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Effect of Continuous Administration of Interleukin 2 on Active Specific Chemoimmunotherapy with Extracted Tumor-specific Transplantation Antigen and Cyclophosphamide¹

Division of Immunology and Organ Transplantation, Department of Surgery, The University of Texas Medical School at Houston, Texas 77030

Injection of purified human interleukin 2 (IL-2) directly into the spleen has been shown to potentiate the effect of specific chemoimmunotherapy, using butanol-extracted tumor-specific transplantation antigen (TSTA) and cyclophosphamide (CY) in a C3H/HeJ murine methylcholanthrene-induced fibrosarcoma model. Since IL-2 has a relatively short half-life in serum, continuous infusion of this lymphokine via the intrasplenic (i.s.), i.v., or i.p. routes was administered in an attempt to maintain therapeutic tissue levels. Primary hosts bearing 7-day (4-mm) or 14-day (>10-mm) established s.c. methylcholanthrene F tumors were treated with weekly s.c. doses of 1 µg 1-butanol-extracted, isoelectrophoretically purified TSTA, the first of which was combined with a single i.p. injection of 20 mg/kg CY, and/or a 10-day continuous infusion of 120 units IL-2/day by one of the three routes. IL-2 delivered by all routes either by continuous infusion or by bolus injection augmented the chemoimmunotherapeutic efficacy of TSTA/CY against 7-day established tumors. On the other hand, the outcome of 14-day (>10-mm) established tumors depended upon the method and route of administration of IL-2: continuous infusion via the i.v., i.p., or i.s. route prolonged host survival beyond that obtained by bolus administration. Continuous i.s.-IL-2 infusion greatly prolonged, continuous i.p.-IL-2 (120 units/day) slightly extended, and continuous i.v.-IL-2 had no effect on host survival. In a spontaneous pulmonary metastasis model following amputation of a tumor-bearing limb, only the triple regimen of TSTA/CY/i.s.-IL-2 decreased the number of lung colonies and prolonged host survival. Continuous infusion i.s.-IL-2 (120 units/day, 10 days) combined with TSTA/CY induced tumor-specific cytotoxic T-cells, as documented by in vitro ⁵¹chromium release cytolytic and in vivo local adoptive transfer assays. Based upon the residual local adoptive transfer assay activity of spleen cells depleted of specific lymphocyte subpopulations using monoclonal antibodies, the immune effectors generated by i.s.-IL-2 plus TSTA/CY bear the Thy 1⁺, Lyt 2⁺ phenotype and those by i.p. or i.v.-IL-2 plus TSTA/CY, the Thy⁺, L3T4⁺ markers. Thus continuous i.s.-IL-2 infusion appears to augment cytotoxic T-cell induction in tumor-bearing hosts undergoing stimulation of helper elements by TSTA and inhibition of suppressor cells by CY.

¹ Supported by Grant CA 29592-06 from the National Cancer Institute, NIH.

² To whom requests for reprints should be addressed, at Division of Immunology and Organ Transplantation, The University of Texas Medical School at Houston, 6431 Fannin, Suite 6240 MSMB, Houston, TX 77030.

Received 6/10/87. Revised 9/10/87. Accepted 9/29/87.