Preclinical studies in animals were undertaken to investigate the antitumor effects and toxicities of recombinant cytokines and effector cells in adoptive immunotherapy models of established cancer. A. Tumor Necrosis Factor (TNF). We showed that the systemic administration of TNF alone at high dose or at lower doses with other cytokines (IL-2, IFN-alpha), or with chemotherapeutic agents can effectively reduce or eradicate serially passaged weakly-immunogenic sarcomas as well as spontaneous autochthonous tumors in mice. TNF does not affect transplants of normal,skin or fetal cardiac transplants. Tumor-bearing (TB) mice were shown to have greater sensitivity to acute toxicity of high-dose TNF compared to non-TB mice. The lethal effects of TNF can be substantially decreased by treatment with fluid resuscitation and with direct therapy that is antagonistic to oxygen radical formation (i.e. bismuth subnitrate). B. Interleukin-6 (IL-6). We showed that purified IL-6 when administered alone at high dose or at lower doses in combination with TNF mediated the regression of established weakly-immunogenic sarcomas in mice; toxicities were not observed at the doses of IL-6 used. The antitumor effect of IL-6 was mediated through a radiosensitive host component. C. Tumor Infiltrating Lymphocytes (TIL). We have defined tissue culture conditions for the optimum growth of murine TIL with in vitro cytolytic specificity and increased therapeutic potency that incorporates purification of T cells from tumors, repetitive restimulation with irradiated autologous tumor cells in the presence of low concentrations of IL-2.
