Recently there has been renewed interest in strategies aimed at generating active antitumor immune responses in patients with cancer. In most instances, the identity of the relevant tumor associated antigens is not known. Consequently, autologous or allogeneic tumor cells have been used as a source of antigen for vaccination. This approach has taken advantage of the recent identification of factors that regulate the priming of systemic immunity. Tumor cells genetically modified in vitro to secrete cytokines or express co-stimulatory molecules have been studied for the ability to activate systemic antitumor immunity when used as a vaccine. Such studies in animal models demonstrate that vaccination with a number of genetically modified tumor cell vaccine constructs results in protection against a subsequent systemic tumor challenge, or eradication of a small pre-established systemic tumor burden. These studies form the basis for several on going phase I clinical trials exploring this approach in patients with solid tumors. While these early studies have been promising, there is evidence to suggest that the systemic immunity primed by tumor vaccination has limited efficacy against more advanced tumor burdens. We and others have shown that with time, tolerance to tumor antigens develops, and with further tumor progression, a more global tumor-induced immunosuppression occurs. Consequently, tumor cell vaccination may hold the greatest promise if preceded by a significant reduction in tumor burden. For many malignancies, autologous bone marrow transplantation offers the greatest opportunity to achieve a state of minimal residual disease. Furthermore, the reconstitution of the immune system following transplantation may restore the capacity to respond to tumor associated antigens to which tolerance had been established. The major focus of this project is to explore the integration of tumor-specific active immunotherapy with myeloablative chemotherapy and autologous peripheral blood stem-cell (PBSC) transplantation. This strategy will be studied in an animal model of B cell lymphoma, as well as in patients with indolent lymphoma and multiple myeloma. Targeting these initial studies to the therapy of two B-cell lineage malignancies will enable an analysis of immunity raised to a defined tumor-specific antigen, i.e. immunoglobulin idiotype protein. in this way, we seek to address unambiguously the ability to generate tumor specific immunity in the transplant setting.
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