Review

Neoantigens in cancer immunotherapy

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Science  03 Apr 2015:
Vol. 348, Issue 6230, pp. 69-74
DOI: 10.1126/science.aaa4971

Figures

  • Fig. 1 Cancer exome–based identification of neoantigens.

    Tumor material is analyzed for nonsynonymous somatic mutations. When available, RNA sequencing data are used to focus on mutations in expressed genes. Peptide stretches containing any of the identified nonsynonymous mutations are generated in silico and are either left unfiltered (16, 17), filtered through the use of prediction algorithms [e.g., (1013)], or used to identify MHC-associated neoantigens in mass spectrometry data (15, 20). Modeling of the effect of mutations on the resulting peptide-MHC complex may be used as an additional filter (20). Resulting epitope sets are used to identify physiologically occurring neoantigen-specific T cell responses by MHC multimer-based screens (13, 22) or functional assays [e.g., (11, 12)], within both CD8+ [e.g., (1113, 19, 39)] and CD4+ (16, 18) T cell populations. Alternatively, T cell induction strategies are used to validate predicted neoantigens [e.g., (10, 20)].

  • Fig. 2 Estimate of the neoantigen repertoire in human cancer.

    Data depict the number of somatic mutations in individual tumors. Categories on the right indicate current estimates of the likelihood of neoantigen formation in different tumor types. Adapted from (50). It is possible that the immune system in melanoma patients picks up on only a fraction of the available neoantigen repertoire, in which case the current analysis will be an underestimate. A value of 10 somatic mutations per Mb of coding DNA corresponds to ~150 nonsynonymous mutations within expressed genes.

  • Fig. 3 Characteristics of melanoma neoantigens.

    (Top) For a group of CD4+ T cell neoantigens (8 epitopes) and CD8+ T cell neoantigens (13 epitopes) identified by cancer exome–based screens, the frequency of mutation of that residue in a cohort of ~20,000 human tumor samples (51) is depicted. (Bottom) For the same group of CD4+ T cell and CD8+ T cell neoantigens, the fraction of encoding mutations that occurs within known oncogenes (52) is depicted.

  • Fig. 4 Strategies to target the patient-specific neoantigen repertoire.

    (A) Immunotherapy is given in combination with interventions such as radiotherapy that enhance exposure to autologous neoantigens. (B) Potential neoantigens are identified as in Fig. 1 steps 1 to 3, a patient-specific vaccine is produced, and this vaccine is given together with adjuvant and T cell checkpoint-blocking antibodies. (C) Potential neoantigens are identified as in Fig. 1 steps 1 to 3, T cells that are specific for these neoantigens are induced or expanded in vitro, and the resulting T cell product is given together with T cell checkpoint-blocking antibodies.

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