|Neoantigen vaccine against glioblastoma enhances
intratumoral T cell functions
A total of 10 patients were recruited into the trial. Somatic mutations were determined using whole-exome sequencing between surgically resected glioblastoma samples (formalin-fixed paraffin-embedded tissue) and autologous PBMC. A median of 116 somatic single-nucleotide variants per tumour were observed, among which was a median of 59 coding mutations per tumour. The expression of a proportion of those mutated genes was confirmed by RNA sequencing. Peptide vaccines were selected according to predictions on binding affinity to HLA-I molecules. A median of 12 (range, 7 to 20) vaccines with a median amino acid length of 24 (range, 15 to 30) was produced. Four pools of vaccines, each of which contained 3 to 5 peptides, were administered to patients after radiotherapy following a schedule of five priming doses and two booster injections along with an adjuvant.
Among the 10 recruited patients, eight received five priming vaccines, but only three completed booster vaccines. Adverse events were limited to grade 1 and 2 events. No toxicities were dose-related, or caused does delay and/or discontinuation. All patients died from disease progression. Median progression-free survival was 7.6 months, and median overall survival was 16.8 months.
Vaccinated patients that were not treated with dexamethasone indicated enhanced immune responses. PBMC collected from patients on dexamethasone during priming vaccinations failed to produce IFNgamma, but PBMC from patients that were not treated with dexamethasone did so. CD4+ T cells from patients that were not treated with dexamethasone produce IFNgamma, IL2 and TNF. CD8+ T cells from one patient that was not treated with dexamethasone were specific to tumour neoantigens. Increased numbers of CD8+ and CD4+ T cells were found in the relapsed tumours compared to surgically resected tumours in patients who did not receive dexamethasone, whereas this increase was not seen in those who were on dexamethasone. Single-cell T cell receptor sequencing revealed a fraction of newly recruited T cells were indeed neoantigen-specific T cells. These neoantigen-specific T cells were also detected in PBMC. Single-cell RNA sequencing of T cells isolated from recurrent tumours of a patient that were not treated with dexamethasone revealed that the majority of CD8+ T cells were effector T cells, and only a small portion of CD4+ T cells were regulatory T cells. Therefore, neoantigen vaccination has the potential to treat a cold tumour like glioblastoma when dexamethasone can be avoided. As mentioned in the paper, T cells collected from the relapsed tumour after vaccination commonly expressed PD-1, indicating a hot tumour microenvironment and possible co-application of immune checkpoint inhibitors along with neoantigen vaccines.