The research within our LUMC departments is conducted within departmental research programmes. The research programme below is embedded within the department of Immunology.
Aim and focus
The aim of the research program is to gain insight in the interaction between the immune system and tumors and to exploit this knowledge for the development of diagnostics and therapy. New concepts are conceived and tested in mouse models, in vitro and by bioinformatic analysis of patient-derived datasets. Focus is on the adaptive immune response, specifically the cytotoxic T cell response and its regulation by helper T cells, dendritic cells and costimulatory and coinhibitory receptors.
A research line on therapeutic vaccination connects to the clinic, using innovative vaccine design, incorporating knowledge on dendritic cell biology and CD4 T cell help. Ongoing clinical studies with peptide-based vaccines are based on the antigenicity of human papillomavirus (HPV). Collaboration with biotech companies are in place to test vaccine and antibody-based approaches in immunotherapy.
Position in international context
This research line has a good international position, in particular with respect to investigation of the molecular and cellular basis of the helper and cytotoxic T cell response, antigen-presentation, costimulation, dendritic cell biology and the design and evaluation of defined synthetic vaccine modalities.
Content / highlights / achievements
- The demonstration that peptide-based vaccines are superior in inducing therapeutic anti-tumor immunity in mice and of HPV-specific T-cell immunity in HPV positive cancer patients.
- The synthetically defined and patented TLR2 ligand UPam, which improved potency of peptide based vaccines by direct conjugation is in Phase I clinical trial in oropharyngeal cancer patients.
- The demonstration that effectiveness of immune-modulatory antibodies in tumor-bearing mice is related to particular T cell responses in the circulation and to local immune activation in tumor-draining lymphoid organs.
- The demonstration that effective cancer immunity can be achieved by combination protocols of classical cancer treatment protocols like chemotherapy plus photodynamic-ablation therapies, and chemotherapy plus vaccination.
- The gain of knowledge on T cell fitness related to vaccines and immunotherapy; in particular the significance of T cell costimulation by TNF receptor family members.
- The discovery how CD4 T cell help for the cytotoxic T cell response is connected to T cell dysfunction in cancer and chronic infection)
Future themesInitiation of the cytotoxic T cell response under influence of CD4 T cell help will be examined in cellular and molecular detail in human and mouse to identify novel key mechanisms that shape the effector and memory T cell response. Signal transduction in regulatory versus conventional T cells will be explored by multi-omics approaches. Aim of this work is to identify new target molecules or cell populations for immunotherapeutic intervention.
Vaccination strategies will be improved by synthetic approaches to combine peptide vaccines with defined immune-stimulating molecules, DNA-based vaccines and formulations for in vivo delivery (collaboration the LIC and LACDR, UL) and developed for GMP setting (KFT, LUMC). This will set the stage for cancer vaccines for defined tumor antigens and neo-epitopes. By exome sequencing and MHC-peptide elution/MS approaches these epitopes are identified as targets for personalized therapeutic vaccination strategies.
The suppressive tumor environment and system-wide immunity will be analyzed in cellular and molecular detail. The different subsets of T cells, myeloid cell types and suppressive cytokines will be studied and approaches for combination therapies will be tested in our in vivo tumor models, and where possible related to human cancers. Mechanistic studies in mice will be directed at identifying optimal combined modality treatment strategies with agonistic antibodies targeting TNFR family members and blocking antibodies to PD-1 and/or CTLA-4 to activate anti-tumor immunity. Rational combination of such approaches with vaccination, radio-ablation, chemotherapy or adoptive T cell therapy (ACT) will be explored.
Cohesion within LUMC
This research program is conducted in close collaboration with multiple groups within the LUMC, in particular with the Depts. of Medical Oncology, Gynecology, Pharmacy, Pediatrics, Radiology, Pathology (HPV, cervical neoplasia, neo-epitopes), Surgery (colorectal cancer), Cellular and Chemical Biology and Human Genetics (genomics).