Neoantigens have emerged as prime targets for cancer immunotherapy in the past decade and researchers continue to explore approaches to improve antigen selection and immunogenicity for vaccine development.

Two prominent researchers in this field discussed the potential for personalized cancer vaccines during the symposium Cancer Vaccines: New Developments and Clinical Response on Wednesday, April 13. The session can be viewed on the virtual platform by registered meeting participants through July 13, 2022.

“It is now a well-established concept that spontaneous T-cell recognition of neoantigens in patients drives antitumor responses of checkpoint blockade, as well as other T-cell therapies,” said Ugur Sahin, MD, who discussed advances in predicting and classifying neoantigens with the goal of developing individualized vaccines.

“What is also clear is that only 1 percent to 2 percent of mutations are recognized spontaneously by T cells,” added Sahin, of BioNTech AG, Mainz, Germany.

Because different patients have different sets of mutations, researchers are developing algorithms and machine-learning tools to assist in identifying and prioritizing mutations that are likely to be recognized by T cells. Sahin and his colleagues employed a new classification of neoantigens—guarding, restrained, and ignored neoantigens—based on how they confer proficient antitumor immunity in a given clinical context.

“We know that the restrained neoantigens that are formed during tumor formation have an overall frequency of about 1 percent to 2 percent, similar to the frequency of neoantigens, which are preformed and cross-recognized by heterologous immunity. Whereas, ignored neoantigens, which can be induced and empowered by personalized neoantigen vaccines, have an overall frequency of 15 percent to 25 percent,” Sahin explained. “So, the real value for personalized cancer vaccines might be to mobilize this particular type of neoantigens. Emerging evidence from preclinical studies, as well now from neoantigen vaccine studies in humans, will tell us about the overall value and efficacy of these different types of neoantigens.”

Lélia Delamarre, PhD, from Genentech, followed with further discussion of tumor antigen immunogenicity and described how tumor specificity makes neoantigens ideal therapeutic targets.

“These mutations that are accumulating in cancer have the potential to be recognized as foreign by the immune system, and there is now evidence that neoantigens can elicit protective immune responses,” she said.

Delamarre cited data from a study in which investigators infused neoantigen-specific T cells that lead to tumor regression in patients with KRAS-mutated tumors.

“They showed that the T cells can distinguish the mutation from the corresponding wild-type peptide and that the neoantigen-specific T cells do not recognize the wild-type peptides,” she said. “They only get activated by the mutated peptides, which really indicates that this mutated peptide is recognized as foreign by the immune system.”

Moving forward, Delamarre said that neoantigen prediction is critical, but improving the characterization of immunogenic peptides requires more data.

“We need large-scale immunopeptidomics data to better predict antigen presentation, and also more immunogenicity data to help better predict which of the mutated peptides that are present actually are eliciting T-cell response,” Delamarre said.