Grafting of T lymphocytes with an antibody-directed specificity allows the cells to be targeted to any tumor-associated antigen for which a monoclonal antibody exists. Moreover, such chimeric T-cell receptors provide T-cell activation in a non-MHC-restricted manner, efficiently bypassing major mechanisms by which tumors commonly escape immune detection. We propose that expression of chimeric antitumor receptors on Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) will allow these cells to retain their known advantages while adding specificity and effector function directed to residual tumor cells, thereby extending the applicability of antitumor CTL immunotherapy. This hypothesis will be tested by expressing GD2-specific, single-chain antibody (scFv) chimeric T-cell receptors on either primary T lymphocytes or EBV-specific cytotoxic T-cell lines from neuroblastoma patients, and then evaluating the safety, in vivo expansion and persistence, and antitumor activity of the modified cells in patients with advanced neuroblastoma. These studies will be extended by preparing chimeric receptor-bearing T cells that express human scFV antibodies we have developed that are specific for neuroblastoma and testing their safety and efficacy in neuroblastoma patients. Upon conclusion of the project, we will have established whether EBV-specific CTLs can be used successfully as carriers for tumor-targeted chimeric receptors, and whether their functionality is superior to that of primary T cells expressing the same receptors. The value of Project 3 will be enhanced by interactions with Project 1 (new approaches to overcoming host resistance mechanism) as well as Project 2 (boosting of chimeric receptor T-cell responses with immunogenic peptides).
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