The goal of hematopoietic cell transplantation (HCT) for hematologic malignancies is sustained eradication of disease. While high dose chemo/radiotherapy can contribute to tumor destruction, it is clear from pre-clinical models and clinical studies that immune mediated allogeneic effects, termed graft-vs-leukemia (GVL) effects, are central to the therapeutic effect of allogeneic HCT. Successful trials of adoptive immunotherapy with donor lymphocytes infusions (DLI) and promising reports of non-myeloablative stem cell transplants (NST) have shifted the therapeutic focus of allogeneic hematopoietic cell transplantation (HCT) away from high dose chemo/radiotherapy and toward anti-tumor effects mediated by the donor's immune system. Initial attempts to augment this graft-vs-leukemia (GVL) activity after NST have included early withdrawal of immune suppression or early administration of unfractionated donor lymphocyte infusions. The success of these strategies has been limited by the accelerated development of GVHD. If leukemia specific responses rather than broad allogeneic reactivity could be induced, then it might be possible to promote GVL in the absence of GVHD. The studies proposed in this Project will examine strategies aimed at inducing and augmenting anti-leukemic immunity early after allogeneic transplantation without necessarily stimulating broad allo-reactive responses. Based upon murine models and human trials that have established the feasibility, safety, and immunologic activity of GM-CSF secreting autologous tumor vaccines, we will initiate a series of clinical trials utilizing this strategy in the allogeneic transplant setting. We hypothesize that paracrine secretion of GM-CSF by the irradiated/modified leukemia cells should attract professional antigen presentation cells (APCs), such as dendritic cells, to the leukemia cells, and stimulate these APCs to present leukemia antigens to donor lymphocytes, thereby triggering a leukemia specific allo-immune effect. We hope from these trials to establish the optimal immunologic milieu to promote immunization early after transplantation. We will correlate functional and phenotypic parameters of immune reconstitution with vaccine mediated induction of tumor specific immunity, paying particular attention to the role of regulatory T cells. Examination of T and B cell responses to vaccination will hopefully lead to discovery of genes that could serve as targets for subsequent vaccination protocols. Further augmentation of tumor specific immunity through CTLA-4 antibody blockade will be explored in the allogeneic transplant setting in patients who have or have not been previously immunized with GM-CSF based vaccines.
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