Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

Preventive dendritic cell vaccination in healthy Lynch syndrome mutation carriers

Date

10 Oct 2016

Session

Immunotherapy of cancer

Presenters

Harm Westdorp

Citation

Annals of Oncology (2016) 27 (6): 359-378. 10.1093/annonc/mdw378

Authors

H. Westdorp1, M.A.J. Gorris2, S. Boudewijns3, T. Bisseling4, A.L. de Goede5, M.M. van Rossum6, M.J.L. Ligtenberg7, G. Schreibelt2, I.D. Nagtegaal8, C.G. Figdor2, W. Gerritsen9, N. Hoogerbrugge10, I..J.M. de Vries3

Author affiliations

  • 1 Tumor Immunology And Medical Oncology, Radboud University Medical Centre Nijmegen, 6525 GA Nijmegen - Nijmegen/NL
  • 2 Tumor Immunology, Radboud University Medical Centre Nijmegen, Nijmegen/NL
  • 3 Tumor Immunology And Medical Oncology, Radboud University Medical Centre Nijmegen, Nijmegen/NL
  • 4 Gastroenterology, Radboud University Medical Centre Nijmegen, Nijmegen/NL
  • 5 Pharmacy, Radboud University Medical Centre Nijmegen, Nijmegen/NL
  • 6 Dermatology, Radboud University Medical Centre Nijmegen, Nijmegen/NL
  • 7 Human Genetics, Radboud University Medical Centre Nijmegen, Nijmegen/NL
  • 8 Pathology, Radboud University Medical Centre Nijmegen, Nijmegen/NL
  • 9 Medical Oncology, Radboud University Medical Centre Nijmegen, Nijmegen/NL
  • 10 Human Genetics, Radboud University Medical Centre Nijmegen, 6500 HB - Nijmegen/NL
More

Resources

Background

Lynch syndrome (LS) is an autosomal dominantly inherited syndrome caused by monoallelic germline aberrations affecting one of the DNA mismatch repair (MMR) genes. Defects in the DNA MMR pathway underlie the development of microsatellite instability in LS-associated cancer. The cumulative risk of colorectal cancer varies between 10-80% and is strongly associated with the causative germline defect. MMR deficiency in tumor DNA causes shifts in the translational reading frame resulting in the production of altered peptides, called neopeptides. These are considered ‘foreign’ by the immune system. This was the rationale for a preventive neoantigen-based vaccination study with dendritic cells (DCs). DCs are the antigen-presenting cells of our immune system as a result of their naive T cell priming and T cell activation capabilities.

Methods

We recruited HLA-A*02.01 positive patients known to be a germline MMR-gene mutation carrier without signs of LS-associated disease or more than 5-years beyond detection of a non-metastasized LS-associated cancer. The primary endpoint was to investigate the safety and feasibility of DC vaccinations. Secondary objectives were to evaluate whether monocyte-derived peptide-loaded DC can induce an immune response to the selected neoantigens (caspase-5 and TGF-ßRII) and the tumor-associated antigen carcinoembryonic antigen (CEA).

Results

All patients (n = 20) were recruited within a year. DC vaccinations were on average well tolerated. No participants were hospitalized during study treatment. In all vaccinated mutation carriers flu-like symptoms occurred. In 17 of 20 patients an injection site reaction developed upon intradermal DC administration. One patient experienced grade 4 fever (>40 °C > 24 hours), as a result study treatment was discontinued. In all tested patients a cellular immune response against the control antigen was seen. Functional neoantigen- or CEA-specific T cells were shown in the challenged skin upon DC vaccination in 15 of 20 patients.

Conclusions

Preventive DC vaccination is feasible and safe in LS mutation carriers and functional neoantigen- and CEA-specific immune responses were shown. This study opens perspectives for future immunotherapy trials with the intention of cancer prevention.

Clinical trial identification

ClinicalTrials.gov NCT01885702

Legal entity responsible for the study

N/A

Funding

This work was supported by Grant 951.00.106 of the Netherlands Organization for Scientific Research (NWO), two Radboudumc Ph.D. grants and a Koningin Wilhelmina Onderzoeksprijs (KWO)-Grant KUN2009-4402 from the Dutch Cancer Society (KWF). CG Figdor is recipient of European Research Council (ERC) Advanced grant PATHFINDER (269019) and a NWO Spinoza grant. IJM de Vries is recipient of NWO Vici Grant 918.14.655.

Disclosure

W. Gerritsen: Consult for Aglaia Biomedical Ventures, Supervisory board for PsytoBe, Speakers fee from J&J and BMS, and Advisory boards for Amgen, BMS, Janssen-Cilag, Sanofi, Astellas, Bayer, and Merck. All other authors have declared no conflicts of interest.

Resources from the same session

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings