The development of Saccharomyces (yeast) vaccines for cancer therapy

点击翻译按钮获取中文摘要

Vaccination with a recombinant Saccharomyces cerevisiae expressing a tumor antigen breaks immune tolerance and elicits therapeutic antitumor responses. Saccharomyces cerevisiae, a nonpathogenic yeast, has been used previously as a vehicle to elicit immune responses to foreign antigens, and tumor-associated antigens, and has been shown to reduce tumor burden in mice. Studies were designed to determine if vaccination of human carcinoembryonic antigen (CEA)-transgenic (CEA-Tg) mice (where CEA is a self antigen) with a recombinant S. cerevisiae construct expressing human CEA (yeast-CEA) elicits CEA-specific T-cell responses and antitumor activity. CEA-Tg mice were vaccinated with yeast-CEA, and 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 (s.c.) pancreatic tumor models. These studies demonstrate that recombinant yeast can break tolerance and that (a) yeast-CEA constructs elicit both CEA-specific CD4+ and CD8+ T-cell responses; (b) repeated yeast-CEA administration causes increased antigen- specific T-cell responses after each vaccination; (c) vaccination with yeast-CEA at multiple sites induces a greater T-cell response than the same dose given at a single site; and (d) 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 s.c. pancreatic tumor models. Vaccination with a heat-killed recombinant yeast expressing the tumor-associated antigen CEA induces CEA-specific immune responses, reduces tumor burden, and extends overall survival in CEA-transgenic (CEA-Tg) mice. These studies thus form the rationale for the incorporation of recombinant yeast-CEA and other recombinant yeast constructs in cancer immunotherapy protocols. In another study, recombinant Saccharomyces cerevisiae (yeast-CEA) was shown to be a potent activator of murine dendritic cells (DCs). Recombinant Saccharomyces cerevisiae (yeast) represents a unique and attractive vehicle to deliver antigens in vaccine immunotherapy protocols for cancer or infectious disease, in that it has been shown to be extremely safe and can be administered multiple times to hosts. In the studies reported here, we describe the effects of treatment with recombinant yeast on murine immature DCs. Yeast expressing human CEA as a model antigen was studied. Injection of mice subcutaneously with yeast-CEA resulted in rapid increases in major histocompatibility complex (MHC) class II+ cells and total antigen-presenting cells in draining lymph nodes. Post-treatment with yeast-CEA, DCs rapidly elevated both MHC class I and class II, numerous costimulatory molecules and other DC maturation markers, and secreted a range of Type I inflammatory cytokines. Gene expression arrays also revealed the rapid up-regulation of numerous cytokine and chemokine mRNAs, as well as genes involved in signal transduction and antigen uptake. Functional studies demonstrated enhanced allospecific reactivity of DCs following treatment with yeast-CEA or control yeast. Additionally, treatment of DCs with yeast-CEA resulted in specific activation of CEA-specific CD8+ T cells in an MHC-restricted manner in vitro. Lastly, vaccination of CEA-Tg mice with yeast-CEA elicited antigen-specific CD4(+) and CD8+ immune responses in vivo. Thus, these findings taken together form a scientific rationale for the use of recombinant yeast in vaccination protocols for cancer or infectious diseases.