Personalized Cancer Vaccine/Pembrolizumab Feasible, Effective in Newly Diagnosed GBM

A personalized neoantigen vaccine (NeoVax) combined with pembrolizumab (Keytruda) yielded a median overall survival (OS) of 36.9 months in patients with newly diagnosed MGMT-methylated glioblastoma, compared with 25.3 months in propensity-matched institutional standard-of-care controls, according to findings from an oral session at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.¹ In patients with MGMT-unmethylated disease, the median OS was 19.0 months vs 16.7 months in matched controls.

“Personalized cancer vaccines are a promising modality for immunomodulation, particularly for tumors that have a relatively cold microenvironment,” stated David A. Reardon, MD, director of the Center for Neuro-Oncology and Alperin Family Chair in Neuro-Oncology at Dana-Farber Cancer Institute, during the presentation.1

Among unmethylated patients, the timing of PD-1 blockade relative to vaccine administration produced a counterintuitive finding. Patients in cohort 1B, who initiated pembrolizumab after vaccine priming, had inferior OS compared with those in cohorts 2 and 3, where pembrolizumab was introduced prior to vaccination (P = .041). “Contrary to what we predicted, we saw the opposite, where patients who received PD-1 blockade after vaccine priming, cohort 1B, had an inferior outcome compared to patients who received PD-1 blockade prior to vaccine initiation,” Reardon noted.¹

NeoVax generated immunogenic responses across all 4 cohorts. In vitro ELISpot analyses showed no differences in epitope immunogenicity between arms, while ex vivo ELISpot responses were broader in unmethylated patients. Critically, unmethylated patients who mounted ex vivo T cell responses had significantly improved OS vs those who did not (P = .017), and TCR clonotype persistence associated with vaccination was durable out to 2 years.

Analysis of tumor-infiltrating lymphocytes (TILs) in patients who underwent subsequent resection revealed an upregulation of effector T cells post-vaccination in both MGMT-methylated and unmethylated patients. A key difference between cohorts emerged in regulatory T cell (Treg) dynamics: Tregs were significantly elevated post-vaccination in unmethylated patients who did not receive temozolomide (P = .0045), but not in the methylated Cohort 1A, where temozolomide was administered (P = 1.00).²

Among the most intriguing findings from the baseline tumor transcriptional analysis was the association of the mesenchymal (MES) subtype with improved OS following NeoVax plus anti-PD-1 therapy (HR favorable; P = .031). “We were intrigued by this because we know the mesenchymal subtype has a poor outcome relative to standard-of-care therapy,” Reardon explained, “but we went back to see if this may be distinct in our immunotherapy-treated patients.”¹

In a validation cohort of 171 patients with glioblastoma treated with immune checkpoint blockade alone at Dana-Farber, patients with MES (n = 10) had significantly longer OS than patients without MES (n = 16; P = .0019), and tumors with high human leukocyte antigen (HLA) class I expression (HLAI^hi; n = 10) outperformed HLAI^lo tumors (n = 10; P = .000087). This reinforced the MES subtype as a candidate predictive biomarker across immunotherapy approaches in GBM.

The study enrolled patients with newly diagnosed glioblastoma who had undergone gross total resection, had a Karnofsky Performance Status of 70 or greater, adequate organ function, and were not on dexamethasone. Tumor tissue obtained at surgery underwent DNA and RNA sequencing and HLA typing to identify coding mutations predicted to yield immunogenic neoepitopes for a given patient's HLA alleles. The top 10 to 20 neoepitope peptides were synthesized and administered subcutaneously with poly ICLC as the NeoVax regimen, using a priming schedule of 5 doses over 4 weeks followed by 2 booster doses at 8-week intervals.

The trial enrolled patients across 4 cohorts: cohort 1A comprised patients with MGMT-methylated disease who also received standard temozolomide; cohorts 1B, 2, and 3 enrolled patients with MGMT-unmethylated disease who received no temozolomide, with pembrolizumab introduced at varying time points relative to vaccine priming.

Reardon outlined several next steps for the platform, including validating the MGMT-methylated results with PD-1 initiated prior to NeoVax, as the unmethylated data suggest is the preferred sequencing; evaluating the addition of temozolomide in unmethylated patients to exploit its Treg-depleting activity; and exploring whether additional booster doses further augment immune responses and improve outcomes.

References

1. Reardon DA, Ghannam JY, Kovarsky D, et al. A personalized neoantigen vaccine reprograms the immune landscape of glioblastoma. J Clin Oncol. 2026;44(suppl 16):2006. doi:10.1200/JCO.2026.44.16_suppl.2006
2. Sanchez-Perez LA, Choi BD, Archer GE, et al. Myeloablative temozolomide enhances CD8⁺ T-cell responses to vaccine and is required for efficacy against brain tumors in mice. PLoS One. 2013;8(3):e59082. doi:10.1371/journal.pone.0059082