A104

Studies were designed to determine if vaccination of human carcinoembryonic antigen (CEA)-transgenic mice (where CEA is a self-antigen) with a heat-killed recombinant S. cerevisiae construct expressing human CEA (yeast-CEA) elicits dendritic cell (DC) activation, CEA-specific T-cell responses and antitumor activity. CEA-transgenic mice were vaccinated with yeast-CEA, and maturation of DCs was studied. In addition, CD4+ and CD8+ T-cell responses were assessed after one and multiple administrations or vaccinations at multiple sites per administration. Antitumor activity was determined by tumor growth and overall survival in both pulmonary metastasis and subcutaneous pancreatic tumor models. These studies demonstrate that recombinant yeast can indeed break tolerance and that a) vaccination with yeast-CEA induces the maturation of DCs; b) treatment of DCs with yeast-CEA resulted in specific activation of CEA-specific CD8+ T cells in vitro in an MHC-restricted manner; c) yeast-CEA constructs can elicit both CEA-specific CD4+ and CD8+ T-cell responses in vivo; d) repeated yeast-CEA administration causes increased antigen-specific T-cell responses after each vaccination; e) vaccination with yeast-CEA at multiple sites induces a greater T-cell response than the same dose given at a single site; f) tumor-bearing mice vaccinated with yeast-CEA show a reduction in tumor burden and increased overall survival compared to mock-treated or control yeast-vaccinated mice in both pulmonary metastasis and subcutaneous pancreatic tumor models. These studies thus form the rationale for the incorporation of recombinant yeast-CEA and other recombinant yeast constructs in cancer immunotherapy protocols.

AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics-- Oct 22-26, 2007; San Francisco, CA