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Daniel H. Fowler, M.D.
Immune Therapy Using Rapamycin-Resistant T Cells
Graft Engineering Using Rapamycin-Resistant Donor Th2 Cells for Low-Intensity Allogeneic Hematopoietic Stem Cell Transplantation
Immune T cells can be functionally defined in terms of their cytokine secretion profile: CD4+, Th1 and CD8+, Tc1 cells primarily secrete IL-2 and IFN-, whereas CD4+, Th2 and CD8+, Tc2 cells primarily secrete IL-4, IL-5, IL-10, and IL-13. These Th1/Tc1 (type I) and Th2/Tc2 (type II) subsets are cross-regulatory in vivo: in the setting of murine allogeneic bone marrow transplantation, we have found that type I cells initiate graft-versus-host disease (GVHD), whereas type II cells mediate reduced GVHD and inhibit type I-mediated GVHD. In murine models, we have also found that graft-versus-leukemia (GVL) and graft-versus-tumor (GVT) effects against breast cancer cells are primarily mediated through type I immunity. Although type II cells may be therapeutic for indolent malignancy or minimal residual disease, it is likely that type I immunity will be required to cure more aggressive or advanced disease. As such, we are currently evaluating methods to utilize type I immunity in the allogeneic transplantation setting, including a strategy that administers a T cell replete allograft (type I immunity) that is supplemented by additional donor CD4+, Th2 cells. In an initial clinical trial involving n=28 Th2 cell recipients, we established a dose of Th2 cells that resulted in the post-transplant secretion of both type I and type II cytokines and was associated with significant anti-tumor responses in patients with refractory hematologic malignancy; however, GVHD remained a limiting factor to this approach. In light of this information, we have developed a second-generation approach to Th2 cell therapy that involves Th2 cell generation in vitro in the presence of the immune suppression drug rapamcyin (sirolimus). Such rapamycin-resistant murine Th2 cells (Th2.rapa) have an enhanced capacity to promote type II immunity and to prevent GVHD; furthermore, in graft rejection models, we have found that donor Th2.rapa cells facilitate the engraftment of genetically disparate allografts by a mechanism that involves the Th2 polarization of host T cells. Based in part on these results, a clinical trial utilizing Th2.rapa cells has been initiated (protocol 04-C-0055). This protocol also utilizes a short-course of rapamycin drug therapy post-transplant. In the current protocol design, subjects receive allogeneic hematopoietic stem cell transplantation and donor Th2.rapa cells after either a very low intensity conditioning regimen (fludarabine in combination with a total cyclophosphamide dose, 1200 mg/m2); in some recipients, patients receive the Th2.rapa cells remote from any transplant preparative regimen. The overall goal of these studies is to improve the safety of transplantation (by reducing the intensity of conditioning; by modulating GVHD) and to improve the anti-tumor efficacy of transplantation (by infusion of rapamycin-resistant effector T cells of balanced cytokine profile).
Among our collaborators are Ronald Gress, David Halverson, Steven Pavletic, and Dennis Hickstein (ETIB); David Stroncek, Hanh Khuu, Susan Leitman (NIH Department of Transfusion Medicine); Drs. Scott Rowley, Michele Donato, Andre Goy, Andrew Pecora, and Robert Korngold at the Hackensack University Medical Center; and Drs. Carl June and Bruce Levine (Abramson Family Cancer Research Institute; University of Pennsylvania Cancer Center).
This page was last updated on 11/21/2013.