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Daniel H. Fowler, M.D.
Allogeneic Th1/Tc1 and Th2/Tc2 Cells for the Treatment of Hematologic Malignancy and Breast Cancer
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 through day 14 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) or without fludarabine/cyclophosphamide conditioning. Because initial subjects have had rapid donor engraftment and a low incidence of GVHD, it is possible that donor Th2 cells may find utility as a new strategy to promote engraftment with reduced GVHD. We have also initiated a new protocol (08-C-0088) that will extend our efforts in low-intensity transplantation to the setting of metastatic renal cell carcinoma using the following transplant strategy: pentostatin-based immune depletion, Th2.rapa cell infusion, and single-agent sirolimus GVHD prophylaxis.
Among our collaborators are Michael Bishop, Ronald Gress (ETIB); Olivier Rixe, Tito Fojo (NCI-Medical Oncology Branch); David Stroncek, Hanh Khuu, Susan Leitman (NIH Department of Transfusion Medicine); and Carl June and Bruce Levine (Abramson Family Cancer Research Institute; University of Pennsylvania Cancer Center).
This page was last updated on 2/19/2013.