Immunomodulation and Hematopoietic Stem Cell Transplantation
The focus of our research for the past decade has been the development of treatment strategies to modulate the immune system of patients with cancer. These efforts are based on studies of patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for hematologic malignancies. Although allogeneic transplantation can cure a proportion of these individuals, success is limited by transplant-related complications such as graft-versus-host disease (GVHD). It has long been recognized that T lymphocytes from the donor marrow play a pivotal role in the pathogenesis of GVHD. In patients undergoing HSCT, depleting donor marrow T cells with an antibody to a T cell surface structure results in a dramatic decrease in the incidence of GVHD. This approach also eliminates the need for immune-suppressive medications. These agents can be toxic, causing organ damage and increasing susceptibility to infection. Recently we have explored strategies to selectively infuse CD8+ depleted lymphocytes in hopes of prompting graft-versus-leukemia (GVL) activity without producing GVHD. We validated this strategy in a randomized trial of CD8-depleted donor lymphocyte infusions after T cell-depleted allotransplantation, and are now conducting further trials on CD8 depletion. While T cell depletion reduces GVHD, its effect on immune reactivity may lead to an increased risk of relapse of certain leukemias after transplantation. Preserving and restoring this GVL activity without compromising safety is a major thrust of our clinical and laboratory research. Working within the Cell Manipulation Core Facility, we have begun to identify specific T cell populations that may play a critical role in mediating antileukemia activity. We are exploring the role of regulatory T cells (Tregs) in the development of GVHD and GVL reactions, and have initiated a clinical trial to augment GVL reactivity using an antibody to CTLA4Ig, a molecule that controls immune reactions.We are also investigating vaccination strategies for preventing relapse in allogeneic transplant patients. Previously, in collaboration with Dr. Glenn Dranoff, we found that vaccination with irradiated autologous tumor cells - genetically engineered to secrete granulocyte-macrophage colony stimulating factor (GM-CSF) - induced histologic, cellular, and humoral evidence of autologous antitumor immunity in nontransplant patients. We are combining vaccine approaches with the administration of allogeneic donor stem cells in hopes of inducing a synergistic antileukemia effect.