Overcoming the obstacles for developing effective tumor neoantigen vaccines

Targeting cancer with therapeutic vaccines is considered as an approach to treat cancer either as a stand-alone treatment or in combination with immunotherapies. The genetic changes of cancer cells, have the potential to generate altered or new protein products, termed neoantigens, which are immunologically seen as foreign. These tumor neoantigens differ from host cells this potentially makes them ideal vaccine targets. Although endogenous T cell immunity against neoantigens exists in patients, as implied by the dependence of immune checkpoint immunotherapy (ICI) success on mutational burden, in the majority of cases these responses fail to control cancer. Therefore, therapeutic vaccines that boost existing endogenous or elicit de novo T cell responses against neoantigens could raise anti-cancer immunity to clinically relevant levels and simultaneously improve or expand the efficacy of ICI. Despite, however, more than 100 clinical trials having been conducted with therapeutic tumor neoantigens vaccines, very little, if any, clinical benefit has been demonstrated. The reason for these vaccine failures is that a number of critical obstacles remain to be overcome, before neoantigen vaccines can deliver clinical benefit. These obstacles relate to neoantigen selection, vaccine platform, adjuvant potency, T cell recruitment and function, and tumor microenvironment. Overcoming such obstacles will require novel vaccine strategies and combination therapies.