Tumor neoantigens: building a framework for personalized cancer immunotherapy
Matthew M. Gubin, … , Elaine R. Mardis, Robert D. Schreiber
Matthew M. Gubin, … , Elaine R. Mardis, Robert D. Schreiber
Published August 10, 2015
Citation Information: J Clin Invest. 2015;125(9):3413-3421. https://doi.org/10.1172/JCI80008.
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Review Series

Tumor neoantigens: building a framework for personalized cancer immunotherapy

Abstract

It is now well established that the immune system can recognize developing cancers and that therapeutic manipulation of immunity can induce tumor regression. The capacity to manifest remarkably durable responses in some patients has been ascribed in part to T cells that can (a) kill tumor cells directly, (b) orchestrate diverse antitumor immune responses, (c) manifest long-lasting memory, and (d) display remarkable specificity for tumor-derived proteins. This specificity stems from fundamental differences between cancer cells and their normal counterparts in that the former develop protein-altering mutations and undergo epigenetic and genetic alterations, resulting in aberrant protein expression. These events can result in formation of tumor antigens. The identification of mutated and aberrantly expressed self-tumor antigens has historically been time consuming and laborious. While mutant antigens are usually expressed in a tumor-specific manner, aberrantly expressed antigens are often shared between cancers and, therefore, in the past, have been the major focus of therapeutic cancer vaccines. However, advances in next-generation sequencing and epitope prediction now permit the rapid identification of mutant tumor neoantigens. This review focuses on a discussion of mutant tumor neoantigens and their use in personalizing cancer immunotherapies.

Authors

Matthew M. Gubin, Maxim N. Artyomov, Elaine R. Mardis, Robert D. Schreiber

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Figure 3

Neoantigen-specific T cell therapy.

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Neoantigen-specific T cell therapy. Patient tumor cells and normal tissu...
Patient tumor cells and normal tissue are subjected to whole-exome sequencing and RNA-Seq to identify expressed nonsynonymous somatic mutations. These mutations are pipelined into MHCI epitope prediction algorithms to prioritize a list of candidate antigens and/or may be expressed as minigenes used for the identification and expansion of mutant neoantigen–specific autologous T cells isolated from blood or tumor of the same patient. Ex vivo–expanded T cells are then infused back into the cancer patient. Alternatively, expressed mutations predicted to form neoantigens by MHCI epitope–binding algorithms are confirmed and then used to generate neoantigen vaccines.