Vaccination with a Recombinant Saccharomyces cerevisiae Expressing a Tumor Antigen Breaks Immune Tolerance and Elicits Therapeutic Antitumor Responses

Abstract

Purpose: 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 selfantigen) with a recombinant S. cerevisiae construct expressing human CEA (yeast-CEA) elicits CEA-specificT-cell responses and antitumor activity. Experimental Design: 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 s.c. pancreatic tumor models.Results: 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-specificT-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. Conclusions: 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-Tg mice. These studies thus form the rationale for the incorporation of recombinant yeast-CEA and other recombinant yeast constructs in cancer immunotherapy protocols.

Identification and characterization of a cytotoxic T-lymphocyte agonist epitope of brachyury, a transcription factor involved in epithelial to mesenchymal transition and metastasis

“…They contain the recombinant protein, are heat killed, and are thus relatively safe compared to other forms of cancer therapy [40]. Previous studies have shown that recombinant yeast are efficiently taken up by human or murine DCs, which are consequently matured to express high levels of costimulatory molecules and produce high levels of type I cytokines [41,42]. Preclinical studies have shown that yeast-CEA can activate human CD8 + and CD4 + T cells in vitro , and show anti-tumor activity vs. CEA-expressing murine tumors [33,42].…”

Gene Therapy of Pancreatic Cancer

“…Other IFNs have been tested in immunotherapy approaches. The delivery of INFA in carcinoembryogenic antigen (CEA)-expressing pancreatic tumors cells resulted in major cytotoxicity through CD8 + and natural killer (NK) cells at the tumor site [55]. Moreover, transfer of INFB with a lentivirus in xenograft models resulted in tumor progression inhibition [56].…”

Coexpression of human perforin improves yeast-mediated delivery of DNA and mRNA to mammalian antigen-presenting cells

“…So far, several yeast genera have been shown to deliver viral or tumor antigens to antigen-presenting cells (APCs). [1][2][3][4][5][6] Besides these proteinaceous antigens, yeast cells are also able to transport antigen-encoding DNA and mRNA to a variety of mammalian APCs. 7,8 An advantage of this yeast-based delivery is the targeted transport of antigenencoding DNA or mRNA directly to APCs, thereby inducing adaptive immune responses such as CD8 + cytotoxic T-cell activation.…”