Daniel H. Fowler, M.D.
Daniel H. Fowler, M.D.
Senior Investigator
Head, Cytokine Biology Section

Center for Cancer Research
National Cancer Institute

Building 10 - Hatfield CRC, Room 3-3132
Bethesda, MD 20892-1203
301-435-8641

Allogeneic stem cell transplantation (SCT) is limited by graft-versus-host disease (GVHD), graft rejection, conditioning-related toxicity, and insufficient graft-versus-tumor (GVT) effects. Through use of murine models and clinical trials, the Fowler Lab has developed a new approach to allogeneic SCT that begins to overcome these obstacles, namely: minimization of host conditioning (pentostatin-based regimens that do not induce neutropenia) and infusion of donor CD4+ T cells with an improved balance of GVT and GVHD effects (a mix of Th1 and Th2 cells rendered rapamycin-resistant). A phase II clinical trial using the first generation of this approach has been published and next generation trials are being implemented in patients with chemotherapy-refractory lymphoma.

Areas of Expertise
1) Allogeneic stem cell transplantation 2) Adoptive T cell therapy 3) Th1/Th2 biology 4) Rapamycin 5) Graft-versus-host disease 6) Pentostatin

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-γ, 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 NCI-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).

Collaborators. Among our collaborators are Ronald Gress, David Halverson, Steven Pavletic, and Dennis Hickstein (ETIB); David Stroncek, Hanh Khuu, and 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).

Scientific Focus Areas:
Cancer Biology, Clinical Research, Immunology, Stem Cell Biology
Selected Recent Publications
  1. Fisher V, Khuu H, David-Ocampo V, Byrne K, Pavletic S, Bishop M, Fowler DH, Barrett AJ, Stroncek DF.
    Transfusion. 54: 1088-92, 2014. [ Journal Article ]
  2. Fowler DH.
    Immunol Rev. 257: 210-25, 2014. [ Journal Article ]
  3. Elinoff JM, Bagci U, Moriyama B, Dreiling JL, Foster B, Gormley NJ, Salit RB, Cai R, Sun J, Beri A, Reda DJ, Fakhrejahani F, Battiwalla M, Baird K, Cuellar-Rodriguez JM, Kang EM, Pavletic SZ, Fowler DH, John Barrett A, Lozier JN, Kleiner DE, Mollura DJ, Childs RW, Suffredini AF.
    Biol. Blood Marrow Transplant. 20: 969-78, 2014. [ Journal Article ]
  4. Bevans MF, Mitchell SA, Barrett JA, Bishop MR, Childs R, Fowler D, Krumlauf M, Prince P, Shelburne N, Wehrlen L, Yang L.
    Biol Blood Marrow Transplant. 20: 387-95, 2014. [ Journal Article ]
  5. Bassim CW, Fassil H, Mays JW, Edwards D, Baird K, Steinberg SM, Williams KM, Cowen EW, Mitchell SA, Cole K, Taylor T, Avila D, Zhang D, Pulanic D, Grkovic L, Fowler D, Gress RE, Pavletic SZ.
    Bone Marrow Transplant. 49: 116-21, 2014. [ Journal Article ]

Dr. Fowler is tenured senior clinical investigator at the Center for Cancer Research, National Cancer Institute (NCI) in Bethesda, Md. Dr. Fowler received his M.D. (1987) from Wayne State University in Detroit, Mich. After internal medicine and pediatrics training at Wayne State, Dr. Fowler completed the medical oncology fellowship at NCI (1993). After fellowship, Dr. Fowler evaluated the role of Th1/Th2 and Tc1/Tc2 donor T-cell subsets in the modulation of murine allogeneic transplantation responses, and is currently implementing clinical trials to evaluate T cell allograft engineering strategies. The most recent version of the clinical trial efforts is evaluating rapamycin-resistant donor T cells; a phase II clinical trial has been completed, and follow-up studies are now being implemented.

Name Position
Shoba M. Amarnath Ph.D. Staff Scientist
Austin Cheng Summer Student
Tania Felizardo Ph.D. Postdoctoral Fellow (Visiting)
Jason E. Foley M.S. Research Biologist
David C. Halverson M.D. Staff Clinician
Steven Larrick Summer Student
Nina Rao Postbaccalaureate Fellow
Samuel Taylor Postbaccalaureate Fellow

Summary

Allogeneic stem cell transplantation (SCT) is limited by graft-versus-host disease (GVHD), graft rejection, conditioning-related toxicity, and insufficient graft-versus-tumor (GVT) effects. Through use of murine models and clinical trials, the Fowler Lab has developed a new approach to allogeneic SCT that begins to overcome these obstacles, namely: minimization of host conditioning (pentostatin-based regimens that do not induce neutropenia) and infusion of donor CD4+ T cells with an improved balance of GVT and GVHD effects (a mix of Th1 and Th2 cells rendered rapamycin-resistant). A phase II clinical trial using the first generation of this approach has been published and next generation trials are being implemented in patients with chemotherapy-refractory lymphoma.

Areas of Expertise
1) Allogeneic stem cell transplantation 2) Adoptive T cell therapy 3) Th1/Th2 biology 4) Rapamycin 5) Graft-versus-host disease 6) Pentostatin

Clinical Trials

Research

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-γ, 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 NCI-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).

Collaborators. Among our collaborators are Ronald Gress, David Halverson, Steven Pavletic, and Dennis Hickstein (ETIB); David Stroncek, Hanh Khuu, and 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).

Scientific Focus Areas:
Cancer Biology, Clinical Research, Immunology, Stem Cell Biology

Publications

Selected Recent Publications
  1. Fisher V, Khuu H, David-Ocampo V, Byrne K, Pavletic S, Bishop M, Fowler DH, Barrett AJ, Stroncek DF.
    Transfusion. 54: 1088-92, 2014. [ Journal Article ]
  2. Fowler DH.
    Immunol Rev. 257: 210-25, 2014. [ Journal Article ]
  3. Elinoff JM, Bagci U, Moriyama B, Dreiling JL, Foster B, Gormley NJ, Salit RB, Cai R, Sun J, Beri A, Reda DJ, Fakhrejahani F, Battiwalla M, Baird K, Cuellar-Rodriguez JM, Kang EM, Pavletic SZ, Fowler DH, John Barrett A, Lozier JN, Kleiner DE, Mollura DJ, Childs RW, Suffredini AF.
    Biol. Blood Marrow Transplant. 20: 969-78, 2014. [ Journal Article ]
  4. Bevans MF, Mitchell SA, Barrett JA, Bishop MR, Childs R, Fowler D, Krumlauf M, Prince P, Shelburne N, Wehrlen L, Yang L.
    Biol Blood Marrow Transplant. 20: 387-95, 2014. [ Journal Article ]
  5. Bassim CW, Fassil H, Mays JW, Edwards D, Baird K, Steinberg SM, Williams KM, Cowen EW, Mitchell SA, Cole K, Taylor T, Avila D, Zhang D, Pulanic D, Grkovic L, Fowler D, Gress RE, Pavletic SZ.
    Bone Marrow Transplant. 49: 116-21, 2014. [ Journal Article ]

Biography

Dr. Fowler is tenured senior clinical investigator at the Center for Cancer Research, National Cancer Institute (NCI) in Bethesda, Md. Dr. Fowler received his M.D. (1987) from Wayne State University in Detroit, Mich. After internal medicine and pediatrics training at Wayne State, Dr. Fowler completed the medical oncology fellowship at NCI (1993). After fellowship, Dr. Fowler evaluated the role of Th1/Th2 and Tc1/Tc2 donor T-cell subsets in the modulation of murine allogeneic transplantation responses, and is currently implementing clinical trials to evaluate T cell allograft engineering strategies. The most recent version of the clinical trial efforts is evaluating rapamycin-resistant donor T cells; a phase II clinical trial has been completed, and follow-up studies are now being implemented.

Team

Name Position
Shoba M. Amarnath Ph.D. Staff Scientist
Austin Cheng Summer Student
Tania Felizardo Ph.D. Postdoctoral Fellow (Visiting)
Jason E. Foley M.S. Research Biologist
David C. Halverson M.D. Staff Clinician
Steven Larrick Summer Student
Nina Rao Postbaccalaureate Fellow
Samuel Taylor Postbaccalaureate Fellow