Much evidence suggests that the anti- tumor immune response contributes significantly to the therapeutic efficacy of bone marrow transplantation in the treatment of patients with hematologic malignancies. In fact, the reduced relapse rates observed in the setting of allogeneic transplantation when compared to other treatment modalities is likely the result of immune mediated """"""""graft-versus-tumor"""""""" effects. Unfortunately, because of the lack of tumor-specificity of the allo-response, what is gained by a reduction in relapse rates is lost in the morbidity and mortality of graft versus host disease and its treatment. In contrast, autologous transplantation has a relatively favorable safety profile, while preserving the benefit of chemo/radiation used at dosed beyond what can be given without stem cell support. Accordingly, effects to augment anti-tumor immunity during autologous transplantation may provide means to diminish relapse rates without concomitant increase toxicity. In mouse models, a measurable graft-versus-tumor effect can upon T-cell recognition of tumor- associated antigens, rather than host minor antigens . However, this response is rapidly extinguished in the post transplant period in association with tumor progression. In contrast, vaccination during the period of immune reconstitution with irradiated autologous tumor cells plus a paracrine source of GM-CSF sustains this response, which closely correlates with freedom from relapse. Furthermore, immunization prior to the collection of the graft results in significant adoptive transfer of anti-tumor immunity to the tumor- bearing transplant recipient. Therefore, the overall objective of this proposal is to enhance the anti-tumor immune response in the setting of autologous peripheral blood stem cell (PBSC) transplantation through the successful integration of tumor-specific vaccination and adoptive immunotherapy.
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