Our Science – Fowler Website

Daniel H. Fowler, M.D.

Experimental Transplantation and Immunology Branch Head, Cytokine Biology Section Investigator 10 Center Drive Building 10 CRC, Room 3-3132 Bethesda, MD 20892-1203 Phone:   301-435-8641 Fax:   301-480-4354 E-Mail:   dhfowler@helix.nih.gov Link: Other Homepage

Biography

Upon completion of medical school and residency at Wayne State University, Dr. Fowler completed medical oncology training at the NCI in 1991. After a research fellowship in the NCI Experimental Immunology Branch, he returned to the NCI's former Medicine Branch in 1995. In 1996, he received the Translational Research Award from the Leukemia Society of America. Dr. Fowler was selected as a tenure track investigator at the NIH, where he continues to develop new approaches to modulation of the immune system after allogeneic transplantation. Current research utilizes animal models and pilot clinical trials to evaluate the role of ex vivo expanded donor Th2 cells that are generated in the presence of the immune modulation drug rapamycin.

Research

View Dr. Fowler's Current Clinical Trials

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 8/7/2008.