Balogh, Andria et al. (2009) A central role for Foxp3+ regulatory T cells in K-Ras-driven lung tumorigenesis. PLoS One 4:e5061
Mariotti, Jacopo; Foley, Jason; Jung, Unsu et al. (2008) Ex vivo rapamycin generates apoptosis-resistant donor Th2 cells that persist in vivo and prevent hemopoietic stem cell graft rejection. J Immunol 180:89-105

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