Yeast-Based Vaccine Induces Immune Responses and Reduces Tumor Size in Mice

Abstract

Vaccination with a heat-killed, nontoxic yeast that is genetically engineered to synthesize a common tumor protein can induce a specific and repeated antitumor immune responses in mice. In murine models of colon and pancreatic cancer, vaccination extends overall survival and reduces tumor size in animals that were injected with cancer cells expressing the same protein that was engineered into the yeast.These findings by scientists at the National Cancer Institute were published in the July 1, 2008, issue of Clinical Cancer Research. The results may provide a rationale for evaluating yeast vaccines in cancer immunotherapy studies in humans.The type of yeast used in this study, Saccharomyces cerevisiae, does not cause disease in humans and has been used as a delivery vehicle for antigens; proteins usually present on the surface of cells or organisms that stimulate immune responses. The tumor-associated antigen made by the genetically engineered yeast in this study is carcinoembryonic antigen (CEA), which is commonly found in cancers of the colon, rectum, stomach, breast, and lung.The authors point out that in several clinical trials, recombinant S cerevisiae vehicles have been found to be safe in both cancer and infectious disease settings. In a Phase Ib trial, a yeast construct expressing the hepatitis C virus (HCV) NS3-core fusion protein was administered to patients with chronic HCV. An interim analysis from this trial suggests that the yeast construct is safe for use in humans; no serious adverse events or dose-limiting toxicities have been reported.The authors note that at the time of the report, 12 (41%) of 29 patients had mounted cellular immune responses to HCV. “In a cancer setting, a phase I clinical trial with a S. cerevisiae construct expressing mutated Ras was conducted in patients with Ras+ cancers. Again, no treatment-related serious adverse events were observed, indicating a platform-wide safety profile for administration of heat-killed recombinant yeast to treat chronic diseases. In addition, 19 of 21 vaccinated patients showed >2-fold antigen-specific responses. As a result, a placebo-controlled adjuvant phase II trial in patients with mutated Ras+ fully resected pancreatic cancer is under way.”The current research was designed to determine the effects of this yeast-based vaccine on tumor growth and overall survival using colon and pancreatic cancer models. The studies demonstrated that the vaccine can elicit both CD4+ and CD8+ T-lymphocyte responses, which recruit additional immune cells and then attack and destroy cells that bear foreign or tumor-associated antigens. Additional findings from this study showed that successive administration of the vaccine resulted in increasing antigen-specific T-cell responses. Vaccination with the yeast–CEA vaccine at multiple sites induced greater T-cell responses than when the same dose of vaccine was given at a single site. Furthermore, tumor-bearing mice vaccinated with yeast–CEA had reduced tumor volumes and increased overall survival compared with control mice.In this study, the researchers performed 24 tests on mice that received either no treatment or the yeast–CEA vaccine. They found that body weight measurements, blood cell counts, serum enzyme levels, and assays for autoimmunity were all within the normal range for the vaccinated mice and were similar to those of control mice, indicating no toxicity or autoimmunity associated with the yeast-CEA vaccine.“The data reported here show that vaccination with yeast-CEA can break tolerance and induce CEA-specific CD4+ and CD8+ T-cell responses, effectively reduces tumor burden, and extends overall survival in tumor-bearing mice without adverse effects.”See “Vaccination with a recombinant Saccharomyces cerevisiae expressing a tumor antigen breaks immune tolerance and elicits therapeutic antitumor responses.” Clin Cancer Res. 2008;14:4316–4325. Vaccination with a heat-killed, nontoxic yeast that is genetically engineered to synthesize a common tumor protein can induce a specific and repeated antitumor immune responses in mice. In murine models of colon and pancreatic cancer, vaccination extends overall survival and reduces tumor size in animals that were injected with cancer cells expressing the same protein that was engineered into the yeast. These findings by scientists at the National Cancer Institute were published in the July 1, 2008, issue of Clinical Cancer Research. The results may provide a rationale for evaluating yeast vaccines in cancer immunotherapy studies in humans. The type of yeast used in this study, Saccharomyces cerevisiae, does not cause disease in humans and has been used as a delivery vehicle for antigens; proteins usually present on the surface of cells or organisms that stimulate immune responses. The tumor-associated antigen made by the genetically engineered yeast in this study is carcinoembryonic antigen (CEA), which is commonly found in cancers of the colon, rectum, stomach, breast, and lung. The authors point out that in several clinical trials, recombinant S cerevisiae vehicles have been found to be safe in both cancer and infectious disease settings. In a Phase Ib trial, a yeast construct expressing the hepatitis C virus (HCV) NS3-core fusion protein was administered to patients with chronic HCV. An interim analysis from this trial suggests that the yeast construct is safe for use in humans; no serious adverse events or dose-limiting toxicities have been reported. The authors note that at the time of the report, 12 (41%) of 29 patients had mounted cellular immune responses to HCV. “In a cancer setting, a phase I clinical trial with a S. cerevisiae construct expressing mutated Ras was conducted in patients with Ras+ cancers. Again, no treatment-related serious adverse events were observed, indicating a platform-wide safety profile for administration of heat-killed recombinant yeast to treat chronic diseases. In addition, 19 of 21 vaccinated patients showed >2-fold antigen-specific responses. As a result, a placebo-controlled adjuvant phase II trial in patients with mutated Ras+ fully resected pancreatic cancer is under way.” The current research was designed to determine the effects of this yeast-based vaccine on tumor growth and overall survival using colon and pancreatic cancer models. The studies demonstrated that the vaccine can elicit both CD4+ and CD8+ T-lymphocyte responses, which recruit additional immune cells and then attack and destroy cells that bear foreign or tumor-associated antigens. Additional findings from this study showed that successive administration of the vaccine resulted in increasing antigen-specific T-cell responses. Vaccination with the yeast–CEA vaccine at multiple sites induced greater T-cell responses than when the same dose of vaccine was given at a single site. Furthermore, tumor-bearing mice vaccinated with yeast–CEA had reduced tumor volumes and increased overall survival compared with control mice. In this study, the researchers performed 24 tests on mice that received either no treatment or the yeast–CEA vaccine. They found that body weight measurements, blood cell counts, serum enzyme levels, and assays for autoimmunity were all within the normal range for the vaccinated mice and were similar to those of control mice, indicating no toxicity or autoimmunity associated with the yeast-CEA vaccine. “The data reported here show that vaccination with yeast-CEA can break tolerance and induce CEA-specific CD4+ and CD8+ T-cell responses, effectively reduces tumor burden, and extends overall survival in tumor-bearing mice without adverse effects.” See “Vaccination with a recombinant Saccharomyces cerevisiae expressing a tumor antigen breaks immune tolerance and elicits therapeutic antitumor responses.” Clin Cancer Res. 2008;14:4316–4325.