Lessons learned from patients
Investigating mechanisms of resistance to immunotherapy
Immunotherapy is an attractive approach to add to current therapeutic concepts. Tumors can be recognized and controlled by the immune system. Despite the presence of tumor-specific T cells in cancer patients, the tumor usually escapes immune control. Co-inhibitory molecules including CTLA-4 and PD-1 are expressed on T cells upon their activation and prevent the immune response from overshooting during infections. PD-1 and CTLA-4 are therefore often referred to as immune checkpoints (IC). In the context of cancer, however, such molecules prevent protective effector responses. The development and clinical success of antibodies targeting CTLA-4, PD-1 (immune checkpoint inhibitors) or its ligands hence revolutionized cancer treatment. To date, these treatments have become standard of care for aggressive cancers. Malignant pleural mesothelioma (MPM) and advanced non-small cell lung cancer (NSCLC) are aggressive cancers with poor prognosis also with standard of care treatment. Checkpoint inhibitors have shown some success in early trials for this disease; however, most of the patients do not respond or develop resistant tumors by time. Therefore, understanding the mechanisms of resistance (initial or aquired) is fundamental for the development of further treatments. We are dedicated in collecting clinical radiological and molecular data as well as collecting patients' derived samples to investigate markers correlated to response or resistance.
Role of radiological assesment (FET-PET and FDG-PET) in patients with non-small cell lung cancer treated with immunotherapy
Response assessment of non-small cell lung cancer patients with brain metastasis undergoing immunotherapy is difficult due to possible pseudoprogression. We are interested in the radiological features of brain metastasis upon treatment with radiotherapy and immunotherapy in combination. For initial staging an 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) is performed. FDG is a radioactively labeled sugar absorbed heavily by tumor cells and detected through a PET scanner. However, FDG uptake might be also due to local immune response caused by the recruitment of neutrophils, lymphocytes, and macrophages. We will address whether the FDG-uptake of the tumor lesion is representative of the tumor cells or of the immune system at the tumor site. Moreover, integrated radiological data and biomarkers might help to identify those patients developing side effects, as inflammation at the tumor site, under immunotherapy. Moreover, we aim to evaluate the radiological features of brain metastases upon treatment with immunotherapy and local radiotherapy by 18F-Fluorethyltyrosin PET (FET-PET) in 4 pts.
Analysis of c-MET expression in metastatic non-small cell lung cancer
Approximately 3% of NSCLC adenocarcinoma have a mutation in the receptor tyrosin kinase c-MET, where a targeted therapy for c-MET with Crizotinib is approved. However, the majority of adenocarcinomas do not display any mutation in c-MET. We are interested in c-MET expression in those patients and combine the expression data with clinical data and therapy outcome. Thus, we identify patients with c-MET amplification and overexpression who could also benefit from Crizotinib treatment.
Analysis of changes of PD-L1 expression in non-small cell lung cancer
Currently, the effect of standard platinum-based chemotherapy on PD-L1expression in patients with non-small cell lung cancer remains unknown. We are investigating if platinum-based chemotherapies induce PD-L1 expression in the tumor tissue, which could favor the synergy with immunotherapy. Thus, we are analysing PD-L1 expression in initial tumor samples and after treatment.
Exploring the expression of immunomodulatory molecules on mesothelioma
We have detected in mesothelioma samples from more than 300 patients the expression of the immune markers CSF1R, CD276 and ICOSL. It is intriguing why mesothelioma cells express so frequently such immunoregulatory markers on their surface. Therefore, targeting these molecules might have an impact on both tumor cells, the immune system and consequently on tumor progression.
Preclinical evaluation of new combinatorial treatments for lung cancer and mesothelioma
Many cancer patients do not respond to immunotherapy or develop resistant tumors by time. Therefore, new therapeutic strategies need to be developed for those patients. Our aim is to evaluate new combinatorial treatments consisting of a combination of targeted therapies and chemotherapy to immune-checkpoint innhibitors and to understand their underlying mechanism of action in our immunocompetent mouse models for mesothelioma and lung cancer.