The main goal of tumor immunotherapy Is to obtain tumor specific T cell responses capable of eradicating disseminated disease and providing protection against recurrence. Recent advances in our knowledge mechanisms of T cell activation have aided In the design of rational strategies to obtain this goal. One particularly significant advance has been the realization that T cell activation requires costimulary signals mediated by CD28 in addition to antigen-specific signals, and that tumor cells do not provide costimulation. This has led to strategies of lmmunotherapy that manipulate costimulation, such as induction of expression the costimulatory ligand B7 or enhancement of tumor antigen presentation by costimulation competent host antigen presenting cells. However, it has recently been demonstrated that T cell responses are negatively regulated by CTLA-4. We have demonstrated that blockade of the inhibitory signals of CTLA-4 can greatly enhance antitumor responses. We now propose to extend these studies and: 1.Determine the effectiveness of CTLA-4 blockade,alone and in combination with other immunomodulatory agents in subcutaneous tumor models that represent a spectrum of Inherent immunogeniclty and have relevance to models of metastasis and primary tumors. The effectiveness of CTLA-4 will be assessed by itself and in combination with other immunomodulatory agents that rely on costimulation, including B7, GM-CSF, and antigen-pulsed dendritic cells. Treatment protocols will be compared with respect to effectiveness in eradication of established tumors and longevity of protection to tumor rechallenge. 2.Determine the effectiveness of optimized protocols Involving CTLA-4 blockade in the treatment of experimental metastases, using models for melanoma, renal carcinoma, and prostatic carcinoma. 3.Determine the effectiveness of optimized protocols for involving CTLA- blockade in the treatment and prevention of primary tumors. 4.Examine the mechanisms involved in enhancement of antitumor immunity by protocols involving CTLA-4 blockade. We will identify lymphocytes involved in rejection and in induction of immunity, determine the effects on relative contributions of the tumor cells and host cells in antigen presentation, and test the hypothesis that CTLA- 4 blockade reveals normally silent tumor epitopes. 5.Examine the possibility that autoimmunity might accompany tumor rejection induced by CTLA-4 blockade.
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