Project 4 Program Director/Principal Investigator (Last, First, Middle): JoneS, Rlchard J. Allogeneic BMT (alloBMT) is the treatment of choice for eligible patients with hematologic malignancies that are incurable by chemotherapy. Donor T cell mediated graft-versus-tumor effects have the potential to eradicate residual cancer cells that survive pre-transplant cytotoxic therapies. T cell recognition of alloantigens as well as leukemia-associated antigens (LAAs) has been reported to contribute to this effect. Historically, the beneficial impact of allorecognition on relapse-free survival has been largely offset by the toxicities of graft-versus-host-disease (GVHD) and its treatment, and attempts to diminish the latter by donor T cell depletion or recipient immunosuppression have resulted in increased rates of relapse. The studies pioneered in PROJECT 4 have led to the development of high doses of cyclophosphamide.in the early post- BMT period (PT/Cy) as a strategy for generating bi-directional tolerance. As a result, patients treated with PT/Cy have achieved stable hematopoietic engraftment with low rates of GVHD, even in HLA-haploidentical donor/recipient pairs. With this innovation, relapse rather than GVHD is now the major cause of transplant failure. As demonstrated by mouse studies in PROJECT 2, adoptive transfer of lymphocytes from donors primed with a cancer vaccine significantly reduces relapse rates in syngeneic, tumor-bearing recipients. These results led to clinical trials testing the integration of a therapeutic leukemia vaccine into the setting of autologous BMT, which demonstrated that the response to a vaccine administered pirior to graft harvest correlated significantly with post-BMT relapse-free survival. We now propose to evaluate donor vaccination as a strategy to improve the outcome of alloBMT. However, two impediments in bringing donor vaccination into the alloBMT setting are: 1) the risk of inducing autoimmunity in the healthy donor, and 2) the potential to increase the incidence or severity of GVHD. Accordingly, we have chosen to target an antigen that is not expressed in normal tissues of healthy donors, but is aberrantly expressed in many myeloid leukemias. A collaboration between PROJECT 1 and PROJECT 2 has led to the discovery that PRAME, a cancer testis antigen, is one of the few identified LAAs that is abundantly expressed in leukemic stem cells (LSCs), but is absent from normal hematopoietic stem cells. This proposal seeks to link these three fundamental discoveries in GVHD prophylaxis (Project 4), adoptive transfer of vaccine pnmed immunity (Project 2), and LSC antigen expression (Project 1) to improve the outcome of alloBMT.
With newer procedures for reducing the morbidity and mortality of alloBMT, the major cause of transplant failure is relapse. This proposal addresses this limitation by studying vaccination of healthy BMT donors against a leukemia-associated antigen, so as to transfer immune cells capable of killing residual leukemia in the patient. The proposal also studies shortening the duration of pharmacologic immunosuppression so as to facilitate the timely application of post-transplantation immunotherapy.
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