Autologous bone marrow transplantation (BMT) is effective therapy for patients with high-risk lymphomas and acute leukemias, with apparent cure in 20-50% of patients. Autologous BMT has also shown promising results in breast cancer where a 10-20% disease-free survival has been reported in patients with metastatic disease. Tumor recurrence is the major cause for autologous BMT failure. Animal models suggest that a 25-50% improvement in relapse rates would probably require no more than an average of 1-2 logs of additional tumor cell kill; however, this small amount of additional tumor likely represents the most drug-resistant population of cells. In addition, cytotoxic regimens for BMT are at or near non-hematologic dose-limiting toxicity hindering a further increase in the intensity of these regimens. Immunologic approaches for eradicating tumor should be particularly effective after autologous BMT, as they would be used in a period of minimal residual disease, and should be truly non-cross-resistant with the cytotoxic therapy. A syndrome similar to graft-versus-host disease (GVHD) can be induced with cyclosporine (CsA) in animal models of autologous BMT. The animal studies suggest that this syndrome generates antitumor activity similar to that seen with allogeneic GVHD, but without the toxicity associated with allogeneic GVHD. Autologous GVHD can also be induced with CsA in patients, and it appears that autologous GVHD also produces a clinically significant antitumor effect. The magnitude of this anti-tumor effect will be determined in phase II and III trials of CsA-induced autologous GVHD in patients with relapsed non-Hodgkin's lymphomas and acute myeloid leukemia. Preclinical animal studies have demonstrated that upregulating Ia expression (the target antigen of autologous GVHD) with alpha or gamma interferon will enhance the anti-tumor effect associated with autologous GVHD without increased toxicity. We have found that alpha interferon is a potent upregulator of Ia expression in hematologic malignancies whereas only gamma interferon will upregulate Ia in breast cancer. Trials of alpha interferon with autologous GVHD in patients with relapsed lymphomas and gamma interferon with autologous GVHD patients with metastatic breast cancer have been initiated. Mechanisms responsible for the anti-tumor effect and the effectiveness of immunomodulation will be studied in vitro using effector cells and tumor obtained from the patients. These clinical and laboratory studies should provide new strategies for improving the efficacy of autologous BMT.
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