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.
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).
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.
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.
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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.
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.