BIOLOGICAL EFFECTS OF RHIL-12

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The studies proposed in this application will explore several issues pertinent to the use of recombinant Interleukin-12 (rhIL-12) in patients with advanced cancer. One of the specific objectives is to clarify the mechanism by which a prior injection of rhIL-12 appears to desensitize patients to the toxic effects of this cytokine. The studies relating to this goal include Scatchard analyses to assess IL-12 receptor expression and measurements of MAPK activity induced in vitro with IL-12 to assess the integrity of signaling pathways downstream of the IL-12 receptor. Several proposed studies deal with various membrane-associated TNF family members such as the fas ligand and CD4O- L which are likely to be expressed on certain T cell populations in response to the administration of rhIL-12. The biological effects of these molecules, either on the cell surface or shed into the plasma, overlap substantially with those of TNF and it is possible that they may play a role in the tumor regression or toxicity induced by rhIL-12 treatment. IL-12 is a potent inducer of IFN-gamma synthesis. One of our proposed studies involves a detailed analysis by RT-PCR of the cytokine genes expressed by TIL isolated from patients receiving rhlL-I 2. Finally, several of our studies are focused on the effects of IL-I 2 administration on activation-induced apoptosis in T cells. This is one of the mechanisms by which the CD4+ T cells population is progressively diminished in patients infected with HIV and may also affect the viability of certain lymphoid cells within tumor infiltrates. IL-I 2 has been reported to inhibit activation- or fas-mediated apoptosis in vitro and one of the goals of this application is to see if this effect is demonstrable in vivo.