Are we getting closer to a successful neoantigen cancer vaccine?

Although significant advances in immunotherapy have revolutionized the treatment of many cancer types over the past decade, the field of vaccine therapy, an important component of cancer immunotherapy, despite decades-long intense efforts, is still transmitting signals of promises and awaiting strong data on efficacy to proceed with regulatory approval. The field of cancer vaccines faces standard challenges, such as tumor-induced immunosuppression, immune response in inhibitory tumor microenvironment (TME), intratumor heterogeneity (ITH), permanently evolving cancer mutational landscape leading to neoantigens, and less known obstacles: neoantigen gain/loss upon immunotherapy, the timing and speed of appearance of neoantigens and responding T cell clonotypes and possible involvement of immune interference/heterologous immunity, in the complex interplay between evolving tumor epitopes and the immune system. In this review, we discuss some key issues related to challenges hampering the development of cancer vaccines, along with the current approaches focusing on neoantigens. We summarize currently well-known ideas/rationales, thus revealing the need for alternative vaccine approaches. Such a discussion should stimulate vaccine researchers to apply out-of-box, unconventional thinking in search of new avenues to deal with critical, often yet unaddressed challenges on the road to a new generation of therapeutics and vaccines.