Systemic chemotherapy combined with local adoptive immunotherapy cures rats bearing 9L gliosarcoma

Abstract

Survival of Fischer rats bearing 9L gliosarcoma in the brain was measured to determine the efficacy of 1) systemically administered chemotherapy with local adoptive immunotherapy (chemo-adoptive immunotherapy) or 2) systemically administered chemo-immunotherapy. Winn assays, where tumor instillation coincided with the start of treatment, and one-week established tumor assays were conducted. Survival of chemo-adoptive immunotherapy treated groups given intraperitoneal cyclophosphamide and intracranial lymphokine activated killer cells and recombinant Interleukin-2 was significantly extended when compared to sham treated control groups, to groups given chemotherapy with intraperitoneal cyclophosphamide, and to groups treated by local adoptive immunotherapy with intracranial lymphokine activated killer cells and Interleukin-2. The killer cells were generated from spleens of donor rats that either had or had not been given cyclophosphamide 24 h earlier. Long-term survivors (9/39), sacrificed at day 70, were obtained only in the chemo-adoptive immunotherapy treated groups; 7/39 had no histologic evidence of tumor and had focal sterile abscesses at the site of killer cell instillation. Average group weight plotted over time showed that there was acceptable toxicity with chemo-adoptive immunotherapy; the toxicity was identical to that obtained with systemic cyclophosphamide treatment. In contrast, survival of chemo-immunotherapy treated groups given systemic cyclophosphamide and Interleukin-2 was not significantly extended from groups which were sham treated or treated only with systemic Interleukin-2. Rapid decline of average group weight plotted over time and early deaths following chemo-immunotherapy treatment indicated that the regimen was toxic. The effect of cyclophosphamide administration on the splenocytes of donor rats and the LAK cells generated from them was determined by in vitro studies analyzing cell number, viability, phenotypic expression and cytotoxicity against 9L tumor. In the treatment of this intracranial neoplasm, the beneficial effects of cyclophosphamide were determined to occur in situ in the tumor-bearing host. No benefit resulted from cyclophosphamide treatment of donor rats that supplied splenocytes for LAK cell production.