Development of resistance to MOPC-315 plasmacytoma after intralesional and intraperitoneal melphalan therapy of tumor-bearing BALB/c mice. II. Enhancement of in vitro cell-mediated cytotoxicity by combined chemotherapy-immunotherapy

Abstract

As previously reported, tumor-bearing BALB/c mice can be cured by split-course melphalan therapy, with 40-60% of the treated animals developing resistance to subsequent challenge with viable MOPC-315. The present study deals with the identification of effector-cytotoxic cells that may be developed as a result of chemotherapy-induced tumor regression and their possible potentiation by active, specific immunization with melphalan- and glutaraldehyde-treated MOPC-315 plasmacytoma cells. The cytotoxic potential of spleen-derived lymphocytes in treated animals could be demonstrated only after in vitro sensitization against mitomycin-treated MOPC-315 cells. Lymphocyte-mediated cytotoxicity, as measured against syngeneic 51Cr-labeled MOPC-315, could be detected in melphalan-cured animals and was significantly enhanced by active immunization as compared to the cytotoxicity seen in normal and tumor-bearing mice. With the use of M109 syngeneic, unrelated tumor cells as control targets in the assay, no cytotoxicity was detected. Macrophage cytotoxicity was not significantly enhanced in any of the treatment groups described, with these assays performed 6-8 weeks following treatment and cure. When in vitro killing of MOPC-315 targets was tested with the use of peritoneal macrophages harvested shortly following cure of ascitic tumor by ip injected melphalan, the cytotoxic response was significantly enhanced. In conclusion, following chemotherapy-mediated cure of established MOPC-315 tumors, splenic lymphocytes exhibited enhanced antitumor cytotoxicity, which was further augmented by active immunization. Macrophage activation, as measured by direct cytotoxicity against MOPC-315 targets, was found to occur locally and early following the event of melphalan-induced tumor regression.