Neoantigens, which are derived from tumor-specific protein-coding gene mutations, are exempt from central tolerance, can generate robust immune responses and function as bona fide antigens that facilitate tumor rejection. A strategy of using multi-epitope and personalized neoantigen vaccination has previously been tested in patients with high-risk melanoma. We demonstrated that this strategy is feasible for glioblastoma (GBM) which typically has a relatively low mutation load and an immunologically 'cold' tumor microenvironment. We conducted whole exome sequencing (WES) of tumor and normal cells from individual GBM patients to identify tumor-specific mutations. We assessed the expression of mutated alleles by RNA-sequencing of tumor, and used personalized neoantigen-targeting vaccines to immunize newly diagnosed GBM patients 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 GBM patients, 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 tumor-infiltrating T cells. Using single-cell T cell receptor analysis, we provided an evidence that neoantigen-specific T cells from the peripheral blood can migrate into an intracranial GBM tumor. Neoantigen-targeting vaccines thus have the potential to favorably alter the immune environment of GBM.In order to discover cancer antigens derived from annotated and unannotated protein-coding regions of the genome, we carried out matched ribosome profiling (Ribo-Seq) on two GBM samples. We discovered novel or unannotated open reading frames (nuORFs) and their expression levels as well as somatic mutations within the nuORFs, which could be used to predict potential neoantigens.

A Phase I Study With a Personalized Neoantigen Cancer Vaccine in Glioblastoma Multiforme

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