Biologic cancer therapy, featuring the transfer of activated lymphocytes and IL-2 has rapidly evolved over the past several years. We have conducted pre-clinical evaluations of immunotherapy using murine pulmonary metastasis, survival, and subdermal models. Using anti-CD3 activation of TIL, we have shown a reproducible increase in TIL growth and cytotoxicity. We have studied the role of cytoxan in the adoptive transfer of TIL and evaluated lymphocyte subpopulations in the murine tumor models. Over the past 5 years, we have conducted human clinical trials, first using low-dose systemic IL-2 plus LAK cells, and more recently with TIL. Improvements in the rate of clinical response to this type of therapy can be attained by focused efforts to understand the basic biologic events necessary for the in vivo tumor eradication. This proposal will address additional issues related to understanding the immunobiology TIL, LAK cells and specifically sensitized T cells, as it relates to cancer immunotherapy. Using a congenic B6 murine model we have been able to reproduce the anti-tumor effects of TIL/IL-2 therapy on pulmonary metatastases as well as subdermal tumor. This model will be used to determine whether the in vivo anti-tumor response is mediated solely by donor TIL or by re- cruitment of anti-tumor effector cells by the host. Monoclonal antibody depletion of specific lymphocyte populations with known functional activity will be used to study the participation of host CD8+, CD4+, and NK cells in tumor eradication, Additionally, we will study the functional activity of donor TIL with respect to cytokine production and tumoricidal activity. In situ hybridization of cytokine probes to regressing tumor sections will document the cellular signals required for tumor eradication in vivo. Similar studies are proposed for LAK cells and specifically sensitized T lymphocytes. These studies will compare the differences and similarities of these effector cells with TIL. Effectors will be tested in both the pulmonary metastases and subdermal models and compared to TIL. Dif- ferences in effector cell function and the effect exerted on the host will examined by in situ hybridization as described above. In vitro studies of human TIL will help identify the biologically relevant subpopulations. Studies will also be undertaken to characterize human bulk and TIL subpopulations with emphasis on cytotoxicity and cytokine production. In vitro human cytotoxicity and cytokine production will be prospectively compared with the response to adoptively transferred TIL. TIL with defined functional traits will be evaluated in patients with renal cell carcinoma and melanoma. These approaches should extend our knowledge about the immunobiology of cancer.
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