Journal
NATURE
Volume 565, Issue 7738, Pages 234-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-018-0792-9
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Funding
- Ben and Catherine Ivy Foundation
- Blavatnik Family Foundation
- Mathers Foundation
- Broad Institute SPARC program
- National Institutes of Health [NCI-1RO1CA155010-02]
- Francis and Adele Kittredge Family Immuno-Oncology and Melanoma Research Fund
- Faircloth Family Research Fund
- NIH/NCI [R21 CA216772-01A1]
- NCI [R50CA211482]
- Zuckerman STEM Leadership Program
- Benoziyo Endowment Fund for the Advancement of Science
- SPORE [P50 CA165962]
- DFCI Center for Cancer Immunotherapy Research fellowship
- Howard Hughes Medical Institute Medical Research Fellows Program
- American Cancer Society [PF-17-042-01-LIB]
- [NHLBI-5R01HL103532-03]
- [NHLBI-T32HL007627]
- [P01 CA163205]
- [NCI-SPORE-2P50CA101942-11A1]
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Neoantigens, which are derived from tumour-specific protein-coding mutations, are exempt from central tolerance, can generate robust immune responses(1,2) and can function as bona fide antigens that facilitate tumour rejection(3). Here we demonstrate that a strategy that uses multi-epitope, personalized neoantigen vaccination, which has previously been tested in patients with high-risk melanoma(4-6), is feasible for tumours such as glioblastoma, which typically have a relatively low mutation load(1,7) and an immunologically 'cold' tumour microenvironment(8). 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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