Yeast-based immunotherapy and the threshold of EGFR expression for immune recognition against glioma overexpressing self-antigen
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1405 The administration of Tarmogens™, which are whole, heat-inactivated Saccharomyces cerevisiae yeast containing defined quantities of target antigens, elicit T cell-mediated immune responses that recognize and ablate antigen-bearing tumors. Yeast are avidly taken up via pattern recognition receptors, such as glucan, mannan and Toll-like receptors (TLRs) on antigen-presenting dendritic cells (DCs), initiating an innate immune response. This innate immune response drives DC maturation and secretion of pro-inflammatory cytokines, followed by the MHC-mediated presentation of yeast-expressed tumor antigens to initiate antigen-associated adaptive responses. Yeast may be administered repeatedly without the generation of neutralizing host anti-yeast antibodies, thus boosting tumor antigen-specific immune responses against over-expressed self or mutated tumor antigens. We previously described that Tarmogens delivering mutated Ras proteins elicited therapeutic protection against carcinogen-induced mutant Ras-expressing lung tumors in mice (Cancer Res 64: 5084). A Phase 1 trial treating colorectal and pancreas cancer patients with the mutant Ras-expressing Tarmogens demonstrated the safety and immunogenicity of this approach. In the present studies, yeast delivering human or rat EGFR as the tumor antigen (GI-3000 Tarmogens) were tested as immunotherapeutics against intracranial rat glioma challenge. Intranasal administration of GI-3000 expressing either rat or human EGFR proteins resulted in antigen-specific protection against intracranial challenge with 9L glioma transfected with non-mutated rat or human EGFR in Fischer rats. The immune-mediated tumor ablation was dependent on EGFR overexpression, as demonstrated by flow cytometry of tumor cells isolated and analyzed from responding and non-responding animals. The profile of cell surface EGFR density revealed an antigen threshold below which tumor cells were not recognized by cell-mediated immune responses. The apparent requirement for EGFR overexpression in immune-mediated protection may explain the absence of grossly observable off-target effects in tissues with normal levels of EGFR expression. These preclinical data indicate that Tarmogen administration is capable of breaking tolerance to overexpressed self antigens, supporting clinical evaluation in relevant cancer indications such as EGFR-overexpressing glioblastomas.