Intrasplenic administration of interleukin-2 to potentiate specific chemoimmunotherapy in tumor-bearing mice.

Augmentation of specific chemoimmunotherapy by daily, intrasplenic injection of interleukin-2 (IL-2) was assessed in a methylcholanthrene (MCA)-induced fibrosarcoma model in C3H/HeJ mice. Daily access to the spleen was achieved by relocating the organ into the subcutis while leaving its blood supply intact. Following intrasplenic injection of 80 units of human IL-2 into MCA-F tumor-bearing mice for 6 days, spleen cells tested in the local adoptive transfer assay showed specific neutralization of MCA-F, but not the antigenically different MCA-D, tumor. Depletion of the spleen cell population with monoclonal antibodies and complement showed that the responding cell bore the surface markers Thy 1.2 and Lyt 2. Mice bearing established MCA-F tumors underwent a variety of chemoimmunotherapy regimens, including 1 microgram of 1-butanol, extracted isoelectrophoretically purified tumor-specific transplantation antigen, a single i.p. dose of cyclophosphamide (20 mg/kg), and/or either i.p. or intrasplenic injection of 80 units of IL-2. Specific triple chemoimmunotherapy including daily intrasplenic IL-2, but not i.p., administration was superior in the degree of tumor neutralization to all single or double therapy protocols. Furthermore, the combined triple modality inhibited spontaneous lung colonization by clone 9-4, a highly metastatic variant of MCA-F; both the numbers of lung colonies (median, 17; range, 2 to 55, versus median, 3, range, 0 to 42; P less than 0.005) and the incidence were decreased. The combined treatment group displayed 35% of hosts free of lung metastasis, while 100% of the control animals had lung colonies (P less than 0.02). Thus antitumor immunity was augmented in vivo using IL-2 delivered by intrasplenic, but not i.p., injection. Furthermore, chemoimmunotherapy including intrasplenic IL-2 injection potentiated the antitumor immunity achieved with combined tumor-specific transplantation antigen and cyclophosphamide.