Recent demonstrations of T-lymphocyte-mediated antigen-specific responses against some human tumors, and the more potent effects of these cells in preclinical models, have re-focused much of the dialogue for biological therapy to potentiation of T-lymphocyte-mediated antitumor effects. This project uses the well-characterized Renca murine renal cancer and DA-3 mammary tumor models to study the induction of antitumor T-lymphocyte- mediated responses, the mechanisms by which positive effects are achieved, and the reasons why T lymphocytes in tumor-bearing mice may not respond as predicted. Although even established Renca can be successfully treated by several biological therapy approaches through the induction of T- lymphocyte-mediated effects, such responses are not triggered spontaneously, even though Renca is moderately immunogenic. One possible reason for this is altered expression of nuclear transcription factors that occur as a function of time after tumor implantation. Studies are underway to further characterize these alterations t determine their possible relationship to tumor progression, and to ascertain the impact of these charges on the ability of BRM to induce antitumor responses. In this latter regard, we are also studying two other approaches to T-cell stimulation. We are using rhIL-7 as a T-cell stimulant and have shown that it has potent effects on T cells as well as some antitumor effects. Second, we ar developing a comprehensive vaccine-type gene therapy approaches whereby T cells and antigen presenting dendritic cells are recruited through the use of antigen, chemokines and GM-CSF. The effects of the recruited cells will then be potentiated by Renca or fibroblast transfectants that express co-stimulatory cytokines (IL-2, IL-4, IL-7, or IL-12). Through such an approach we will optimize both MHC Class I and Class II-dependent pathways for induction of T-lymphocyte mediated responses to cancer. The ability to induce antitumor responses in normal versus tumor-bearing mice is being compared for tumor regression and T- cell signaling biochemistry. Through these studies, we are developing new information regarding the regulation of T-cell-mediated antitumor effects in tumor-bearing hosts.
