Professor of Medicine
Harvard Medical School
Connell O'Reilly Cell Manipulation and Gene Transfer Laboratory
Cell Manipulation Core Facility
Dana-Farber Cancer Institute
44 Binney Street
Boston, MA 02115
Office phone: (617) 632-3465
Fax: (617) 632-5167
Allogeneic hematopoietic stem cell transplantation (HSCT) is widely used in the treatment of patients with hematologic malignancies, but it remains a very toxic treatment. Both the effectiveness and toxicity of HSCT are primarily mediated by donor T cells in the stem cell graft. Those T cells that target antigens expressed on recipient leukemia cells play an important role in eradicating residual malignant cells and preventing leukemia relapse after transplant. Those T cells that target antigens expressed by normal tissues in the recipient are the primary mediators of graft versus host disease (GVHD) and thus lead to substantial toxicities. In the past three years, our laboratory has focused on the development of novel strategies for identifying the target antigens of graft versus leukemia (GVL) and GVHD.
To characterize immune function after transplant, a series of laboratory studies first examined the phenotype and function of engrafted donor cells at various times after HSCT, demonstrating significant defects in the function of mature T cells and the reconstitution of new T cells with a diverse T cell repertoire. In part, this immune deficiency appears to be due to defects in thymic function and the ability to generate new T cells from marrow stem cells. These defects are most severe for 3-6 months after transplant, but the generation of new T cells usually recovers to normal levels 6-12 months post transplant. Infusion of additional mature donor T cells appears to enhance the reconstitution of the donor immune system following transplant.
Donor T cells are also the primary cells responsible for elimination of residual leukemia that may persist after transplant despite intensive high-dose therapy. In a series of studies, we have begun to identify several leukemia-associated antigens that appear to be targets of the GVL response after HSCT. We found that patients who had evidence of immunologic rejection of their leukemia also developed antibody responses to antigens expressed by these tumor cells. The development of high-titer antibody responses to novel leukemia-associated antigens correlated closely with immune rejection of the leukemia. Antibody responses to the antigens were not detectable in patients with acute or chronic GVHD and in patients who had no evidence of GVL. Further analysis of two of these antigens, termed CML28 and CML66, demonstrated that they are widely expressed by leukemia cells and other malignant cells - making these antigens potential targets for future vaccines to enhance immunity and prevent relapse after allogeneic HSCT.