Radiotherapy and TRAIL for cancer therapy

The use of radiotherapy and concomitant chemotherapy substantially improved cure rates in patients with different malignant tumours. However, it is unlikely that further improvements based on conventional chemotherapy may be achieved in the future since increased rates of acute side effects already limit the value of these approaches. Additionally, the increased local control rates are counterweighted by still high rates of distant failures resulting in low net gains for the patients. Thus, there is a currently unmet need for the integration of target-specific drugs improving local control as well distant control into radiation based treatment protocols. In this regard, the death-receptor ligand TNF-α-related apoptosis-inducing ligand (TRAIL/Apo2L) and TRAIL-receptor agonistic antibodies were shown to display a high selectivity for tumour cells and act synergistically with conventional chemotherapy drugs and radiation. Up to now it has been shown that radiation strongly sensitises malignant cells to TRAIL and TRAIL-agonistic antibodies. Synergistic induction of apoptosis was demonstrated in a majority of malignant cell types and xenograft models. Especially in those cells types displaying only weak responses to either treatment alone, strong sensitising effects were described. Moreover, in merely all normal cells and tissues no synergistic effects were found. Depending on cell type and experimental setting, the efficacy of combined treatment is determined by the p53-status, the balance between pro- and anti-apoptotic Bcl-2 proteins and modulation of TRAIL-receptor signal transduction.

► TRAIL-receptor agonists show tumour-specific cytotoxicity through direct cell-death induction.
► Reasonable toxicity profile.
► TRAIL-receptor stimulation results in profound radiosensitisation of malignant cells in vitro and in vivo.
► Strong synergistic cell-death induction especially in radioresistant cells.
► Ongoing clinical trials combining TRAIL-agonists with chemotherapy.