Neoantigen-based cancer immunotherapy

Abstract

Emerging clinical evidence on the role of the antitumor activity of the immune system has generated great interest in immunotherapy in all cancer types. Recent clinical data clearly demonstrated that human tumor cells express antigenic peptides (epitopes) that can be recognized by autologous tumor-specific T cells and that enhancement of such immune reactivity can potentially lead to cancer control and cancer regression in patients with advanced disease. However, in most cases, it is unclear which tumor antigens (Ags) mediated cancer regression.Mounting evidence indicates that numerous endogenous mutated cancer proteins, a hallmark of tumor cells, can be processed into peptides and presented on the surface of tumor cells, leading to their immune recognition in vivo as "non-self" or foreign. Massively parallel sequencing has now overcome the challenge of rapidly identifying the comprehensive mutational spectrum of individual tumors (i.e., the "mutanome") and current technologies, as well as computational tools, have emerged that allow the identification of private epitopes derived from their mutanome and called neoantigens (neoAgs). On this basis, both CD4 + and CD8 + neoantigen-specific T cells have been identified in multiple human cancers and shown to be associated with a favorable clinical outcome.Notably, emerging data also indicate that neoantigen recognition represents a major factor in the activity of clinical immunotherapies. In the post-genome era, the mutanome holds promise as a long-awaited 'gold mine' for the discovery of unique cancer cell targets, which are exclusively tumor-specific and unlikely to drive immune tolerance, hence offering the chance for highly promising clinical programs of cancer immunotherapy.

Development and Optimization of a GMP-Compliant Manufacturing Process for a Personalized Tumor Lysate Dendritic Cell Vaccine

“…Indeed, as neo-antigens are not expressed by healthy tissues, they can be recognized as non-self by the immune system, and are thus a target of choice for immunotherapy. To avoid the long and expensive process of neo-antigens identification and production [7][8][9][10], tumor lysate represents an attractive source of antigens for indications where surgery can be performed.…”

An Update on the Relevance of Vaccine Research for the Treatment of Metastatic Melanoma

“…Evidence supporting this view has steadily increased during the past decade. For instance, in addition to the disappointing clinical results with peptide and allogeneic cancer cell line vaccines, we now know that the vast majority of metastatic melanoma cells are associated with hundreds to thousands of nonsynonymous mutations that may result in transcription and translation into proteins that are foreign to that patient's immune system, that is, they are neoantigens, and therefore immunogenic [20][21][22][23][24]. Most of the nonsynonymous mutations in cancer cells are passenger rather than driver mutations.…”

Informatics for Cancer Immunotherapy

“…Many are self-antigens that are aberrantly expressed or post-translationally modified [202] , while others are non-self viral [203] or somatic mutation-derived tumor antigens [204] . Somatic mutation-derived tumor antigens are also called "neoantigens" and are important targets for tumor rejection [205][206][207][208][209][210] .…”