Major accomplishments include: (a) The design and development of recombinant vectors containing transgenes for a tumor-associated antigen (TAA) and three T-cell costimulatory molecules (B7.1, ICAM-1, LFA-3, designated TRICOM--a TRIad of COstimulatory Molecules) and their optimization for use to enhance CD8+ and CD4+ T-cell responses and anti-tumor activity against established tumors. Optimal activity was shown to be achieved with diversified prime with recombinant vaccinia and boosting with recombinant avipox vectors, both with GM-CSF. These studies have led to several clinical trials for a range of human carcinomas. (b) The demonstration for the first time that the use of costimulation in vector-based vaccines, while moderately enhancing the level of T-cell induction, greatly enhances (up to 100-fold) the functional avidity of T cells generated. Moreover, demonstration for the first time that the addition of GM-CSF to vaccine further enhances the functional avidity of T cells generated. These studies have important implications in the analyses of immune responses in vaccine clinical trials. (c) The demonstration that murine T cells actually acquire major histocompatibility complex/costimulatory molecule complexes from antigen-presenting cells (APCs) and the demonstration for the first time of the functional relevance of this acquisition in the expansion and regulation of naive vs memory T cells. (d) The demonstration that low-dose cyclophosphamide not only alters the number of regulatory T cells, but also alters their function. (e) The first comparison of systemic (subcutaneous (s.c.)) vs intratumoral (i.t.) vaccinations and the demonstration that optimal T-cell responses and anti-tumor activity can be achieved by vaccine priming s.c. and boosting i.t. These findings have now been translated to clinical studies. (f) The demonstration that introducing more signal 1 (antigen) to tumor via intratumoral vaccination can enhance anti-tumor T-cell responses and anti-tumor activity and the demonstration that vector-mediated introduction of costimulatory molecules into tumor target cells can enhance the level of signaling and subsequent lytic ability of reacting T cells via increasing the number of immunologic synapses. These findings have now also been translated to clinical studies. (g) The demonstration of the importance of antigen cascade in therapeutic responses to vaccine, where the induction of T cells to antigens distinct from those in the vaccine are shown to play an extremely important role in therapeutic responses. These studies have important implications in the analyses of immune responses in vaccine clinical trials and in the selection of new targets for vaccine-mediated therapy.Major scientific achievements include: (a) Carrying out immunotoxicology studies, with emphasis on the analysis of autoimmune phenomena, involving new vaccines and combination therapies, for IND approval of agents and strategies for clinical trials. (b) The development and FDA approval for clinical studies of eight new recombinant vaccines, one agonist peptide vaccine, and two radionuclide-conjugated recombinant immunoglobulins. These recombinant vector-based vaccines were developed in a science-based incremental manner to contain transgenes for one, then three costimulatory molecules along with one, then two transgenes for TAAs.
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