CHEMOTHERAPY INDUCED IMMUNE-MEDIATED TUMOR ERADICATION

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The long term objective of our program is to elucidate the mechanism(s) through which a widely used anticancer drug (melphalan) potentiates the tumor eradicating immunity in mice bearing a large tumor and extensive metastases. Although the tumor model that we will use, the MOPC-315 plasmacytoma, is not very immunogenic, following low-dose chemotherapy a CD8+ T-cell-dependent antitumor immunity develops in the hitherto immunosuppressed tumor bearers with sufficient potency to completely eradicate the large tumor burden not eradicated through the direct antitumor effects of the drug. To further characterize the CD8+ T-cells that are required for tumor eradication, we will analyze the T-cell receptor (TCR) repertoire of CD8+ T-cells derived from the regressing tumors. This will be done utilizing a panel of monoclonal antibodies directed against various V-beta gene segments of the TCR. In addition, with the aid of CD8+ T-cell clones, we will attempt to correlate the use of a particular V-beta segment(s) with a particular anti-MOPC-315 reactivity. Subsequently, we will determine the importance of T-cells expressing the particular V-beta gene product(s) to the therapeutic outcome of low-dose chemotherapy. Since a large number of macrophages is first evident in the s.c. tumor nodules of lowdose melphalan treated MOPC-315 tumor bearers two days after the appearance of a massive CD8+ lymphocytic infiltrate, experiments are proposed to determine if the CD8+ T-cells actually recruit macrophages into the tumor site as well as determine the importance of the macrophages for the therapeutic outcome. Experiments are also planned to determine if low-dose chemotherapy leads to the acquisition of potent tumor eradicating immunity in MOPC-315 tumor bearers as a result of elimination of the suppressive activity of CD4+ T-cells. We have worked out conditions under which the tumor eradicating immunity is reduced and, consequently, the effectiveness of the chemotherapeutic protocol is also decreased. Under these conditions, if the chemotherapy does not eliminate the suppressive activity of the CD4+ T-cells for tumor eradicating immunity, elimination of the CD4+ T-cells by the use of anti-L3T4 antibody can result in a more potent tumor eradicating immunity and a better cure rate. The potential importance of the proposed studies can be best summarized by a quotation from a recent review article on active immunotherapy of human melanoma exploiting the immunopotentiating effects of cyclophosphamide. In this article Berd and Mastrangelo (1) show that their results corroborate the findings in animal models and state that "application of ideas developed through basic investigation in immunoregulation will lead to more effective immunotherapy of human cancer."