Autologous bone marrow transplantation (BMT) is effective therapy for patients with high-risk lymphomas and acute leukemias. Autologous BMT has also shown promising preliminary results in some drug-responsive solid tumors like breast and ovarian cancer. Tumor recurrence is the major cause of autologous BMT failure. Modification of cytotoxic preparative regimens has not made impact on occurrence of tumor relapse after autologous BMT. Moreover, currently used cytotoxic regimens for BMT are at or near non- hematologic dose-limiting toxicity hindering a further increase in the intensity of these preparative regimens. Innovative approaches for improving the antitumor activity of autologous BMT are therefore needed. A syndrome similar to graft-versus-host disease (GVHD) can be induced with cyclosporine (CsA) in animal models of autologous GVHD. The animal studies demonstrate that this syndrome generates antitumor activity similar to that seen with allogeneic GVHD without significant post-transplant mortality. This syndrome is mediated by autoreactive T-lymphocytes directed against Ia antigens. Both animal models and clinical data demonstrate that it should be possible to amplify the antitumor effect associated with autologous GVHD by modulating the effector and/or the target cells. The interferons, that upregulate Ia antigen expression on tumor cells, and low-dose IL-2 enhance the antitumor effect of autologous GVHD, without increasing toxicity. The overall aim of this aim of this proposal is to continue studies on the antitumor effect of autologous GVHD in preclinical models and clinically. Specifically, animal models will be used to further investigate the mechanisms responsible for the antitumor effect of autologous GVHD and to examine approaches for enhancing the antitumor effect particularly by enhancing tumor cell recognition. Clinical studies of CsA-induced autologous GVHD will be based on the principles developed from the preclinical studies. Laboratory studies monitoring the immunomodulatory effects of autologous GVHD will guide the clinical trials, particularly as to the best means to enhance the antitumor efficacy of autologous GVHD.
Showing the most recent 10 out of 456 publications
