Zie ook in gerelateerde artikelen hiernaast of hieronder. 

16 mei 2026: Bron: Nature d.d. 12 mei 2026

Uit een fase I veiligheidsstudie blijkt dat immuuntherapie met een gepersonaliseerd DNA kankervaccin, GNOS-PV01 genoemd, bij patiënten met een hersentumor van het type Glioblastoma met een ongemethyleerd MGMT-gen uitstekende resultaten laat zien op ziekteprogressievrije tijd en mediane overall overleving. 
De mediane ziekteprogressievrije overleving was 8,5 maanden, de mediane algehele overleving was 16,3 maanden en de overleving na 24 maanden was 33%, inclusief één langdurige overlevende die 4 jaar na de eerste operatie nog steeds in leven is. Dit blijkt uit de resultaten van een fase 1 studie bij totaal 34 deelnemende patiënten waarvan er 9 in aanmerking kwamen voor een gepersonaliseerd DNA kankervaccin, GNOS-PV01 geheten. 

Belangrijkste onderzoeksresultaten vertaald in het Nederlands zijn:

  • Het voordeel van het DNA-vaccin: In tegenstelling tot eerdere vaccins maakt dit op DNA gebaseerde vaccin het mogelijk om tot 40 unieke kankereiwitten (neoantigenen) per patiënt te targeten – twee keer zoveel als elk eerder kankervaccin.
  • Van "koud" naar "heet": Glioblastoom is doorgaans een "koude" tumor, wat betekent dat deze zich verbergt voor het immuunsysteem. Dit vaccin transformeert de tumoromgeving in een "hete" omgeving, waardoor deze vatbaar wordt voor een immuunreactie.
  • Brede doelwitdekking: Door zich te richten op een breed scala aan neoantigenen in verschillende delen van de tumor, voorkomt het vaccin dat de kanker aan het immuunsysteem ontsnapt, zelfs als de tumor evolueert en specifieke doelwitten verliest.
  • Overlevingsmijlpalen: 1 jaarsmeting: Twee derde van de deelnemers overleefde één jaar, vergeleken met het historische gemiddelde van 40%.
  • 2 jaars meting: Een derde van de deelnemers leefde nog na twee jaar, een verdubbeling van de historische overlevingspercentages.
  • Lange termijn: Eén patiënt is bijna vijf jaar na de eerste diagnose nog steeds vrij van terugval.
  • Veilige integratie: Het vaccin veroorzaakte geen ernstige bijwerkingen en werd toegediend naast de standaard bestraling en postoperatief herstel.
Het volledige studierapport is gepubliceerd in Nature en is gratis in te zien of te downloaden. Klik op de titel van het abstract:

Adjuvant personalized multivalent neoantigen DNA vaccination for MGMT unmethylated glioblastoma: a phase 1 trial

Nature Cancer (2026) Cite this article


Abstract

Glioblastoma is a fatal disease with a median prognosis of 12–18 months. Recent studies have shown encouraging results using neoantigen-based vaccines to stimulate glioblastoma-directed immune responses, but overall immunogenicity has been low. Here, we report the results of an open-label, single-arm, phase 1 clinical trial (GT-20) to evaluate the safety and feasibility (primary endpoints) as well as immunogenicity and preliminary clinical activity (secondary endpoints) of GNOS-PV01 monotherapy, a DNA-based personalized therapeutic cancer vaccine administered following surgical resection and radiation for patients with MGMT unmethylated glioblastoma. The GT-20 study vaccinated nine patients, using up to 40 neoantigens per patient (range, 17–40) without causing any serious adverse events, unexpected toxicities or dose-limiting toxicities. The vaccine induced activation and expansion of circulating peripheral T cells in all evaluated patients, except one who was being treated with dexamethasone. The secondary endpoint was to evaluate 6 month progression-free survival and 12 month overall survival; each observed in 66.7% of patients. Median progression-free survival was 8.5 months, median overall survival was 16.3 months and survival at 24 months was 33%, including one long-term survivor still alive 4 years from the time of initial surgery. This study met the pre-specified endpoints and supports the use of GNOS-PV01 as a potentially impactful component of glioblastoma immunotherapy. ClinicalTrials.gov: NCT04015700.

Main

Glioblastoma (GBM) is the most common primary central nervous system malignancy in adults. It has a median overall survival of less than 20 months with standard-of-care surgical resection, radiotherapy and temozolomide chemotherapy1,2. Patients with GBM with unmethylated promoter regions of the MGMT (O6-methylguanine methyltransferase) gene do not benefit from temozolomide, a DNA-damaging chemotherapy, owing to the active DNA repair mechanisms facilitated by high MGMT expression3. Therefore, new therapeutic options are desperately needed for this subgroup of patients.

Immune-activating therapies, such as immune checkpoint inhibitors, have demonstrated efficacy across many cancer types but have not improved survival in GBM. Randomized phase 3 studies showed no survival benefit from the addition of PD-1 blockade therapy to standard-of-care treatment in newly diagnosed patients4,5 or at recurrence6. These poor responses may be attributed to extensive intra-tumoral heterogeneity, large populations of immunosuppressive myeloid cells, relatively low tumor mutational burden (TMB) and/or both local and systemic immune effector cell dysfunction7,8. Patients with GBM display profound T cell dysfunction owing to tumor-specific features9 and to treatment with temozolomide and dexamethasone.

Neoantigen cancer vaccination is a versatile platform that has emerged as an approach to clonally expand and, potentially, repolarize immune effectors that destroy malignant cells. In GBM, prior vaccination studies demonstrated that synthetic peptide vaccines generated T cell immunity to both patient tumor-specific neoantigens and to shared tumor-associated antigens10,11,12,13,14,15. In addition, cell-based approaches using infusion of autologous dendritic cells or mRNA pulsed with tumor lysate have shown similar results16,17. These initial studies have supported the feasible use and preliminary efficacy of therapeutic cancer vaccines in GBM, but further optimization of these platforms is needed, as cautioned by the failed randomized controlled trials to date13,16. As such, imparting durable anti-tumoral immunity will probably require a multi-epitope vaccine delivery system designed to target widely distributed antigens, with respect to the documented spatial heterogeneity of neoantigen diversity in GBM18. Incorporation of multi-sector sampling from multiple tumor sites served as a basis for neoantigen selection in the ‘NeoVax’ phase 1 clinical trial (ClinicalTrials.gov: NCT03422094), which identified a wider breadth of spatially heterogeneous candidate neoantigens in GBM12. However, the incorporation and subsequent evaluation of all candidates was constrained by manufacturing challenges related to cost, scalability, solubility and production time of the synthetic long peptide platform12.

To address these challenges, we incorporated multi-sector sampling into the design and production of personalized neoantigen DNA vaccines, a platform that can accommodate a broader range of neoantigens than peptide vaccines19. Here, we report the results from nine patients enrolled in the ‘GT-20’ DNA vaccine phase 1 clinical trial (ClinicalTrials.gov: NCT04015700). For each patient, a bespoke DNA vaccine was generated, targeting up to 40 spatially distributed neoantigens (range, 17–40) using the same antigen selection strategy and personalized variant antigens by cancer sequencing (pVAC-seq) pipeline as previously described12. Vaccine-induced immune responses were evaluated through bulk T cell receptor (TCR) sequencing, in vitro functional assays and a unique method of T cell enrichment coupled with single-nuclei RNA sequencing (snRNA-seq). The results from this study will inform subsequent trials that aim to explore combinatorial therapeutic approaches in this disease setting to maximize efficacy.

Referenties;

  1. Stupp, R. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987–996 (2005).

    Article CAS PubMed Google Scholar 

  2. Pouyan, A. et al. Glioblastoma multiforme: insights into pathogenesis, key signaling pathways, and therapeutic strategies. Mol. Cancer 24, 58 (2025).

    Article CAS PubMed PubMed Central Google Scholar 

  3. Hegi, M. E. et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 352, 997–1003 (2005).

    Article CAS PubMed Google Scholar 

  4. Omuro, A. et al. Radiotherapy combined with nivolumab or temozolomide for newly diagnosed glioblastoma with unmethylated MGMT promoter: an international randomized phase III trial. Neuro. Oncol. 25, 123–134 (2023).

    Article CAS PubMed PubMed Central Google Scholar 

  5. Lim, M. et al. Phase III trial of chemoradiotherapy with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma with methylated MGMT promoter. Neuro. Oncol. 24, 1935–1949 (2022).

    Article CAS PubMed PubMed Central Google Scholar 

  6. Reardon, D. A. et al. Effect of nivolumab vs bevacizumab in patients with recurrent glioblastoma: the Checkmate 143 phase 3 randomized clinical trial. JAMA Oncol. 6, 1003–1010 (2020).

    Article PubMed PubMed Central Google Scholar 

  7. Read, R. D. et al. Glioblastoma microenvironment—from biology to therapy. Genes Dev. 38, 360–379 (2024).

    CAS PubMed PubMed Central Google Scholar 

  8. Sharma, P. et al. Tumor microenvironment in glioblastoma: current and emerging concepts. Neurooncol. Adv. 5, vdad009 (2023).

    PubMed PubMed Central Google Scholar 

  9. Chongsathidkiet, P. et al. Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors. Nat. Med. 24, 1459–1468 (2018).

    Article CAS PubMed PubMed Central Google Scholar 

  10. Keskin, D. B. et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature 565, 234–239 (2019).

    Article CAS PubMed Google Scholar 

  11. Hilf, N. et al. Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature 565, 240–245 (2019).

    Article CAS PubMed Google Scholar 

  12. Johanns, T. M. et al. Integrating multisector molecular characterization into personalized peptide vaccine design for patients with newly diagnosed glioblastoma. Clin. Cancer Res. 30, 2729–2742 (2024).

    Article CAS PubMed PubMed Central Google Scholar 

  13. Weller, M. et al. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol. 18, 1373–1385 (2017).

    Article CAS PubMed Google Scholar 

  14. Ahluwalia, M. S. et al. Phase IIa study of SurVaxM plus adjuvant temozolomide for newly diagnosed glioblastoma. J. Clin. Oncol. 41, 1453–1465 (2023).

    Article CAS PubMed Google Scholar 

  15. Reardon, D. A. et al. Ltbk-01. Ino-5401 and Ino-9012 delivered intramuscularly (IM) with electroporation (EP) in combination with cemiplimab (Regn2810) in newly diagnosed glioblastoma. Neuro. Oncol. 22, ii237 (2020).

    Article PubMed Central Google Scholar 

  16. Liau, L. M. et al. Association of autologous tumor lysate-loaded dendritic cell vaccination with extension of survival among patients with newly diagnosed and recurrent glioblastoma: a phase 3 prospective externally controlled cohort trial. JAMA Oncol. 9, 112–121 (2023).

    Article PubMed PubMed Central Google Scholar 

  17. Mendez-Gomez, H. R. et al. RNA aggregates harness the danger response for potent cancer immunotherapy. Cell 187, 2521–2535.e21 (2024).

    Article CAS PubMed PubMed Central Google Scholar 

  18. Schaettler, M. O. et al. Characterization of the genomic and immunologic diversity of malignant brain tumors through multisector analysis. Cancer Discov. 12, 154–171 (2022).

    Article CAS PubMed Google Scholar 

  19. Yarchoan, M. et al. Personalized neoantigen vaccine and pembrolizumab in advanced hepatocellular carcinoma: a phase 1/2 trial. Nat. Med. 30, 1044–1053 (2024).

    Article CAS PubMed PubMed Central Google Scholar 

  20. Newman, A. M. et al. Determining cell type abundance and expression from bulk tissues with digital cytometry. Nat. Biotechnol. 37, 773–782 (2019).

    Article CAS PubMed PubMed Central Google Scholar 

  21. Hundal, J. et al. pVAC-Seq: a genome-guided in silico approach to identifying tumor neoantigens. Genome Med. 8, 11 (2016).

    Article PubMed PubMed Central Google Scholar 

  22. de Graaf, J. F. et al. Neoantigen-specific T cell help outperforms non-specific help in multi-antigen DNA vaccination against cancer. Mol. Ther. Oncol. 32, 200835 (2024).

    Article PubMed PubMed Central Google Scholar 

  23. Bhojnagarwala, P. S. et al. A synDNA vaccine delivering neoAg collections controls heterogenous, multifocal murine lung and ovarian tumors via robust T cell generation. Mol. Ther. Oncolytics 21, 278–287 (2021).

    Article CAS PubMed PubMed Central Google Scholar 

  24. Pham, J. et al. Treatment practices and survival outcomes for IDH-wildtype glioblastoma patients according to MGMT promoter methylation status: insights from the U.S. National Cancer Database. J. Neurooncol. 172, 655–665 (2025).

    Article CAS PubMed PubMed Central Google Scholar 

  25. Wick, W. et al. Molecularly matched targeted therapies plus radiotherapy in glioblastoma: the phase 1/2a N2M2 umbrella trial. Nat. Med. 31, 3534–3541 (2025).

    Article CAS PubMed PubMed Central Google Scholar 

  26. Chronister, W. D. et al. TCRMatch: predicting T-cell receptor specificity based on sequence similarity to previously characterized receptors. Front. Immunol. 12, 640725 (2021).

    Article CAS PubMed PubMed Central Google Scholar 

  27. Wang, A. Z. et al. Glioblastoma-infiltrating CD8+ T cells are predominantly a clonally expanded GZMK+ effector population. Cancer Discov. 14, 1106–1131 (2024).

    Article CAS PubMed Google Scholar 

  28. Ruiz-Moreno, C. et al. Charting the single-cell and spatial landscape of IDH-wild-type glioblastoma with GBmap. Neuro. Oncol. 27, 2281–2295 (2025).

    Article CAS PubMed PubMed Central Google Scholar 

  29. Wu, X. et al. Targeting MHC-I molecules for cancer: function, mechanism, and therapeutic prospects. Mol. Cancer 22, 194 (2023).

    Article CAS PubMed PubMed Central Google Scholar 

  30. Zaretsky, J. M. et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375, 819–829 (2016).

    Article CAS PubMed PubMed Central Google Scholar 

  31. Weber, J. S. et al. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study. Lancet 403, 632–644 (2024).

    Article CAS PubMed Google Scholar 

  32. Stupp, R. et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA 318, 2306–2316 (2017).

    Article CAS PubMed PubMed Central Google Scholar 

  33. Stupp, R. et al. Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial. JAMA 314, 2535–2543 (2015).

    Article CAS PubMed Google Scholar 

  34. Yarchoan, M., Hopkins, A. & Jaffee, E. M. Tumor mutational burden and response rate to PD-1 inhibition. N. Engl. J. Med. 377, 2500–2501 (2017).

    Article PubMed PubMed Central Google Scholar 

  35. Kelly, B. J. et al. Churchill: an ultra-fast, deterministic, highly scalable and balanced parallelization strategy for the discovery of human genetic variation in clinical and population-scale genomics. Genome Biol. 16, 6 (2015).

    Article PubMed PubMed Central Google Scholar 

  36. Richters, M. M. et al. Best practices for bioinformatic characterization of neoantigens for clinical utility. Genome Med. 11, 56 (2019).

    Article PubMed PubMed Central Google Scholar 

  37. Duperret, E. K. et al. A synthetic DNA, multi-neoantigen vaccine drives predominately MHC class I CD8+ T-cell responses, impacting tumor challenge. Cancer Immunol. Res. 7, 174–182 (2019).

    Article CAS PubMed PubMed Central Google Scholar 

  38. Janetzki, S. et al. Results and harmonization guidelines from two large-scale international Elispot proficiency panels conducted by the Cancer Vaccine Consortium (CVC/SVI). Cancer Immunol. Immunother. 57, 303–315 (2008).

    Article PubMed Google Scholar 

  39. Hao, Y. et al. Dictionary learning for integrative, multimodal and scalable single-cell analysis. Nat. Biotechnol. 42, 293–304 (2024).

    Article CAS PubMed Google Scholar 

  40. Korsunsky, I. et al. Fast, sensitive and accurate integration of single-cell data with Harmony. Nat. Methods 16, 1289–1296 (2019).

    Article CAS PubMed PubMed Central Google Scholar 

  41. Korotkevich, G. et al. Fast gene set enrichment analysis. Preprint at bioRxiv https://doi.org/10.1101/060012 (2021).

  42. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).

hersentumoren, Glioblastoma, immuuntherapie, GNOS-PV01, gepersonaliseerd DNA kankervaccin, fase I studie, MGMT-gen, Methylguanine methyltransferase, temozolomide, ziekteprogressievrije tijd, overall overleving


Gerelateerde artikelen
 

Gerelateerde artikelen

GNOS-PV01, een gepersonaliseerd >> Oncolitisch virus MVR-C5252 >> CAR-T celtherapie maakt dat >> Immuuntherapie met specifieke >> CAR-T celtherapie rechtstreeks >> Gepersonaliseerde vorm van >> mRNA vaccin doet hersentumoren >> DCVax-L verbetert overall >> Craniopharyngiomas, goedaardige >> Immuuntherapie met Natural >>