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Nature. 2019 Jan;565(7738):234-239. doi: 10.1038/s41586-018-0792-9. Epub 2018 Dec 19.

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

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
2
Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
3
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
4
Harvard Medical School, Boston, MA, USA.
5
Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA.
6
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
7
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
8
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
9
Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
10
Department of Bio- and Health Informatics, Technical University of Denmark, Kongens Lyngby, Denmark.
11
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
12
Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
13
Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
14
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
15
Oncovir Inc, Washington, DC, USA.
16
Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
17
Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA.
18
Neon Therapeutics Inc, Cambridge, MA, USA.
19
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. david_reardon@dfci.harvard.edu.
20
Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. david_reardon@dfci.harvard.edu.
21
Harvard Medical School, Boston, MA, USA. david_reardon@dfci.harvard.edu.

Abstract

Neoantigens, which are derived from tumour-specific protein-coding mutations, are exempt from central tolerance, can generate robust immune responses1,2 and can function as bona fide antigens that facilitate tumour rejection3. Here we demonstrate that a strategy that uses multi-epitope, personalized neoantigen vaccination, which has previously been tested in patients with high-risk melanoma4-6, is feasible for tumours such as glioblastoma, which typically have a relatively low mutation load1,7 and an immunologically 'cold' tumour microenvironment8. 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.

PMID:
30568305
DOI:
10.1038/s41586-018-0792-9

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