Olivera J. Finn, Ph.D. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Hundreds of molecules differentially expressed on tumors versus normal cells, tumor associated antigens (TAA), have been incorporated in various forms into vaccines to be administered to patients with cancer in hope of boosting or eliciting new immune responses to control tumor growth. One such antigen is the epithelial mucin MUC1 that is over-expressed and hypoglycosylated on tumor cells compared to normal tissues and recognized as such by human antibodies and T cells. This tumor form of MUC1 is found on all human adenocarcinomas and preclinical and clinical studies of MUC1 vaccines were performed in breast, pancreatic, colon, ovarian, prostate and lung cancer among others. While responses to the vaccine could be documented, they were of low titter (antibodies) and low frequency (T cells). Clinical responses were rare. These studies helped elucidate, however, multiple immunosuppressive mechanisms in the tumor microenvironment responsible for the failure of MUC1 vaccines, implicated also in failures of other therapeutic cancer vaccines. The newest immunotherapy approaches directed to releasing tumor-induced immunosuppression, such as the checkpoint inhibitors, have had impressive successes in some patients and in some cancers that have been refractory to all other therapies. There is expectation that therapeutic vaccines in combination with checkpoint inhibitors or other immune modulators would be more effective than when given alone and animal studies support that. Alternatively, TAA vaccines could be tested for cancer prevention under the hypothesis that in the absence of tumor-induced immunosuppression they would be most efficacious. We tested immunogenicity and safety of a MUC1 peptide vaccine in 40 individuals with premalignant colonic polyps, precursors to colon cancer. High affinity IgG responses were generated and long-term immune memory in 47% of individuals. Lack of response in 53% of participants was associated with increased levels of circulating myeloid-derived suppressor cells (MDSCs). Immunogenicity and safety results were replicated in a larger (110 participants) placebo controlled efficacy trial that is currently in the follow up phase. The latest trial is testing immunogenicity and safety in 40 current or former smokers for prevention of lung cancer.
Funding: NCI R35CA210039
Credits: None available.
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