T cell immunity to autologous tumors is the predominant immune response that has potential to influence the outcome of disease. Augmentation of this immunity for cancer treatment by the transfer of lymphoid cells has been referred to as """"""""adoptive immunotherapy"""""""". The success of this form of therapy is critically dependent on the ability to isolate tumor-sensitized T cells in cancer patients and to stimulate and propagate these cells in vitro to large numbers. In animal models, we have demonstrated that lymph nodes (LN) draining a progressive growing tumor contain sensitized T lymphocytes, but such cells are deficient in mediating an antitumor response. However, these """"""""pre-effector"""""""" cells can differentiate into immune effectors by in vitro culture methods. A convenient way to stimulate pre- effector cells is the use of anti-CD3 and IL-2, but the culture system is also predisposed to the generation of irrelevant T cells. In an attempt to selectively activate tumor-reactive lymphocytes, we have recently utilized microbial superantigens. Superantigens bind to MHC class ll molecules to form ligands that interact with distinct Vbeta segments of the T cell antigen receptor (TCR) regardless of other variable components. Among the best studied superantigens are exotoxins secreted by certain Gram positive bacteria such as Staphylococcus aureus. They are small single chain proteins of 24 to 30 kDa and are implicated as the causative agents in a number of diseases. Our studies have demonstrated that some superantigens were capable of activating pre-effector cells for generation of tumor- specific immune effector cells. Thus, the use of a panel of different superantigens will provide a means to directly analyze the diversity of TCRs in shaping the T cell repertoire specific for tumor antigens. The in vivo administration of superantigens to mice leads to massive activation and deletion of responding T cells depending on the dose, frequency and route of administration. Thus, investigations into the potential in vivo use of superantigen may help design innovative approaches for cancer immunotherapy. In addition, the pre-effector cell response is subjected to down-regulation by the tumor-induced specific immune suppression. Because TCR usage in this suppression has not been determined, Va-specific deletion by superantigens may allow the identification and manipulation of these important regulatory cells. Finally, an innovative gene therapy utilizing superantigen expressing tumor cells may afford a means to locally activate T cells without immunosuppressive effects. Because in vivo interactions of superantigens with T cells lead to the secretion of a variety of lymphokines, superantigen-based gene therapy may represent an approach comparable to that utilizing multiple cytokine genes. Therefore, the specific aims in this proposal are: 1) to identify TCR Vbeta gene usage in the antitumor immune response through superantigen activation; 2) to analyze immunologic mechanisms involved in superantigen- induced responses; 3) to evaluate the in vivo effects of superantigens on the development of antitumor immunity and on tumor-induced specific suppression; and 4) to investigate the potential benefits that may he derived from superantigen-based gene therapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Method to Extend Research in Time (MERIT) Award (R37)
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Experimental Therapeutics Subcommittee 1 (ET)
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Cleveland Clinic Lerner
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