Abstract
The field of cancer immunotherapy has seen incredible advancements in the past decades. mRNA-based cancer vaccines generating de novo T cell responses, particularly against tumor-specific antigens (TSAs), have demonstrated promising clinical outcomes and overcome diverse challenges. Despite the high potential of neoantigens to provide personalized immunotherapies through their tumor specificity and immunogenicity, challenges related to the scarcity of immunogenic neoepitopes have prompted continuous research towards finding new tumor-associated antigens (TAAs) and broader therapeutic frameworks, which may now learn from the genuine successes obtained with neoantigens. As an example, human endogenous retroviruses (HERVs) have emerged as potential alternatives to tumor neoantigens due to their high tumoral expression and ability to elicit both T cell reactivity and B cell responses associated with the efficacy of existing immunotherapies. This review aims to assess the status and limitations of TSA-directed mRNA cancer vaccines and the lessons that can be derived from these and checkpoint inhibitor studies to guide TAA vaccine development. We expect that shared B cell, CD4 and CD8 T cell antigen presentation will be key to stimulate continuous T cell expansion and efficacy for tumors that do not contain pre-existing tertiary lymphoid structures. When these structures are present in highly mutated tumors, the current checkpoint-based immunotherapies show efficacy even in immune privileged sites, and vaccines may hold the key to broaden efficacy to more tumor types and stages.