Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial

DB Keskin, AJ Anandappa, J Sun, I Tirosh… - Nature, 2019 - nature.com
DB Keskin, AJ Anandappa, J Sun, I Tirosh, ND Mathewson, S Li, G Oliveira
Nature, 2019nature.com
Neoantigens, which are derived from tumour-specific protein-coding mutations, are exempt
from central tolerance, can generate robust immune responses, and can function as bona
fide antigens that facilitate tumour rejection. Here we demonstrate 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 …
Abstract
Neoantigens, which are derived from tumour-specific protein-coding mutations, are exempt from central tolerance, can generate robust immune responses, and can function as bona fide antigens that facilitate tumour rejection. Here we demonstrate 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. We used personalized neoantigen-targeting vaccines to immunize patients newly diagnosed with glioblastoma following surgical resection and conventional radiotherapy in a phase I/Ib study. Patients who did not receive dexamethasone—a highly potent corticosteroid that is frequently prescribed to treat cerebral oedema 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, we provide 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.
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