T-cells are one of the prime sentinels of the immune system, which sound the alarm and help orchestrate the immune response. Ever since scientists found T-cells inside tumors, they realized that the body does have a natural, albeit mild, immunity to cancer. The T-cells inside tumors recognize antigens on the surfaces of tumor cells, but don’t bind them strongly enough to sound an alarm or initiate a robust immune response.
Scientists have tried several strategies to stimulate those T-cells, from general immune stimulants to synthetic variations on the naturally occurring antigens. Although some of the vaccines showed moderate results in animal models, none has proven effective in humans.
Slansky hypothesized that previous vaccine candidates were unsuccessful because they did not bind strongly enough to the T-cells found inside tumors. As a result, the vaccines failed to stimulate the T-cells into mounting an effective immune response. So, she, structural biologist John Kappler, and Kimberly Jordan, the postdoctoral fellow whose work bridges the two labs, designed peptide vaccines that resemble naturally occurring antigens but bind more strongly to the T-cells found inside tumors.
They evaluated five candidate peptide vaccines. They vaccinated mice twice with the candidate vaccines, then injected colon tumor cells into the mice a week later. The results were quite variable. Two of the vaccines protected few or no mice, three other vaccines kept 60 percent, 90 percent and 100 percent alive and tumor-free for 60 days.
The researchers tried to learn what distinguished the effective peptide vaccines from ineffective ones. They found that the ineffective vaccines strongly stimulated T-cells that recognized the peptide vaccine but not any T-cells that recognized antigen on the cancer cells.
The successful vaccines stimulated T-cells that recognized both the peptide vaccine and the naturally occurring antigen. The successful antigens stimulated the growth of many more T-cells than the ineffective ones. Those T-cells were also highly activated and ready to attack, as evidenced by their production of cytokine signaling molecules. Remarkably, the most successful vaccine varied by only one amino acid from the naturally occurring antigen, which provoked almost no immune response.
“Our theory about the importance of the T-cell peptide bond was correct, but we learned that the peptides must also stimulate T-cells that cross react with the existing antigens and produce a large population of activated T-cells,” said Kappler, professor of Integrated Immunology at the University of Colorado School of Medicine on the Anschutz Medical Campus. “We believe this provides a very promising strategy for developing cancer vaccines. We are now working to learn why a single amino-acid substitution makes such a huge difference in effectiveness.”
The research was supported by grants from the American Cancer Society, the National Cancer Institute and Cancer Research Institute.
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