Experimental studies were undertaken to investigate the antitumor effects and mechanisms of action of recombinant cytokines and gene- modified tumor and effector cells in immunotherapy of cancer. A. Tumor Infiltrating Lymphocytes (TIL). We have functionally and molecularly characterized human TIL retrovirally transduced with the TNF cDNA and have utilized soluble TNF receptor to accurately measure secretion of TNF in vitro. B. Gene-Modified Tumor Cells. We have molecularly engineered murine tumor cells to secrete various cytokines. TNF and IL-2 cDNAs have been introduced into both weakly and non-immunogenic tumors. The host cellular immune response to these cytokine-secreting tumors have been characterized. Interferon-gamma gene-modification corrects an antigen presentation defect in a non-immunogenic sarcoma and elicits therapeutically effective CD8+ TIL reactive against the wild-type tumor, which had not previously produced effective TIL. C. Interleukin 6 and 7. We have demonstrated a potent role for IL-6 in the treatment of established solid tumors in mice that have the capacity to elicit both CD4+ and CD8+ T cell responses. IL-7 has been shown to mediate the generation and expansion of murine antitumor CTL. Adoptively transferred, IL-7 activated CTL have potent antitumor effects in vivo. D. Dendritic (Langerhans) Cells (DC). We have demonstrated that epidermal Langerhans cells and splenic dendritic cells process and present tumor-associated antigens to primed CD4+ T cells in mice. Tumor-pulsed DC are extremely potent stimulators of helper T cell proliferation in vitro.
