Somatic mutations can cause tumours to express mutant proteins that are tumour specific and not expressed on normal cells (neoantigens). In the subset of human tumours with a viral aetiology, the proteins encoded by viral genes are another type of neoantigen.
Neoantigens are an attractive immune target because their selective expression on tumours may minimize immune tolerance as well as the risk of autoimmunity. Therefore, neoantigen-specific therapies may be more effective and less toxic than therapies targeting tumour-associated antigens.
Neoantigens serve a crucial role in the naturally occurring antitumour T cell response, and are also the most important tumour antigens in certain cancers for which immune checkpoint inhibitors have shown clinical efficacy.
As neoantigens are unique and not shared between different patients, neoantigen-targeted therapy will probably need to be on an individual basis. A personalized approach to targeting neoantigens has only recently been possible as a result of major advances in genomics and bioinformatics, including massively parallel sequencing and epitope prediction algorithms.
Two therapeutic platforms that could be used to target neoantigens are adoptive cell therapy (ACT) using neoantigen-specific T cell products, and personalized vaccines encoding predicted neoantigens.
Neoantigen-specific therapies will probably need to be combined with other therapies such as immune checkpoint inhibitors to overcome immunosuppressive mechanisms in the tumour microenvironment that inhibit neoantigen-specific immune responses.
The past decade of cancer research has been marked by a growing appreciation of the role of immunity in cancer. Mutations in the tumour genome can cause tumours to express mutant proteins that are tumour specific and not expressed on normal cells (neoantigens). These neoantigens are an attractive immune target because their selective expression on tumours may minimize immune tolerance as well as the risk of autoimmunity. In this Review we discuss the emerging evidence that neoantigens are recognized by the immune system and can be targeted to increase antitumour immunity. We also provide a framework for personalized cancer immunotherapy through the identification and selective targeting of individual tumour neoantigens, and present the potential benefits and obstacles to this approach of targeted immunotherapy.
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The authors gratefully acknowledge support from the Bloomberg–Kimmel Institute for Cancer Immunotherapy and the Skip Viragh Center for Pancreatic Cancer Research and Clinical Care at Johns Hopkins University, Baltimore, Maryland, USA.
Under a licensing agreement between Aduro BioTech, Inc. and the Johns Hopkins University and E.M.J., the University is entitled to milestone payments and royalty on sales of certain cancer vaccine products (E.M.J.). The other authors have no conflict to disclose.
- Passenger mutations
Mutations that have no effect on the fitness of the cell, and are therefore not implicated in oncogenesis.
- Driver mutations
Mutations that cause a selective advantage to a cell clone and are therefore causally implicated in oncogenesis.
- Nonsynonymous mutations
Point mutations and missense mutations that alter the amino acid sequence of proteins.
- Major histocompatibility complex
(MHC). Cell surface proteins that bind to short sequences of amino acids (epitopes) and display them on the cell surface for recognition by the immune system. MHC class I is present on the surface of virtually all nucleated cells including tumour cells and presents intracellular antigens to CD8+ T cells; MHC class II is present on antigen presenting cells and presents exogenous antigens to CD4+ T helper cells.
Mutations in the tumour genome can cause tumours to express mutant proteins that are tumour specific and not expressed on normal cells — referred to as neoantigens.
- Objective response rates
(ORRs). ORR is a common efficacy end point used in clinical trials of cancer therapies in solid tumours, usually defined as the percentage of patients who experience at least a 30% decrease in tumour diameter on an imaging scan.
- Central and peripheral tolerance
A state in which immune cells are unresponsive to antigens as a result of clonal deletion of autoreactive B cells and T cells, as well as the dampening of potentially autoreactive B cells and T cells through regulatory immune cells and subsequent downregulation of costimulatory molecules.
- Chimeric antigen receptor (CAR) T cells
T cells that are modified to express an antigen recognition domain of a specific antibody fused to an intracellular signalling domain.
- Adoptive cell therapy
(ACT). An immunotherapy treatment in which antitumour lymphocytes are identified, expanded in vitro and then infused into a patient with cancer. The administered antitumour lymphocytes can be autologous (patient's own) or allogeneic (donor).
- Microsatellite instability
(MSI). Increased propensity for changes in microsatellite (short tandem repeat) sequences resulting from defects in DNA mismatch repair.
The ability to induce an immune response.
An immunostimulatory agent designed to enhance the immune response to a vaccine.
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Yarchoan, M., Johnson, B., Lutz, E. et al. Targeting neoantigens to augment antitumour immunity. Nat Rev Cancer 17, 209–222 (2017). https://doi.org/10.1038/nrc.2016.154
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