Shared epitopes create safety and efficacy concerns in several cancer vaccines

Tumor-associated antigens (TAAs) are the targets of several therapeutic cancer vaccines. However, many TAAs contain epitopes identical to unintended targets, creating shared epitopes with other human proteins in normal tissues. Moreover, for some TAAs like ASCL2, KLK2, TPTE, CLDN6, and PSMA, the off-targeted proteins are often expressed at a higher level in healthy tissues than the target in cancer, potentially impacting both the safety and the efficacy of T cell immunity. Altogether, our analysis indicates a suboptimal design of several cancer vaccines currently in clinical development: ATP128, BNT111, BNT112, BNT116, INO-5401. We recommend that next-generation cancer vaccines should integrate rigorous epitope filtering strategies to eliminate shared sequences in TAAs.