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- Study Description
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- Talking Glossary of Genetic Terms
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. We 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. Here we conducted whole-exome sequencing of tumor and normal cells from individual patients with glioblastoma to identify tumor-specific mutations. We assessed the expression of mutated alleles by RNA-sequencing of tumor. 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.
- Study Design:
- Clinical Trial
- Study Type:
- Clinical Trial
- Total number of consented subjects: 10
- Subject Sample Telemetry Report (SSTR)
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- Study Inclusion/Exclusion Criteria
- <p>Study eligibility was assessed among patients seen at the Center for Neuro-Oncology, Dana-Farber Cancer Institute and required: age ≥18 years; Karnofsky performance status ≥70; histopathological confirmation of WHO grade IV glioblastoma (GBM) or variant; tumour MGMT promoter unmethylated by CLIA-certified laboratory; supratentorial tumour with no more than 4 cm in maximal diameter of enhancing tumour on post-operative imaging in any plane; and adequate hepatic, renal and bone marrow function. Patients were excluded if: fewer than five actionable neoepitopes were identified for vaccine generation; they developed disease progression following external beam radiotherapy as defined by Response Assessment in Neuro-Oncology (RANO)19; required more than 4 mg of dexamethasone per day within one week before vaccine initiation; developed active infection; or were pregnant or lactating.
- Molecular Data
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Type Source Platform Number of Oligos/SNPs SNP Batch Id Comment Whole Exome Sequencing Illumina HiSeq 2500 N/A N/A Broad's Illumina content Exome with Nextera library prep RNA Sequencing Illumina HiSeq 2500 N/A N/A Standard Illumina TruSeq and Illumina Tru Seq with a capture step (aka Transcriptome Capture) - Selected Publications
- Diseases/Traits Related to Study (MeSH terms)
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- Primary Phenotype: Glioblastoma
- Links to Related Resources
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- BioProject
- PubMed
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- Clinical Trials
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- Study Attribution
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Principal Investigator
- David Reardon. Dana-Farber Cancer Institute, Boston, MA, USA.
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Principal Investigator