A personalized DNA-based cancer vaccine has shown encouraging early results in patients with one of the deadliest forms of brain cancer, according to a new phase 1 clinical trial published in Nature Cancer. The investigational therapy, known as GNOS-PV01, demonstrated a favorable safety profile and generated strong anti-tumor immune responses in patients with O6-methylguanine-DNA methyltransferase (MGMT)-unmethylated glioblastoma, a subtype that responds poorly to conventional chemotherapy.

Glioblastoma is the most aggressive primary brain tumor in adults, with median survival typically ranging from 12 to 18 months despite surgery, radiotherapy, and chemotherapy. Outcomes are particularly poor in patients whose tumors are MGMT-unmethylated because these tumors retain DNA repair activity that limits the effectiveness of temozolomide, the standard chemotherapy used in glioblastoma treatment.

The phase 1 GT-20 clinical trial explored whether a personalized neoantigen vaccine could help the immune system better recognize and attack tumor cells. The study enrolled nine adults with newly diagnosed MGMT-unmethylated glioblastoma. Researchers performed whole-exome and ribonucleic acid (RNA) sequencing on tumor samples to identify tumor-specific neoantigens capable of triggering immune responses.

Unlike earlier vaccine platforms that targeted only a limited number of tumor antigens, GNOS-PV01 was designed to include up to 40 individualized neoantigens in each patient-specific vaccine formulation. Following surgery and radiotherapy, patients received the vaccine intramuscularly along with electroporation and interleukin-12 (IL-12) plasmid therapy to enhance immune activation. Vaccinations were administered during both priming and booster phases based on patient tolerance.

Investigators reported no unexpected toxicities, dose-limiting adverse events, or serious vaccine-related complications during the study. Most side effects were mild and included injection-site reactions, fatigue, and nausea. Although the trial was primarily designed to evaluate safety, clinical outcomes were encouraging. Approximately 66.7% of patients achieved both six-month progression-free survival and 12-month overall survival. Median progression-free survival was 8.5 months, while median overall survival reached 16.3 months. Notably, one patient remained disease-free more than four years after diagnosis, and nearly one-third of participants survived longer than 24 months.

Immune analyses showed that the vaccine successfully activated circulating T cells in nearly all evaluable patients. Researchers observed increased immune activation markers and enhanced neoantigen-specific responses after vaccination. Patients who developed stronger cluster of differentiation 8 (CD8)-positive T-cell responses generally experienced better overall survival, suggesting that vaccine-induced immune activation may contribute to improved outcomes. Further examination of recurrent tumor samples revealed evidence of vaccine-driven immune activity within the tumor microenvironment. In some patients, investigators identified the expansion of new T-cell clones after vaccination, indicating the development of targeted anti-tumor immune responses.

The study also highlighted the potential negative impact of corticosteroid use during immunotherapy. Patients who received dexamethasone during treatment demonstrated weaker immune activation, reinforcing concerns that steroids may suppress vaccine-induced anti-tumor immunity.The findings build on previous research by Keskin et al., who previously demonstrated enhanced tumor-directed T-cell activity using a personalized peptide-based neoantigen vaccine strategy in newly diagnosed glioblastoma. However, the current GT-20 study differs in its use of a multivalent DNA vaccine platform capable of incorporating a substantially larger number of neoantigens identified through multisector tumor profiling.

Researchers believe this broader neoantigen targeting approach may help address the marked spatial heterogeneity commonly seen in glioblastoma tumors, a major factor limiting the effectiveness of conventional therapies. While the trial involved only a small number of patients and larger studies are still needed, investigators say the findings provide important proof-of-concept evidence supporting personalized neoantigen DNA vaccines as a potential immunotherapeutic strategy for glioblastoma. Future studies are expected to evaluate GNOS-PV01 in combination with immune checkpoint inhibitors and other immunotherapies to determine whether outcomes can be further improved for patients with this highly treatment-resistant cancer.

 

References
1. Garfinkle EAR, Perales-Linares R, Gimple RC, et al. Adjuvant personalized multivalent neoantigen DNA vaccination for MGMT unmethylated glioblastoma: a phase 1 trial. Nat Cancer. 2026.

2. Keskin DB, Anandappa AJ, Sun J, Tirosh I, Mathewson ND, Li S, Oliveira G, Giobbie-Hurder A, Felt K, Gjini E, Shukla SA, Hu Z, Li L, Le PM, Allesøe RL, Richman AR, Kowalczyk MS, Abdelrahman S, Geduldig JE, Charbonneau S, Pelton K, Iorgulescu JB, Elagina L, Zhang W, Olive O, McCluskey C, Olsen LR, Stevens J, Lane WJ, Salazar AM, Daley H, Wen PY, Chiocca EA, Harden M, Lennon NJ, Gabriel S, Getz G, Lander ES, Regev A, Ritz J, Neuberg D, Rodig SJ, Ligon KL, Suvà ML, Wucherpfennig KW, Hacohen N, Fritsch EF, Livak KJ, Ott PA, Wu CJ, Reardon DA. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature. 2019 Jan;565(7738):234‑239.