Division of Molecular Oncology of Gastrointestinal Tumors
Prof. Dr. Rienk Offringa
The Division Molecular Oncology of Gastrointestinal Tumors was founded in 2011 with support from the K.H. Bauer Foundation. The decision to direct research efforts to pancreatic cancer was based on the urgent unmet medical need this disease represents, with incidence and mortality rates still being almost equal, and the fact that Heidelberg University hosts the European Pancreas Center, one of the world’s leading clinics for the treatment of pancreatic cancer.
Our research aims at the implementation of immunotherapy in conjunction with surgery, chemotherapy and/or small molecule inhibitors. The choice for immunotherapy was inspired by recent successes with this approach in the clinic for other cancers, as well as emerging pre-clinical evidence that redirection of immune pathways is one of the most promising avenues towards more effective non-surgical treatment of pancreatic cancer.
Our therapeutic strategy primarily involves two approaches:
- Stimulation of the endogenous immune potential, in particular in the tumor stroma, by means of agonist immunostimulatory monoclonal antibodies
- Exploitation of the most powerful mode of immunotherapy: infusion of ex vivo engineered autologous T-lymphocytes.
Patient-based research is supported by the excellent availability of patient biopsies, including the tissue that represents the interface between tumor and immune system: tumor-draining lymph nodes. Our research in mice focuses on genetically engineered, autochthonous tumor models.
It is essential that our research does not stop at the threshold between lab and clinic. This is why we, together with our partners in the university clinic and at the National Center for Tumor Diseases (NCT), are setting up a pipeline for rationally designed clinical trials in pancreatic cancer. Biomarker research constitutes a pivotal aspect of this rational design, both with respect to patient stratification and evaluation of therapy efficacy.
Initial studies will be staged in patients with non-resectable pancreatic cancer, for which median survival time is ~6 months. Since this leaves insufficient time to boost endogenous T-cell immunity, our approach focuses on boosting endogenous innate immunity or, alternatively, replenishing the patient’s immune system with ex vivo engineered autologous T-cells. Since the median survival time of patients diagnosed with resectable disease is ~1.5 years, modulation of endogenous T-cell immunity will be considered in this patient group.
Although phase I safety studies generally involve end stage patients, it is important that further studies aimed at harnessing the endogenous immune response are implemented in the context of first-line treatment, before the patient’s immune system has deteriorated due to progressive disease and cytotoxic anti-cancer regimens. In practical terms, this currently means combination with standard of care chemotherapy (gemcitabine) for non-resectable disease, and (neo)adjuvant treatment for resectable disease.
Oliveira CC, van Veelen PA, Querido B, de Ru A, Sluijter M, Laban S, Drijfhout JW, van der Burg SH, van Hall *, Offringa R* (2010). The nonpolymorphic MHC Qa-1b mediates CD8+ T cell surveillance of antigen-processing defects. J Exp Med, 207, 207-21
Offringa R. (2009). Antigen choice in adoptive T-cell therapy of cancer. Curr Opin Immunol, 21, 190-9
Bos R, van Duikeren S, Morreau H, Franken K, Schumacher TN, Haanen JB, van der Burg SH, Melief CJ, Offringa R. (2008). Balancing between antitumor efficacy and autoimmune pathology in T-cell-mediated targeting of carcinoembryonic antigen. Cancer Res, 68, 8446-55
van Hall T, Wolpert EZ, van Veelen P, Laban S, van der Veer M, Roseboom M, Bres S, Grufman P, de Ru A, Meiring H, de Jong A, Franken K, Teixeira A, Valentijn R, Drijfhout JW, Koning F, Camps M, Ossendorp F, Karre K, Ljunggren HG, Melief CJ, Offringa R. (2006). Selective cytotoxic T-lymphocyte targeting of tumor immune escape variants. Nat Med, 12, 417-24