Our laboratory's major goal is the development and evaluation of immunologic reagents to treat patients with cancer. One goal has been to evaluate the in vivo effects of both IL-2 and TNF and to determine the mechanism of anti-tumor effects :as well as induction of toxicity. We have demonstrated that IL-2 has major effects on the endothelium, inducing endothelial activation antigens and believe that this may be associated with the capillary leak syndrome. In addition, we have demonstrated that IL-2 induces DR expression on many tumor cells as well as infiltrating T cells and that this appears to correlate with antitumor effects. In addition, IL-2 causes major endocrinologic effects, including the elaboration and release of ACTH, cortisol, and beta endorphin as well as CRH. Major effects on the traffic of peripheral blood mononuclear cells are demonstrated with both IL-2 and TNF as is the elaboration of a novel cytokine, IL-6. Major decreases in the DTH response have been observed in patients undergoing IL-2 treatment. The second major goal of our laboratory is to evaluate the lymphokine-activated killer cell, both its generation as well as lytic specificity. We have demonstrated that normal human monocytes are susceptible to lysis and further that LAK cells can be generated from the bone marrow and peripheral blood with activity against variety of human tumors. Susceptibility to lysis by these effectors is modulated by interferon and TNF treatment of the target cells. Further, a variety of factors have been evaluated including IL-l, IL-3, IL-6, GMCSF, TNF and all of the interferons have been evaluated and found to have no major role in the generation or maintenance of LAK activity. IL-4 has profound effects regulating LAK activity and in addition, allows the enhanced generation of TILs from human melanoma. Evaluation of the role of GMCSF in enhancing poly function following in vivo administration has been evaluated. The role of murine monoclonal antibodies in mediating ADCC as well as their efficacy in in vivo studies in combination with IL-2 or other cytokines are in progress.
