Abstract IA44: Cancer prevention: Dendritic cell enhanced immune responses towards neoantigens in patients with Lynch syndrome

To date, dendritic cell (DC)-based immunotherapy is explored worldwide in clinical vaccination trials with cancer patients. Although during the past 15 years the concept of DC vaccination has been clearly proven and found safe, the number of patients that have long-term benefit is still limited. Therefore the development of bioassays that predict clinical outcome are essential to optimize cellular anticancer immunotherapy. We have developed a robust and simple skin test to evaluate the capacity of tumor-specific T cells to migrate, recognize their targets and exert effector functions. This bioassay detects skin infiltrating T lymphocytes (SKILs) with an elevated antineoplastic potential and hence identifies patients responding to immunotherapy once started. The identification of a biomarker already available before start of treatment would facilitate decision-making regarding (prophylactic) immunotherapy. We recently identified that the ratio between peri/intratumoral T cells in the primary tumor, is an excellent predictor of survival after DC-based immunotherapy in metastatic melanoma patients. Patients with a high density of T cells in primary tumors, hence putative candidates for DC vaccination, are Lynch syndrome patients. They have an up to 80% lifetime risk of colorectal cancer (CRC) due to a germline DNA mismatch-repair gene mutation (Lynch syndrome). MMR deficiency in tumor DNA causes shifts in the translational reading frame resulting in the expression of neoantigens. We exploited these neoantigens for vaccination of Lynch syndrome-associated CRC using DC. Patients were vaccinated with monocyte-derived DC loaded with MHC-class I-binding neoantigens (mutated Caspase-5 and TGF-βRII) and carcinoembryonic antigen (CEA). With our bioassay, we detected SKILs that were able to migrate to the antigen-challenged site, recognize their targets (neoantigens) and exert effector functions shown by high amounts of interferon-γ upon stimulation with neoantigen-loaded target cells. No severe adverse events were detected. Our data emphasize the potency of DC-based immunotherapy to enhance the hosts antitumor immunity. Furthermore, this study paved the way for vaccination aiming at cancer prevention in Lynch syndrome mutation carriers. We recently started a clinical study with the here developed dendritic cells in these lynch syndrome mutation carriers. To date, promising immunological results are noted. Citation Format: Jolanda de Vries, Gerty Schreibelt, Kalijn F. Bol, Harm Westdorp, Steve Boudewijns, Winald R. Gerritsen, Nicoline Hoogerbrugge, Carl G. Figdor. Cancer prevention: Dendritic cell enhanced immune responses towards neoantigens in patients with Lynch syndrome. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr IA44.