FWO-SB-beurs: Development of an mRNA-based vaccine to treat HPV-positive oropharyngeal squamous cell carcinoma: immunogenicity, therapeutic efficacy and safety

The incidence of head and neck cancers is increasing worldwide, especially due to an increase in Human Papillomavirus-positive oropharyngeal squamous cell carcinomas (HPVOPC). These tumors occur mostly at the base of the tongue or on the tonsils. In general, prognosis of HPV-positive tumors is better than that of their negative counterpart, but a subgroup of patients with these tumors has a prognosis comparable to that of patients with HPV-negative tumors. The more lymphocytes invade the tumor, the better the prognosis. This is an indication that immunotherapy could be used with therapeutic purposes. Currently, the first choice of therapy for these tumors is often radiotherapy, combined with chemotherapy and sometimes surgery. However, these approaches are often associated with invalidating sequelae and de-intensification of these therapies is hoped-for. As HPV oncoproteins E6 and E7 need to be expressed continuously to initiate and maintain tumor development, these antigens can be a target for immunotherapy. We want to evaluate a mRNA-based vaccine encoding E6/E7 and TriMix, that could be given adjuvant to the conventional radiotherapy. TriMix mRNA encodes the activation stimuli CD40 ligand (CD40L), a constituvely active form of TLR4 (caTLR4) and the co-stimulatory molecule CD70, resulting in DCs in the right functional status and enhancement of specific T cell proliferation and – differentiation. We propose to investigate the effect of this vaccine in combination with irradiations on the immunologic response directed against the tumor, in the peripheral blood and in the tumor tissue itself. We will determine the therapeutic potential of this strategy in pre-clinical experiments. Murine in vivo studies will be performed on an orthotopic TC-1 mouse model. The effects of the vaccination, radiation and the combination of these two on the peripheral and intratumoral immune response will be assessed. Tumor evolution and survival rates will also be evaluated. After studies in small animal models, human ex vivo studies will be conducted, where emphasis will be placed on the effect of TriMix- and E6/E7-expressing antigen-presenting cells on tumor-infiltrating lymphocytes in tumoral tissue, and the link between intratumoral immune response and peripheral immune response. The information gained from these studies will be implemented for a Phase I clinical trial, where safety, immunogenicity and efficacy of the vaccination will be evaluated.