POSTOPERATIVE IMMUNOTHERAPY OF MURINE C1300-NEUROBLASTOMA

Low-dose cyclophosphamide (CY) is an immunomodulating agent that down-regulates T suppressor cell function. This study investigates postoperative immunotherapy with CY as an alternate treatment for advanced immunogenic tumors such as neuroblastoma that typically respond poorly to traditional high-dose chemotherapy. A/J mice with 1.5-cm subcutaneous C1300-neuroblastoma (C1300-NB) tumors were divided into the following treatment groups: I, untreated (n = 14); II, 85% tumor resection (n = 18); III, sham-operated (n = 18); IV, multiple-dose CY (n = 6); V, 85% resection and single-dose CY (n = 14); VI, 85% resection and multiple-dose CY (n = 14). CY (100 mg/kg, intraperitoneally) was given initially 24 hours post-operatively to groups IV, V, and VI. Groups IV and VI also received weekly maintenance doses of 25 mg/kg CY. Results showed significantly increased survival (log-rank test) in CY-treated groups (IV, V, VI) compared with control groups (I,II,III). Cures were observed only in groups receiving partial resection plus CY (V, 7%; VI, 29%). Although surgical debulking of tumor alone (II) did not enhance survival, the procedure normalized depressed total lymphocyte counts and the subpopulation of Lyt 2,3+ (T suppressor/cytolytic cells) in the immediate postoperative period during which immunotherapy with CY was instigated. This may have contributed to the success of CY immunotherapy. To characterize the tumor-host immune interaction, additional studies were performed. Results showed the following. (1) Mice cured by debulking plus CY (from groups V and VI) could not be successfully reimplanted with C1300-NB, demonstrating immunologic mediation by CY. (2) Injection of antithymocyte serum abrogated the therapeutic effects of CY in tumor-bearing mice, indicating that CY action is T cell-mediated. (3) T cell Concanavalin-A blastogenesis assay demonstrated suppression of T cell stimulation in tumor-bearing mice. This tumor-associated suppression was eradicated by CY treatment (100 mg/kg) of tumor-bearing mice. (4) Treatment of tumor-bearing mice with intravenous anti-IJK serum significantly delayed tumor growth (P = .002), demonstrating a role of IJK cells in C1300-NB growth. These IJK cells are part of the T suppressor network. (5) An increased polymorphonuclear cell count in the peripheral blood was a marker for the presence of tumor tissue, even before the gross tumor was noted. Because this evidence suggests that tumor-associated T suppressor populations contribute to experimental neuroblastoma growth, a trial of treatment of neuroblastoma patients with low-dose CY to inactivate these populations and support host antitumor mechanisms may be indicated, especially in the face of treatment failures with high-dose CY. © 1990.