New findings from phase 1 and 2 trials of personalised DNA vaccines for GBM and nivolumab for grade group 5 prostate cancer.
A personalised DNA vaccine targeting dozens of patient-specific tumour mutations has shown encouraging signs of immune activation and prolonged survival in patients with one of the deadliest forms of brain cancer.
Published in Nature Cancer, the phase I GT-20 trial evaluated an investigational personalised neoantigen DNA vaccine (GNOS-PV01) in patients with newly diagnosed glioblastoma whose tumours lacked MGMT promoter methylation – a subgroup that derives little benefit from standard temozolomide chemotherapy and typically has among the poorest outcomes in neuro-oncology.
Glioblastoma remains the most common primary malignant brain tumour in adults, with a median overall survival of less than 20 months even with surgery, radiotherapy, and chemotherapy.
The personalised vaccines contained up to 40 neoantigens unique to each patient’s cancer, developed from tumour samples collected from multiple regions of each patient’s tumour after surgery. The approach was designed to stimulate a targeted T-cell response while accounting for the substantial genetic diversity seen within glioblastomas.
Nine adults received the intramuscular vaccine, which contained a DNA plasmid encoding interleukin-12, intended to enhance immune activation.
Median progression-free survival was 8.5 months and median overall survival was 16.3 months from surgery. One-third of participants remained alive at two years, compared with historical expectations of around 10–15% for this patient population, while one participant remains disease-free more than four years after diagnosis.
No dose-limiting toxicities or unexpected safety concerns were identified. Most adverse events were mild injection-site reactions, although one participant developed grade 3 cerebral oedema that resolved with bevacizumab, allowing treatment to continue.
The vaccine successfully generated neoantigen-specific T-cell responses in most participants. Six of the seven patients evaluable for immunogenicity demonstrated sustained increases in tumour-reactive T-cell activity following vaccination, with stronger CD8-positive T-cell activation associated with longer overall survival.
The only participant who failed to mount a meaningful immune response received dexamethasone throughout vaccination, reinforcing previous evidence that corticosteroids may suppress anti-tumour immunity.
Tumour tissue obtained from patients requiring repeat surgery also demonstrated increased infiltration of activated CD8-positive T cells following vaccination, providing evidence that vaccine-induced immune cells infiltrated the tumour microenvironment.
Although manufacturing proved feasible, production remained a major logistical challenge. The median interval between completing radiotherapy and receiving the first vaccine dose was 10 weeks – more than double the interval investigators considered optimal for integrating treatment into routine care.
The researchers cautioned that the small sample size prevents firm conclusions regarding clinical benefit. Three patients had already experienced disease progression before receiving their first vaccine dose, reflecting both the aggressive nature of MGMT-unmethylated glioblastoma and the delays associated with manufacturing personalised therapies.
Despite its small size, the study provides evidence that personalised neoantigen DNA vaccination can generate tumour-specific immune responses in glioblastoma – a disease that has historically proven resistant to immunotherapy.
While previous trials of PD-1 inhibitors have failed to improve survival in newly diagnosed or recurrent disease, the trial findings also suggest vaccination may prime the tumour microenvironment for subsequent PD-1 blockade, prompting a follow-up phase I trial evaluating the combination with pembrolizumab.
Nivolumab shows promise in high-risk grade group 5 prostate cancer
Adding nivolumab to standard radiotherapy and androgen deprivation therapy (ADT) may improve disease control in men with the highest-risk localised prostate cancer, according to findings from a phase II trial published in the Journal for ImmunoTherapy of Cancer.
Researchers found that the immune checkpoint inhibitor, when combined with high-dose-rate brachytherapy (HDRBT), external beam radiotherapy, and ADT, achieved a two-year freedom from biochemical recurrence (FFBR) rate of 90.3% in patients with grade group 5 (GG5) prostate cancer, significantly exceeding the prespecified historical benchmark of 75% and suggesting immunotherapy could become a promising treatment intensification strategy for this particularly aggressive subgroup. However, the researchers emphasised that randomised trials are needed to confirm the findings.
Grade group 5 prostate cancer carries a substantially poorer prognosis than lower-grade disease, with high rates of biochemical recurrence, metastatic progression, and prostate cancer-specific mortality despite intensive multimodal treatment. Standard immunotherapy approaches have so far had limited success, but researchers suggested radiotherapy and ADT may enhance anti-tumour immune responses by creating a more favourable tumour microenvironment.
The single-arm, investigator-initiated phase II trial enrolled 31 adults with newly diagnosed high-volume grade group 5 prostate adenocarcinoma between 2018 and 2021. Eligible patients had localised or oligometastatic disease and extensive tumour involvement, defined as more than 30% positive biopsy cores.
Participants received four doses of nivolumab (240mg every two weeks), beginning four weeks before HDRBT, alongside standard ADT, HDRBT, and external beam radiotherapy. The three participants with oligometastatic disease also received metastasis-directed stereotactic radiotherapy.
After a median follow-up of 38.8 months, only six patients (19.3%) experienced biochemical recurrence, and no patient developed local recurrence. All six subsequently developed distant metastatic disease.
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Treatment was generally well tolerated, with a safety profile consistent with previous studies of nivolumab. Definitive or probable nivolumab-related toxicities included acute grade 2 adverse events in 6.3% of patients and acute grade 3 events in a further 6.3%. No grade 4 or higher events or late immune-related toxicities were observed due to treatment.
Post hoc analyses comparing the trial cohort with contemporary and historical controls suggested a significantly lower risk of biochemical failure among patients receiving immunotherapy, although these comparisons were not part of the primary study design.
Pathological response also appeared to predict long-term outcomes. Just over half of participants (51.6%) achieved an early major pathological response during treatment, with these patients experiencing significantly longer metastasis-free survival than those classified as late responders. Patients with late pathological responses who subsequently relapsed all developed both nodal and bone metastases at first recurrence, whereas early responders typically experienced only a single metastatic site.
Additionally, researchers identified a potential biomarker of treatment response. Patients with higher baseline Decipher immunosuppression scores were more likely to achieve an early pathological response (p=0.005) and experienced longer times to metastatic failure (p=0.044), suggesting the genomic signature may help identify patients most likely to benefit from treatment intensification with immunotherapy.
The researchers acknowledged several limitations, including the trial’s non-randomised design, small sample size, and reliance on historical controls for the primary endpoint. The inclusion of patients with oligometastatic disease also limited definitive conclusions regarding comparative efficacy.
Nevertheless, they said the findings provide encouraging evidence that combining immunotherapy with radiotherapy and ADT may improve outcomes in one of the highest-risk prostate cancer populations.
