Murine Hematopoietic Stem Cell Transplantation Models for Graft-versus-tumor, Graft-versus-host disease, and Post-transplant Immune Reconstitution
Allogeneic hematopoietic stem cell transplantation (HSCT) is an important therapy for a variety of malignancies, including leukemias, lymphomas, and advanced solid tumors, such as renal cell carcinoma, as well as a number of nonmalignant diseases, such as aplastic anemia and severe combined immunodeficiency. My laboratory uses murine HSCT models to study clinically important problems in HSCT and to test novel therapeutic strategies.
The therapeutic benefits of HSCT are not only derived from the opportunity to give higher doses of chemotherapy and/or radiation but also from a so-called graft-versus-tumor (GVT) effect, whereby the graft attacks host malignancy.
Yet HSCT is not without complications: graft-versus-host-disease (GVHD) and immune deficiencies after HSCT are important complications of allogeneic HSCT. GVHD is a progressive systemic illness with immunosuppression, wasting, and specific damage to skin, liver, intestines, and the immune system. Even with prophylaxis, most adults have some degree of GVHD after allogeneic bone marrow transplantation.
In continuing collaboration with Dr. Alan Houghton's tumor immunology laboratory here at MSKCC, we are studying the efficacy of post-transplant tumor vaccination in murine HSCT recipients with the goal of enhancing the graft-versus-tumor (GVT) effect.
Although the malignant relapse rate (often indicative of the strength of the GVT effect) is usually inversely related to the severity of GVHD in a given patient, we hypothesize that immunization against specific-tumor antigens, with suitable adjuvant strategies in the post-transplant setting, may decrease the risk of malignant relapse without enhancing the risk of GVHD.
We are employing a variety of tumor vaccines, including whole-cell vaccines, peptide vaccines, and DNA vaccines. We are also studying combinations of vaccines and immune adjuvants (IL-15, anti-CTLA-4 antibody) as well as immune reconstituting agents (IL-7, KGF, T cell precursors). Our vaccine targets include melanoma antigens as well as the leukemia antigen WT1. In addition, we are modeling adoptive transfer cellular therapies in the post-transplant setting.