Specific chemoimmunotherapy in tumor-bearing mice with extracted antigen, cyclophosphamide, and intrasplenic administration of interleukin-2.

Abstract

The effect of daily intrasplenic (I-SP) injection of interleukin-2 (IL-2) in conjunction with specific chemoimmunotherapy with extracted tumor antigens and cyclophosphamide was assessed with the use of methylcholanthrene (MCA)-induced fibrosarcoma in C3H/HeJ mice. Injections of 80 U of human IL-2 were delivered transcutaneously into the spleen (I-SP), which had been relocated to the subcutis with its blood supply intact. Six daily I-SP injections into mice bearing MCA-F tumors activated immune spleen cells (SPC), as evidenced by specific neutralization of the MCA-F, but not the antigenically different MCA-D tumor, in local adoptive transfer assays. The immune cell phenotype was Thy 1.2+ Lyt 2+, based upon abrogation of tumor neutralization after depletion with monoclonal antibodies and complement. In a second series of experiments, primary hosts bearing established MCA-F tumors underwent therapy with 1 microgram 1-butanol extracted, isoelectrophoretically purified TSTA injected subcutaneously, a single intraperitoneal (IP) dose of 20 mg/kg cyclophosphamide (CY), and/or either IP or I-SP IL-2 injection. Triple chemoimmunotherapy with I-SP, but not IP, IL-2 retarded tumor outgrowth more effectively than single or double treatment protocols. Furthermore, in a third series of investigations, the triple therapy group showed both decreased numbers and incidence of spontaneous metastases from a subcutaneous implant of clone 9-4, a highly metastatic variant of MCA-F. Indeed, 35% of hosts that received triple therapy, but none of the animals treated with other regimens, were free of lung metastasis (P less than 0.02). Thus, tumor resistance engendered by chemoimmunotherapy with TSTA and CY is potentiated in vivo by I-SP administration of IL-2.