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Zie ook dit artikel: https://kanker-actueel.nl/kankervaccin-eli-002-2p-stimuleerde-hoge-t-celreacties-bij-patienten-met-voor-immuuntherapie-ongevoelige-kras-gemuteerde-tumoren-en-verbeterde-de-ziekteprogressieve-tijd-bij-patienten-met-alvleesklierkanker-en-darmkanker.html

27 juli 2026: Bron: Nature en Johns Hopkins Kimmel cancer center

mKRAS-vax, een nieuw vaccin gericht op de 6 meest voorkomende KRAS mutaties - G12V, G12A, G12R, G12C, G12D, G13D - geeft aanvullend op immuuntherapie met ipilimumab en nivolumab hoopvolle resultaten bij patiënten met operabele alvleesklierkanker. Het mKRAS-vax vaccin werd voor het eerst getest in 2020 bij patiënten die een operatie hadden ondergaan en een hoog risico liepen op terugkeer van kanker. De fase I studie toonde aan dat wanneer het mKRAS-vax vaccin een sterke immuunrespons opwekte, deze patiënten minstens vijf jaar ziektevrij bleven.

In een andere fase I studie met twintig deelnemers met een erfelijke aanleg voor alvleesklierkanker door aangetoonde aanwezigheid van alvleeskliercystes en een door beeldvorming vastgestelde afwijking aan de alvleesklier ontwikkelden geen van de deelnemers alvleesklierkanker. De onderzoekers ontdekten dat 18 van de 20 deelnemers, oftewel 90%, een sterke immuunreactie op het vaccin ontwikkelden. De deelnemers vertoonden een mediane toename van 18,2 keer in de respons van mutante KRAS-specifieke T-cellen, wat aangeeft dat het vaccin met succes immuuncellen activeerde die in staat zijn KRAS mutaties te herkennen. Aanvullende analyses toonden aan dat het vaccin zowel CD4-positieve T-cellen als CD8-positieve T-cellen reacties opwekte en geheugen-T-cellen produceerde die langdurig aanwezig bleven. Door het vaccin geïnduceerde mutante KRAS-specifieke T-celklonen bleven tot wel twee jaar na vaccinatie aantoonbaar aanwezig.

Twee reacties van aan de studieverbonden oncologen:

"We dachten dat als we een immuunrespons kunnen zien bij kankerpatiënten, het vaccin nog beter zou werken bij mensen met een hoger risico vanwege een familiegeschiedenis, een genmutatie of een cyste in de alvleesklier", aldus  Neeha Zaidi, M.D. universitair hoofddocent oncologie en co-senior auteur van de studie.

"De resultaten van deze studie leveren bewijs dat vaccinatie tegen gemuteerd KRAS duurzame immuunreacties kan opwekken bij mensen met een erfelijke aanleg voor alvleesklierkanker en ondersteunen verder klinisch onderzoek naar deze aanpak", aldus Michael Goggins, M.D, hoogleraar pathologie, interne geneeskunde en oncologie, directeur van het Pancreatic Cancer Early Detection Laboratory en co-senior auteur van de studie.

Hier achtereenvolgens de studie abstracten van beide studies welke beide studieverslagen volledig zijn in te zien of te downloaden:

Mutant KRAS vaccine with dual checkpoint blockade in resected pancreatic cancer: a phase I trial

Nature Communications volume 17, Article number: 1538 (2026) Cite this article

A Publisher Correction to this article was published on 15 April 2026

This article has been updated

Abstract

In this phase I study, we test a pooled synthetic long peptide vaccine targeting the six KRAS mutations (G12V, G12A, G12R, G12C, G12D, G13D) with ipilimumab and nivolumab in resected pancreatic adenocarcinoma. Co-primary endpoints include safety and maximal percent change of IFNγ-producing mutant KRAS T cell responses in the blood within 17 weeks. Secondary endpoints include disease-free survival, overall survival, and maximal percent change of IFNγ-producing mutant KRAS T cell responses at any time after vaccination. Vaccine-related adverse events are grade 1-2. 11/12 and 10/12 patients generate a significant increase in average T cell response to 6 mutant KRAS antigens and tumor-specific response, respectively. Immunophenotyping demonstrate Th1 CD4 central memory and effector memory T cells, and CD8 effector memory T cells at a lower frequency. The vaccine also generates cross-reactive T cells that recognize more than one mutant KRAS antigen. These findings support the safety and diverse anti-tumor immunity of mutant KRAS vaccines (NCT04117087).

En de preventiestudie:

. 2026 Jul 16.
doi: 10.1158/2159-8290.CD-25-2245. Online ahead of print.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) arises from precursor lesions over a decade-plus, offering a window for interception in high-risk individuals, but current surveillance detects a minority of precursors. Mutant KRAS (mKRAS) is present in most PDACs and their precursors, making it an appealing target for immune-based interception. We conducted a phase I, first-in-human study of a peptide vaccine targeting six common KRAS mutations (mKRAS-VAX) in 20 individuals with hereditary PDAC predisposition and a radiographic pancreatic abnormality (NCT05013216) to assess safety, immunogenicity, and T cell persistence. Adverse events were grade 1-2. Vaccination elicited a significant mKRAS-specific T cell response in 18/20 participants (90%). Longitudinal TCR sequencing demonstrated persistence of vaccine-induced mKRAS-specific clonotypes for up to 2 years. Over a median follow-up of 16.5 months, no participants developed PDAC. These findings demonstrate that mKRAS-VAX is safe and generates durable T cell responses, which support the advancement of mKRAS-targeted vaccination for PDAC interception.

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Referenties bij Nature studie:

  1. Desai, N. V. et al. Multidisciplinary neoadjuvant management for potentially curable pancreatic cancer. Cancer Med 4, 1224–1239 (2015).

    Article PubMed PubMed Central Google Scholar 

  2. Gillen, S., Schuster, T., Meyer Zum Büschenfelde, C., Friess, H. & Kleeff, J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med 7, e1000267 (2010).

    Article PubMed PubMed Central Google Scholar 

  3. Daamen, L. A. et al. Preoperative predictors for early and very early disease recurrence in patients undergoing resection of pancreatic ductal adenocarcinoma. HPB (Oxf.) 24, 535–546 (2022).

    Article Google Scholar 

  4. Conroy, T. et al. Five-year outcomes of FOLFIRINOX vs Gemcitabine as adjuvant therapy for pancreatic cancer: a randomized clinical trial. JAMA Oncol. 8, 1571–1578 (2022).

    Article PubMed PubMed Central Google Scholar 

  5. Royal, R. E. et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J. Immunother. 33, 828–833 (2010).

    Article CAS PubMed PubMed Central Google Scholar 

  6. Ho, W. J., Jaffee, E. M. & Zheng, L. The tumour microenvironment in pancreatic cancer - clinical challenges and opportunities. Nat. Rev. Clin. Oncol. 17, 527–540 (2020).

    Article PubMed PubMed Central Google Scholar 

  7. Kanda, M. et al. Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology 142, 730–733.e739 (2012).

    Article CAS PubMed PubMed Central Google Scholar 

  8. andrew_aguirre@dfci.harvard.edu, C. G. A. R. N. E. a. & Network, C. G. A. R. Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer Cell 32, 185-203 (2017).

  9. Awad, M. M. et al. Acquired resistance to KRAS. N. Engl. J. Med 384, 2382–2393 (2021).

    Article CAS PubMed PubMed Central Google Scholar 

  10. Tran, E. et al. T-Cell transfer therapy targeting mutant KRAS in cancer. N. Engl. J. Med 375, 2255–2262 (2016).

    Article CAS PubMed PubMed Central Google Scholar 

  11. Leidner, R. et al. Neoantigen T-cell receptor gene therapy in pancreatic cancer. N. Engl. J. Med 386, 2112–2119 (2022).

    Article CAS PubMed PubMed Central Google Scholar 

  12. Keenan, B. P. et al. A Listeria vaccine and depletion of T-regulatory cells activate immunity against early stage pancreatic intraepithelial neoplasms and prolong survival of mice. Gastroenterology 146, 1784–1794.e1786 (2014).

    Article CAS PubMed PubMed Central Google Scholar 

  13. Pan, J. et al. Immunoprevention of KRAS-driven lung adenocarcinoma by a multipeptide vaccine. Oncotarget 8, 82689–82699 (2017).

    Article PubMed PubMed Central Google Scholar 

  14. Abrams, S. I. et al. Generation of stable CD4+ and CD8 + T cell lines from patients immunized with ras oncogene-derived peptides reflecting codon 12 mutations. Cell Immunol. 182, 137–151 (1997).

    Article CAS PubMed Google Scholar 

  15. Gjertsen, M. K., Saeterdal, I., Saeboe-Larssen, S. & Gaudernack, G. HLA-A3 restricted mutant ras specific cytotoxic T-lymphocytes induced by vaccination with T-helper epitopes. J. Mol. Med (Berl.) 81, 43–50 (2003).

    Article CAS PubMed Google Scholar 

  16. Toubaji, A. et al. Pilot study of mutant ras peptide-based vaccine as an adjuvant treatment in pancreatic and colorectal cancers. Cancer Immunol. Immunother. 57, 1413–1420 (2008).

    Article CAS PubMed PubMed Central Google Scholar 

  17. Gjertsen, M. K., Bjorheim, J., Saeterdal, I., Myklebust, J. & Gaudernack, G. Cytotoxic CD4+ and CD8 + T lymphocytes, generated by mutant p21-ras (12Val) peptide vaccination of a patient, recognize 12Val-dependent nested epitopes present within the vaccine peptide and kill autologous tumour cells carrying this mutation. Int. J. Cancer 72, 784–790 (1997).

  18. Gjertsen, M. K. et al. Vaccination with mutant Ras peptides and induction of T-cell responsiveness in pancreatic carcinoma patients carrying the corresponding RAS mutation. Lancet 346, 1399-1400 95, 92408–6 (1995).

    Google Scholar 

  19. Pant, S. et al. Lymph-node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: the phase 1 AMPLIFY-201 trial. Nat. Med. 2, 531–542(2024).

  20. Kulemann, B. et al. Pancreatic cancer: circulating tumor cells and primary tumors show heterogeneous KRAS mutations. Sci. Rep. 7, 4510 (2017).

    Article ADS PubMed PubMed Central Google Scholar 

  21. Braxton, A. M. et al. 3D genomic mapping reveals multifocality of human pancreatic precancers. Nature 629, 679–687 (2024).

    Article ADS CAS PubMed Google Scholar 

  22. Rojas, L. A. et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature https://doi.org/10.1038/s41586-023-06063-y (2023).

  23. Litchfield, K. et al. Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition. Cell 184, 596–614.e514 (2021).

    Article CAS PubMed PubMed Central Google Scholar 

  24. Levin, N. et al. Identification and validation of T-cell receptors targeting. Clin. Cancer Res 27, 5084–5095 (2021).

    Article CAS PubMed Google Scholar 

  25. Oliveira, G. et al. Preexisting tumor-resident T cells with cytotoxic potential associate with response to neoadjuvant anti-PD-1 in head and neck cancer. Sci. Immunol. 8, eadf4968 (2023).

    Article CAS PubMed PubMed Central Google Scholar 

  26. Kim, S. V. et al. GPR15-mediated homing controls immune homeostasis in the large intestine mucosa. Science 340, 1456–1459 (2013).

    Article ADS CAS PubMed PubMed Central Google Scholar 

  27. Peace, D. J., Chen, W., Nelson, H. & Cheever, M. A. T cell recognition of transforming proteins encoded by mutated ras proto-oncogenes. J. Immunol. 146, 2059–2065 (1991).

    Article CAS PubMed Google Scholar 

  28. Blair, L. M. et al. Oncogenic context shapes the fitness landscape of tumor suppression. Nat. Commun. 14, 6422 (2023).

    Article ADS CAS PubMed PubMed Central Google Scholar 

  29. Liu, C. et al. KRAS-G12D mutation drives immune suppression and the primary resistance of anti-PD-1/PD-L1 immunotherapy in non-small cell lung cancer. Cancer Commun. (Lond.) 42, 828–847 (2022).

    Article PubMed PubMed Central Google Scholar 

  30. Yousef, A. et al. Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma. NPJ Precis Oncol. 8, 27 (2024).

    Article CAS PubMed PubMed Central Google Scholar 

  31. Braumüller, H. et al. T-helper-1-cell cytokines drive cancer into senescence. Nature 494, 361–365 (2013).

    Article ADS PubMed Google Scholar 

  32. Blomberg, O. S. et al. IL-5-producing CD4 + T cells and eosinophils cooperate to enhance response to immune checkpoint blockade in breast cancer. Cancer Cell 41, 106–123.e110 (2023).

    Article CAS PubMed Google Scholar 

  33. Alspach, E. et al. MHC-II neoantigens shape tumour immunity and response to immunotherapy. Nature 574, 696–701 (2019).

    Article ADS CAS PubMed PubMed Central Google Scholar 

  34. Mumberg, D. et al. CD4( + ) T cells eliminate MHC class II-negative cancer cells in vivo by indirect effects of IFN-gamma. Proc. Natl. Acad. Sci. USA 96, 8633–8638 (1999).

    Article ADS CAS PubMed PubMed Central Google Scholar 

  35. Huff, A. L. et al. CD4 T cell-activating neoantigens enhance personalized cancer vaccine efficacy. JCI Insight. https://doi.org/10.1172/jci.insight.174027 (2023).

  36. Tran, E. et al. Cancer immunotherapy based on mutation-specific CD4 + T cells in a patient with epithelial cancer. Science 344, 641–645 (2014).

    Article ADS CAS PubMed PubMed Central Google Scholar 

  37. Kruse, B. et al. CD4 + T cell-induced inflammatory cell death controls immune-evasive tumours. Nature. https://doi.org/10.1038/s41586-023-06199-x (2023).

  38. Oliveira, G. et al. Landscape of helper and regulatory antitumour CD4. Nature 605, 532–538 (2022).

    Article ADS CAS PubMed PubMed Central Google Scholar 

  39. Bear, A. S. et al. Biochemical and functional characterization of mutant KRAS epitopes validates this oncoprotein for immunological targeting. Nat. Commun. 12, 4365 (2021).

    Article ADS CAS PubMed PubMed Central Google Scholar 

  40. Dillard, P. et al. Targeting KRAS mutations with HLA class II-restricted TCRs for the treatment of solid tumors. Oncoimmunology 10, 1936757 (2021).

    Article PubMed PubMed Central Google Scholar 

  41. Bear, A. S. et al. Natural TCRs targeting KRASG12V display fine specificity and sensitivity to human solid tumors. J. Clin. Invest. https://doi.org/10.1172/JCI175790 (2024).

  42. Martinez, R. J., Andargachew, R., Martinez, H. A. & Evavold, B. D. Low-affinity CD4 + T cells are major responders in the primary immune response. Nat. Commun. 7, 13848 (2016).

    Article ADS CAS PubMed PubMed Central Google Scholar 

  43. Straub, A. et al. Recruitment of epitope-specific T cell clones with a low-avidity threshold supports efficacy against mutational escape upon re-infection. Immunity 56, 1269–1284.e1266 (2023).

    Article CAS PubMed Google Scholar 

  44. Black, C. M., Armstrong, T. D. & Jaffee, E. M. Apoptosis-regulated low-avidity cancer-specific CD8( + ) T cells can be rescued to eliminate HER2/neu-expressing tumors by costimulatory agonists in tolerized mice. Cancer Immunol. Res 2, 307–319 (2014).

    Article CAS PubMed PubMed Central Google Scholar 

  45. Singhaviranon, S., Dempsey, J. P., Hagymasi, A. T., Mandoiu, I. I. & Srivastava, P. K. Low-avidity T cells drive endogenous tumor immunity in mice and humans. Nat. Immunol. https://doi.org/10.1038/s41590-024-02044-z (2025).

  46. Martínez-Usatorre, A., Donda, A., Zehn, D. & Romero, P. PD-1 blockade unleashes effector potential of both high- and low-affinity tumor-infiltrating T cells. J. Immunol. 201, 792–803 (2018).

    Article PubMed Google Scholar 

  47. Li, H., Ye, C., Ji, G. & Han, J. Determinants of public T cell responses. Cell Res 22, 33–42 (2012).

    Article PubMed PubMed Central Google Scholar 

  48. Barnhart, H. X. & Barboriak, D. P. Applications of the repeatability of quantitative imaging biomarkers: a review of statistical analysis of repeat data sets. Transl. Oncol. 2, 231–235 (2009).

    Article PubMed PubMed Central Google Scholar 

  49. Cohen, J. D. et al. Detection of low-frequency DNA variants by targeted sequencing of the Watson and Crick strands. Nat. Biotechnol. 39, 1220–1227 (2021).

    Article CAS PubMed PubMed Central Google Scholar 

  50. Van Gassen, S. et al. FlowSOM: Using self-organizing maps for visualization and interpretation of cytometry data. Cytom. A 87, 636–645 (2015).

    Article Google Scholar 

  51. Shannon, C. E. A mathematical theory of communication. SIGMOBILE Mob. Comput. Commun. Rev. 5, 3–55 (2001).

    Article Google Scholar 

  52. Montagne, J. M. et al. Ultra-efficient sequencing of T Cell receptor repertoires reveals shared responses in muscle from patients with Myositis. EBioMedicine 59, 102972 (2020).

    Article CAS PubMed PubMed Central Google Scholar 

  53. Brandenburger, A., Contreras-Tejada, P., La Mura, P., Scarpa, G. & Steverson, K. Agreement and disagreement in a non-classical world. Philos. Trans. R. Soc. A: Math., Phys. Eng. Sci. 382, 20230004 (2024).

    Article ADS MathSciNet Google Scholar 

  54. Danilova, L. et al. The mutation-associated neoantigen functional expansion of specific T cells (MANAFEST) assay: a sensitive platform for monitoring antitumor immunity. Cancer Immunol. Res 6, 888–899 (2018).

    Article CAS PubMed PubMed Central Google Scholar 

  55. Chan, H. Y. et al. A T cell receptor sequencing-based assay identifies cross-reactive recall CD8. Front Immunol. 11, 591 (2020).

    Article ADS CAS PubMed PubMed Central Google Scholar 

  56. Hao, Y. et al. Integrated analysis of multimodal single-cell data. Cell 184, 3573–3587.e3529 (2021).

    Article CAS PubMed PubMed Central Google Scholar 

  57. Heather, J. M. et al. Stitchr: stitching coding TCR nucleotide sequences from V/J/CDR3 information. Nucleic Acids Res 50, e68 (2022).

    Article CAS PubMed PubMed Central Google Scholar 

  58. Thorsson, V. et al. The immune landscape of cancer. Immunity 48, 812–830 (2018).

    Article CAS PubMed PubMed Central Google Scholar 

  59. Ellrott, K. et al. Scalable open science approach for mutation calling of tumor exomes using multiple genomic pipelines. Cell Syst. 6, 271–281.e277 (2018).

    Article CAS PubMed PubMed Central Google Scholar  






alvleesklierkanker, alvleeskliercyste, mKRAS-vax, KRAS mutaties, Johns Hopkins Kimmel Cancer Center, Skip Viragh Center for Pancreatic Cancer, CD4-T-cellen, CD8-T-cellen, preventie, recidief


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