Molecular Oncology of Gastrointestinal Tumors

The Division ‘Molecular Basis of Gastrointestinal Tumors’ was founded with the support of the K.H. Bauer Foundation. Our laboratory is closely associated with the European Pancreas Center of Heidelberg University Hospital, one of the leading pancreatic surgery clinics in the world. Furthermore, we have a long-standing collaboration with the Department of Pancreatic Surgery at Union Hospital, Tongji Medical College, Wuhan, China. Our research focuses on the development of new therapies for pancreatic cancer, in particular pancreatic ductal adenocarcinoma, for which still no satisfactory treatment options are available. Surgical resection of the primary tumor, the only intervention that provides patients a perspective for prolonged survival, is merely available to approximately 20% of patients, because in the majority of cases the disease has already spread to nearby tissues at the time of diagnosis. However, also patients successfully treated by surgery rarely survive longer than 5 years, due to the devastating disease recurrence rate. For patients with recurrent disease, palliative chemotherapy is the only option. The same applies to patients diagnosed with non-resectable disease, due to the complexity of the tumor microenvironment that renders the tumor resistant to various treatment regimens, including cytostatic and immunotherapeutic strategies.

In view of this clinical reality, our research focuses on the development of new neo-adjuvant and adjuvant treatment strategies aimed at increasing the fraction of patients eligible for surgical treatment and at combatting post-surgery disease recurrence. Our lab. was one of the first to show that, in contrast to generally prevailing views, pancreatic tumors harbor tumor-reactive T-cells that can be isolated from patient tumor samples and/or mobilized in vivo through combinations of targeted cytostatic and immunostimulatory drugs. Our current efforts primarily focus on the following two topics:

• The identification and molecular cloning of tumor-reactive T-cell receptors (TCRs) by means of single cell RNA-sequencing (scRNA-seq) from human and mouse tumor samples, followed by the in-depth analysis of the antigen-specificity and therapeutic potential of these TCRs for personalized therapy through the infusion of autologous, genetically engineered T-cells (TCR gene therapy).

• The exploration in clinically relevant mouse tumor models of synergistic combinations of drugs that target different mechanisms driving the malignancy of pancreatic cancer, in particular tumor cell growth, the tumor nurturing influence of the tumor microenvironment, and immunosuppressive pathways.

For both sub-projects, our research is placed in the context of surgical resection of the primary tumor. The TCR gene therapy approach is based on the isolation of tumor-reactive TCRs from the resected tumor specimen, and the infusion of engineered T-cells is aimed at destruction of the remaining disseminated tumor cells with the objective to prevent early disease recurrence. The synergistic drug combinations are applied in the neoadjuvant and adjuvant setting to limit the residual disease load after resection, as well as to optimize the impact of genetically engineered T-cell therapy.

In view of this, we closely collaborate with the aforementioned pancreatic surgery clinics and, for our pre-clinical experiments, make use of an in-house developed, autochthonous mouse model that allows surgical resection of primary pancreatic tumors.