Vaccines have traditionally been used to prevent infectious diseases, whose ability to induce and amplify antigen-specific immune responses has long been considered a potentially valuable tool for the treatment of cancer. Early therapeutic vaccination strategies focused on the abnormally expressed or over-expressed self-antigens in tumors, tumor-associated antigens (TAA). However, this strategy is basically unsuccessful in clinical practice because TAA-specific T cells are affected by central and/or peripheral tolerance. In addition, such TAAs are also expressed to a certain extent in non-malignant tissues, which increases the risk of vaccine-induced autoimmune toxicity.
Mutations in tumor cells can produce new self-antigen epitopes, called neoepitopes or neoantigens. Vaccines based on neoantigens rather than traditional TAAs have several advantages. First, neoantigens are only expressed by tumor cells, so they can trigger a true tumor-specific T cell response, thereby preventing off-target damage to non-tumor tissues. Second, neoantigens are new epitopes derived from somatic mutations, which may bypass the central tolerance of T cells to their own epitopes, thereby inducing immune responses to tumors. In addition, the neoantigen-specific T cell response enhanced by such vaccines persists and enhances immune memory after treatment, making the long-term prevention of disease recurrence possible.
Clinical progress of neoantigen vaccines
At present, there are several personalized neoantigen vaccines in progress of clinical trials. These preliminary studies provide important clues for the immunogenicity and therapeutic potential of personalized neoantigen cancer vaccines.
* GEN-009 is a personalized neoantigen vaccine, containing 4-20 synthetic long peptides selected using the ATLAS epitope discovery platform, using poly-ICLC preparations.
* RO7198457 is a personalized RNA-lipoplex neoantigen vaccine that encodes up to 20 new antigens.
* mRNA-4157 is another lipid-encapsulated RNA neoantigen vaccine that has been tested as a monotherapy in 13 patients with high-risk resectable solid tumors, and combined with pembrolizumab in the treatment of 20 patients with unresectable advanced solid tumors, the latter including 12 patients with disease progression before immune checkpoint inhibitors (ICI) treatment.