Neoantigen Targeting-Dawn of a New Era in Cancer Immunotherapy?

During their development and progression tumors acquire numerous mutations that, when translated into proteins give rise to neoantigens that can be recognized by T cells. Initially, neoantigens were not recognized as preferred targets for cancer immunotherapy due to their enormous diversity and the therefore limited options to develop one fits all pharmacologic solutions. In recent years, the experience obtained in clinical trials demonstrating a predictive role of neoantigens in checkpoint inhibition has changed our view on the clinical potential of neoantigens in cancer immunotherapy. Technological advances such as sequencing of whole cancer genomes, the development of reliable algorithms for epitope prediction, and an increasing number of immunotherapeutic options now facilitate the development of personalized tumor therapies directly targeting a patient's neoantigenic burden. Preclinical studies in mice that support the excellent therapeutic potential of neoantigen-directed immunotherapies have provided blueprints on how this methodology can be translated into clinical applications in humans. Consistently, very recent clinical studies on personalized vaccinations targeting in silico predicted neoepitopes shed a first light on the therapeutic potential of personalized, neoantigen-directed immunotherapies. In our review, we discuss the various subtypes of tumor antigens with a focus on neoantigens and their potential in cancer immunotherapy. We will describe the current methods and techniques of detection as well as the structural requirements for neoantigens that are needed for their recognition by T cells and for tumor destruction. To assess the clinical potential of neoantigens, we will discuss their occurrence and functional relevance in spontaneous and hereditary cancers and their prognostic and predictive value. We will present in detail the existing immunotherapeutic options that exploit the neoantigen burden of tumors encompassing both preclinical efforts that provided convincing technological proof-of-concept and the current clinical studies confirming the potential of neoantigen-directed immunotherapies.