) One of the important recent insights into immune regulation is that, in addition to costimulatory receptors, T cells express """"""""counterregulatory"""""""" receptors, which provide signals inhibitory to T cell activation. The original prediction that transient blockade of these negative regulatory signaling pathways might enhance the potency of cancer vaccines has been recently fulfilled by experiments demonstrating synergy between GM-CSF transduced vaccines and anti-CTLA-4 antibody infusion. In addition to CTLA-4, preliminary evidence exists that additional negative regulatory signals may be mediated by the TNF receptor family members CD30 and OX40. Conversely, evidence is building that enhancement of T cell activation can occur through activation of co-stimulatory pathways mediated by two other TNF receptor family members-CD40 and 41BB. T cell function is also regulated via apoptotic pathways that contract the pool of antigen specific T cells subsequent to their activation (so called activation induced cell death or AICD). Evidence exists that p53 dependent pathways may be important in at least certain forms of AICD. The purpose of this section of the NCDDG proposal is to evaluate both antibodies and drugs which act as either specific antagonists of inhibitory pathways or agonists of co-stimulatory pathways for their ability to enhance HER-2/neu based vaccine function. Specifically we propose to: 1) evaluate antagonist antibodies against CTLA-4, CD30 and OX40, agonist antibodies against 41BB and CD40, and a recently characterized small molecule p53 inhibitor for their abilities to enhance vaccine responses in both na ve and anergic antigen specific T cells utilizing a rapid screen adoptive transfer system, 2) evaluate the ability of promising agents defined in Specific Aim 1 to enhance vaccine induced systemic anti-tumor immunity in the NT2 transplantable HER-2/neu breast tumor model developed in Dr. Jaffee's laboratory and 3)evaluate the optimized combinations of HER-2/neu based vaccines and enhancing agents defined in Specific Aim 2 in the prevention and treatment of spontaneous tumors in the MMTV HER-2/neu transgenic mice.
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