Development of Resistance to MOPC-315 Plasmacytoma After Intralesional and Intraperitoneal Melphalan Therapy of Tumor-Bearing BALB/c Mice. I. Enhancement of In Vivo Rejection Responses by Combined Chemotherapy-Immunotherapy2

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Abstract
Experimental and clinical evidence indicates that some chemotherapeutic agents may enhance tumor cell immunogenicity. This study was undertaken to test the possibility that melphalan [l-phenylalanine mustard (l-PAM)]—a clinically useful drug—can modulate tumor cells in vivo and in vitro in a syngeneic experimental system of MOPC-315 plasmacytoma in BALB/c mice and that this modulation can be expressed in vivo by enhanced tumor resistance. Tumor-bearing mice were treated with l-PAM intralesionally and ip by a split-course chemotherapy to avoid excessive toxicity of the drug. As a result of this treatment, about 60% of the mice had complete tumor regression; of these, 40–60% were resistant to viable tumor cell challenge and were designated as “cured-immune.” Immunogenicity of irradiated MOPC-315 was tested in BALB/c mice; significant protection against tumor cell challenge was not achieved. In vitro l-PAM-treated MOPC-315 cells induced a measurable but weak antitumor response. Combination of both therapeutic approaches, i.e., chemotherapy and active immunization by l-PAM-treated tumor cells, was attempted with the use of various schedules. Immunotherapy given after l-PAM-induced tumor regression significantly enhanced in vivo antitumor response to challenge by 104 and 105 viable MOPC-315 tumor cells. When immunotherapy was attempted before chemotherapy in the presence of actively growing though still occult tumor, it reduced the chemotherapy cure rate and resulted in a low rate of tumor resistance. Addition of BCG did not remarkably affect the results. The findings point to the importance of timing of active immunization relative to tumor load and chemotherapy. The implication is that chemotherapy-induced regression is mediated by host immune mechanisms in this experimental model.