title: Rapamycin-resistant effector T-cell therapy.
abstract: Pharmacologic inhibition of the mechanistic target of rapamycin (mTOR) represents a stress test for tumor cells and T cells. Mechanisms exist that allow cells to survive this stress, including suboptimal target block, alternative signaling pathways, and autophagy. Rapamycin-resistant effector T (T-Rapa) cells have an altered phenotype that associates with increased function. Ex vivo rapamycin, when used in combination with polarizing cytokines and antigen-presenting-cell free costimulation, is a flexible therapeutic approach as polarization to T-helper 1 (Th1)- or Th2-type effectors is possible. Murine T-Rapa cells skewed toward a Th2-type prevented graft rejection and graft-versus-host disease (GVHD) more potently than control Th2 cells and effectively balanced GVHD and graft-versus-tumor (GVT) effects. A phase II clinical trial using low-intensity allogeneic hematopoietic cell transplantation demonstrated that interleukin-4 polarized human T-Rapa cells had a mixed Th2/Th1 phenotype; T-Rapa cell recipients had a balanced Th2/Th1 cytokine profile, conversion of mixed chimerism toward full donor chimerism, and a potentially favorable balance between GVHD and GVT effects. In addition, a phase I clinical trial evaluating autologous T-Rapa cells skewed toward a Th1- and Tc1-type is underway. Use of ex vivo rapamycin to modulate effector T-cell function represents a promising new approach to transplantation therapy.
authors: Experimental Transplantation and Immunology Branch, National Cancer Institute, Center for Cancer Research, Bethesda, MD, USA.
authors: Daniel H
authors: DH
authors: Fowler
mesh_terms: D000818:Animals; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D002986:Clinical Trials as Topic; D004351:Drug Resistance; D006086:Graft vs Host Disease / Q000209:etiology / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D020123:Sirolimus / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Th1/Th2/Th17; apoptosis/autophagy; cytokines; graft versus host disease; transplantation