Neoantigen vaccination

Neoantigens arise from somatic mutations that differ from wild type antigens and are specific to each individual patient, which provide tumor specific targets for developing personalized cancer vaccines. Decades of work has increasingly shown the potential of targeting neoantigens to generate effective clinical responses. Current clinical trials using neoantigen targeting cancer vaccines, including in combination with checkpoint blockade monoclonal antibodies, have demonstrated potent T-cell responses against those neoantigens accompanied by antitumor effects in patients. Personalized neoantigen vaccines represent a potential new class of cancer immunotherapy 1).


They are exempt from central tolerance, can generate robust immune responses and can function as bona fide antigens that facilitate tumour rejection.

It is a truly personalized therapy because most neoantigens are derived from unique mutations in each tumor genome.

Keskin et al., demonstrated that a strategy that uses multi-epitope, personalized neoantigen vaccination, which has previously been tested in patients with high-risk melanoma, is feasible for tumours such as glioblastoma, which typically have a relatively low mutation load, and an immunologically ‘cold’ tumour microenvironment.

They used personalized neoantigen-targeting vaccines to immunize patients newly diagnosed with glioblastoma following surgical resection and conventional radiotherapy in a phase 1/Phase 1 B randomized controlled trial. Patients who did not receive dexamethasone-a highly potent corticosteroid that is frequently prescribed to treat cerebral edema in patients with glioblastoma-generated circulating polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses that were enriched in a memory phenotype and showed an increase in the number of tumour-infiltrating T cells. Using single-cell T cell receptor analysis, they provided evidence that neoantigen-specific T cells from the peripheral blood can migrate into an intracranial glioblastoma tumour. Neoantigen-targeting vaccines thus have the potential to favourably alter the immune milieu of glioblastoma 2).

References

1)

Aldous AR, Dong JZ. Personalized neoantigen vaccines: A new approach to cancer immunotherapy. Bioorg Med Chem. 2018 Jun 1;26(10):2842-2849. doi: 10.1016/j.bmc.2017.10.021. Epub 2017 Oct 19. Review. PubMed PMID: 29111369.
2)

Keskin DB, Anandappa AJ, Sun J, Tirosh I, Mathewson ND, Li S, Oliveira G, Giobbie-Hurder A, Felt K, Gjini E, Shukla SA, Hu Z, Li L, Le PM, Allesøe RL, Richman AR, Kowalczyk MS, Abdelrahman S, Geduldig JE, Charbonneau S, Pelton K, Iorgulescu JB, Elagina L, Zhang W, Olive O, McCluskey C, Olsen LR, Stevens J, Lane WJ, Salazar AM, Daley H, Wen PY, Chiocca EA, Harden M, Lennon NJ, Gabriel S, Getz G, Lander ES, Regev A, Ritz J, Neuberg D, Rodig SJ, Ligon KL, Suvà ML, Wucherpfennig KW, Hacohen N, Fritsch EF, Livak KJ, Ott PA, Wu CJ, Reardon DA. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature. 2018 Dec 19. doi: 10.1038/s41586-018-0792-9. [Epub ahead of print] PubMed PMID: 30568305.

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