Trials with non-specifically cytotoxic LAK (lymphokine activated killer) cells have demonstrated some tumor regression and substantial toxicity. The ultimate goal of this proposal is development of a more effective, safer, specific adoptive immunotherapy regimen for sarcoma patients through improved understanding of the immunobiology of the disease and of the optimal conditions for lymphocyte mediated cytolysis.
The specific aims of this competing renewal are: 1. To further explore the nature of the HLA restriction of T cell clones cytotoxic for sarcomas. Earlier work indicates a high prevalence of the HLA-A2 haplotype and a need for concordance at this haplotype for the generation of specifically cytotoxic lymphocytes. HLA-A2 subtypes responsible for target cell recognition will be defined using isoelectric focusing. The role of concordance at other HLA loci in the generation of specifically cytotoxic T cells will be assessed to determine if the essential phenomenon is concordance or if there is a specific role for A2. 2. To continue the comparison of LAK cells and specifically cytotoxic (educated) T cells. Presence in culture of HLA-A2+ sarcoma cells precludes development of LAK-like cytotoxicity in PBLs. Future studies will assess: (a) cell surface markers using monoclonal antibodies, (b) precursors for LAK or specifically cytotoxic cells using Percoll separation of PBLs, (c) the time in culture when lymphocytes become committed to LAK or specific killing and the durability of that commitment, and (d) the role of HLA concordance in generating LAK or specific killing. 3. To conduct preclinical therapy trials using human sarcomas xenografted in nude mice. Both local (Winn test) and systemic administration of effector cells will be explored to define: (a) relative effectiveness of LAK cells, cloned specifically cytotoxic T cells, educated PBLs and tumor infiltrating lymphocytes, (b) optimal dose and schedule of administration of T cells, and (c) effects of IL-2 alone or with effector cells. It is hoped that these studies will lead to a better understanding of the biology of sarcomas and provide reagents for clinical trials.
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