In a phase I/Ib trial, 8 patients with newly diagnosed glioblastoma were treated with up to 20 long neoantigen peptides admixed with poly-ICLC in a prime-boost schedule following surgery and radiotherapy. Dexamethasone (dex) treatment for cerebral edema prevented T cell responses. Two patients who were not treated with dex during vaccine priming generated circulating, polyfunctional, neoantigen-specific CD4+ and CD8+ T cells that demonstrated an antigen-experienced memory phenotype. Neoantigen-specific T cells also infiltrated relapsed tumors, where they showed signs of cytotoxicity and/or exhaustion.
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.
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. Broad Institute of MIT and
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Harvard Medical School, Boston, MA, USA. Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (4) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (5) Harvard Medical School, Boston, MA, USA. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (6) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (7) Department of Medical Oncology, 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) Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (11) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (12) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (13) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (14) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (15) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Bio- and Health Informatics, Technical University of Denmark, Kongens Lyngby, Denmark. (16) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Harvard Medical School, Boston, MA, USA. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (17) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (18) Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (19) Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. (20) Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. (21) Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. (22) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. (23) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (24) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (25) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (26) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (27) Department of Bio- and Health Informatics, Technical University of Denmark, Kongens Lyngby, Denmark. (28) Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. (29) Harvard Medical School, Boston, MA, USA. Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. (30) Oncovir Inc, Washington, DC, USA. (31) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (32) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA. (33) Harvard Medical School, Boston, MA, USA. Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA. (34) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (35) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (36) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (37) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Harvard Medical School, Boston, MA, USA. Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (38) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (39) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (40) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (41) Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA. (42) Harvard Medical School, Boston, MA, USA. Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. (43) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Harvard Medical School, Boston, MA, USA. Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. (44) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Harvard Medical School, Boston, MA, USA. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (45) Harvard Medical School, Boston, MA, USA. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (46) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Harvard Medical School, Boston, MA, USA. Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (47) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Neon Therapeutics Inc, Cambridge, MA, USA. (48) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (49) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (50) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Harvard Medical School, Boston, MA, USA. (51) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. david_reardon@dfci.harvard.edu. Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. david_reardon@dfci.harvard.edu. Harvard Medical School, Boston, MA, USA. david_reardon@dfci.harvard.edu.
