Project-ID: LS19-004
Project start: 01. March 2021
Runtime: 36 months / ongoing
Funding amount: € 290.000,00

Brief summary

Immune checkpoint inhibitors (ICIs) have recently revolutionized cancer treatment, providing unprecedented clinical benefits. ICI treatment involves antibodies generated against the cytotoxic T-lymphocyte associated protein 4 (CTLA-4), the programmed death receptor 1 (PD-1) or its ligand (PD-L1). However, primary or acquired therapy resistance can affect up to two-thirds of patients receiving ICIs, underscoring the urgency to elucidate the mechanisms of treatment resistance and to design more effective therapeutic strategies. Conventional cancer treatments, including cytotoxic chemotherapy, radiation therapy, and targeted therapy, have immunomodulatory effects in addition to direct cancer cell-killing activities. Although some of these approaches have provided clinical benefits, the lack of knowledge in the functional interactions between conventional cancer therapies and immune checkpoint blockades at the molecular level remains a crucial hurdle in developing rational and optimal combination strategies. Especially in cholangiocarcinoma (CCA), an aggressive hepatobiliary malignancy with poor prognosis and increasing incidence, an effective treatment strategy is urgently needed. For patients with advanced-stage or unresectable CCA, the available systemic chemotherapy (gemcitabine and cisplatin) is of limited effectiveness with a median overall survival below 1 year. However, studies in small number of CCA tumour samples have reported on PD-L1 expression in a substantial proportion of the tumours. These data indicate that CCAs might be amenable to therapy with PD-(L)1 inhibitors. Further investigation of PD-(L)1 as a biomarker for anti-PD-(L)1 therapies is required in order to understand the effects of important covariates, including tumour-cell versus immune-cell expression, primary versus metastatic lesion sampling, prior treatment exposure, and combination of therapies. We thus aim to preclinically evaluate combination strategies for the treatment of CCA. First, we will generate and characterize an orthotopic CCA tumour model. Then we will evaluate if molecular imaging (positron emission tomography, PET) and magnetic resonance imaging (MRI) can be used to visualize CCA tumours within the liver. Thereafter, we aim to find the optimal time point for ICI therapy after induction of chemo- or targeted therapy by assessing therapy-induced changes in tumour immunogenicity. Finally, we will test different treatment combination strategies (sequential versus concurrent) of cisplatin/gemcitabine or VEGF-A inhibitor with a PD-L1 inhibitor in the CCA tumour model. Tumour response will be assessed by imaging and by ex vivo histological and immunohistochemical analysis. In addition, PD-L1 expression will be determined in CCA tumour samples from patients taking into account the various anatomical locations and the different histopathological subtypes. All these efforts aim to develop a treatment concept for CCA suitable for clinical translation.

Keywords:
nuclear medicine, cancer biology, radiology