Preclinical studies in mice were undertaken to investigate the antitumor effects and mechanisms of action of recombinant cytokines and effector cells in adoptive immunotherapy models of established cancer. A. Tumor Infiltrating Lymphocytes (TIL). We have studied the mechanisms whereby adoptively transferred murine TIL mediate tumor regression. Noncytolytic, CD8+ TIL eradicated established lung tumors in irradiated mice. Many cytolytic and noncytolytic CD8+ TIL cultures specifically secreted interferon-gamma and tumor necrosis factor when stimulated with tumor cells in vitro. The antitumor effectiveness of TIL in vivo correlated better with their ability to specifically secrete lymphokines than with their cytotoxicity in vitro. B. Human Tumors in Immunodeficient Mice. We have developed a model of disseminated fresh human malignant melanoma in congenitally immune deficient mice. We have found that the adoptive transfer of autologous melanoma-specific human TIL in conjunction with IL-2 could significantly prolong the survival of mice with disseminated human disease. C. Macrophage Colony Stimulating Factor (M-CSF. We have investigated the biologic and antitumor effects of M-CSF in mice. The systemic administration of high-dose M-CSF elicited a profound localization/ proliferation of macrophages in the livers of treated mice. The combined administration of tumor-specific monoclonal antibody plus M-CSF resulted in synergistic anti-tumor effects against established hepatic metastases from the B16 melanoma. D. Tumor Antigen Processing and Presentation. We have studied whether tumor cells can escape recognition by CTL and subsequent immune eradication by suppressing presentation of endogenous antigen. Certain murine sarcomas failed to present endogenously synthesized viral antigens to specific CTL. The deficiency in presentation by tumor was attributed to a markedly reduced rate of synthesis of MHC class I molecules.
