The
death receptors CD95, TRAILR1 and TRAILR2 induce cell death in many types of
tumor cells. Activation of these receptors has received considerable interest due to its potential use in
cancer therapy. In particular the observation that most primary cells are not or only barely TRAIL-sensitive resulted in the development of targeted
therapy concepts that base on activation of the TRAIL
death receptors by recombinant TRAIL or agonistic
antibodies. Indeed, a variety of preclinical studies and several phase I and II clinical trials show that activation of TRAIL
death receptors effectively induces apoptosis in
cancer cells in vivo without
therapy-limiting toxicity on normal cells. Primary
tumor cells are often sparsely sensitive for TRAIL
death receptor-mediated apoptosis or acquire resistance during
therapy. Sensitization/resensitization of
tumor cells by chemotherapeutic drugs or radiation can therefore be necessary for TRAIL-based
therapies, but this involves the danger of triggering side effects related to the breakage of apoptosis resistance of non-transformed cells. Thus, there is a foreseeable need to develop optimized combination
therapies or to locally restrict TRAIL receptor activation to fully exploit the antitumoral potential of TRAIL
death receptors in the clinic. Although the high sensitivity of hepatocytes for CD95-mediated apoptosis prohibits
therapies resulting in systemic activation of CD95, several studies have shown that this limitation can be overcome by ex vivo treatment regimes or by CD95 activating agonists with cell type-specific activity. This patent review is focused on the
death receptor agonists currently under consideration in clinical trials, but also addresses the hurdles that have to be cleared to broaden and to improve the applicability of the currently used clinical concepts related to
death receptor activation.