Our main objective is to develop strategies for the immunotherapeutic treatment of virus-induced cancer. We focus on the immunotherapy of cervical cancer and liver cirrhosis or -cancer induced by chronic Hepatitis C virus (HCV) infection. The central aim of these strategies is to induce a strong cellular immune response against the tumor involved. For cervical cancer, the tumor antigens aimed for are the E6 and E7 proteins of Human Papillomavirus (HPV), the virus involved in the development of this type of cancer. For liver cancer and cirrhosis, we aim at the induction of an HCV-specific immune response.
Several approaches are being pursued including genetic immunization with recombinant viral vectors based on Semliki Forest virus, immune checkpoint inhibitors and approaches to re-modulate the immunosuppressive tumor environment. We furthermore focus on methods to identify HLA-bound antigenic peptides to generate personalized cancer vaccines.
Semliki Forest virus based immunotherapy
For the SFV-based immunization, several constructs have been generated encoding HPV16 E6 and E7 protein antigens, non-structural proteins of HCV, cytokine and reporter genes. To evaluate the efficacy of the immunization experiments, we established a diversity of immunological read-out systems. In addition, in vivo (immune)therapeutic studies are being performed using murine tumor models. In the past years, we thus demonstrated the enormous potency of this vector system in inducing long-term cellular immune responses and complete regression of established tumors in mice. We currently study the mechanism of action of these immunization strategies in more detail and in combination with novel immunotherapeutic antibodies targeting immune checkpoints. Currently the HPV16 E6E7 targeting SFV-based vaccine is being evaluated in a phase I clinical trial (see clinical trials).
Current HCV treatment focuses on a combination of antiviral drugs. Apart from the enormous costs of the drugs and side effects an important shortcoming of these antiviral treatment is that no protective immune memory against the virus is induced in this at-risk population. Therefore, new treatment options targeting the immune system are needed for HCV-induced liver cancer and for patients with chronic HCV infections. A therapeutic vaccine that specifically targets HCV-infected cells could provide such a novel option. We therefore aim to identify patient-specific HCV epitopes that could constitute the basis for a tailor-made immunotherapy against HCV infection. For this we aim to 1) establish a technology to identify targets for the development of personalized therapeutic vaccines for HCV infections and 2) develop an in vitro assay to test the efficacy of personalized vaccines.
Metabolic reprogramming of tumor-associated macrophages
In solid tumours, high infiltration of immune suppressive myeloid cells (M2-macrophages and myeloid-derived suppressor cells (MDSCs)) is associated with poor prognosis. Therefore, these cells are considered important targets for therapy intervention in the context of immunotherapies. Since phenotype and activity of myeloid cells is related to their metabolic profile we will focus on the manipulation of the metabolic pathways of intra-tumoral myeloid cells to unleash and/or enhance the responsiveness to immunotherapy.
Immunomonitoring of natural responses and responses induced by standard treatment.
In collaboration with Prof dr Hans Nijman (Department of Gynaecology and Obstetrics, UMCG) we study the role of cell-mediated immunity against HPV and P53 in the control of (pre)malignant cervical cancer and ovarian cancer, respectively. In these (longitudinal) studies immune responses and immune effector cells in blood-, tumor- and lymph node samples of patients before, during the course of the treatment (surgery and/or radio chemotherapy) and at several time points after treatment are being characterized.
Several clinical trials have been conducted in direct collaboration with Prof dr Nijman and Prof dr van der Zee (UMCG), Prof dr Cees Melief and Prof dr Sjoerd van de Burg (LUMC) and ISA pharmaceuticals. The department of Molecular Virology conducted the immunomonitoring of the responses. In 2006-2009 two P53 long-peptide immunization trials in ovarian cancer patients were conducted and immunomonitored. These trials demonstrated the safety of the immunization while furthermore cellular immune responses were induced in all patients.
Within the context of a small biotech company “ViciniVax” a phase I clinical trial with Vvax001, i.e. SFV-eE6,7 in patients with a history of a (pre)malignant HPV lesion started in January 2017.