Disturbances in mechanisms that direct abnormal cells to undergo apoptosis frequently and critically contribute to tumorigenesis, yielding a logical target for potential therapeutic intervention. There is currently heightened interest in the extrinsic apoptosis pathway, with several proapoptotic receptor agonists (PARAs) in development. The PARAs include the ligand recombinant human Apo2L/TRAIL and agonistic mAbs. Mechanistic and preclinical data with Apo2L/TRAIL indicate exciting opportunities for synergy with conventional therapies and for combining PARAs with other molecularly targeted agents. Novel molecular biomarkers may help identify those patients most likely to benefit from PARA therapy.
Avi Ashkenazi, Roy S. Herbst
Submitter: Veronica Huber | email@example.com
Authors: Manuela Iero, Paola Filipazzi, Giorgio Parmiani, and Licia Rivoltini
Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Published July 17, 2008
With great interest we read about the advances in cancer therapy using proapoptotic receptor agonists (1). Indeed, TRAIL and its death receptors have entered clinical studies and are gaining increased interest over the last few years. Numerous agonist antibodies targeting the death receptors for TRAIL are currently tested in Phase I-II clinical trials including the most diverse cancer histotypes. These therapies, which are apparently safe and well-tolerated, seem to mediate some clinical benefit in selected patients, in terms of disease stabilization or objective responses. These encouraging results open novel and attractive strategies for the treatment of several types of cancer.
However, not much light has been shed so far on the mechanisms involved in such clinical outcome. In truth, tumor cells are often found in vitro to be resistant to TRAIL-induced apoptosis or lack appropriate receptor expression when cancer lesions are analyzed. Indeed, if retrospectively tested, only a small percentage of tumors specimens express TRAIL death receptors, thus making it complex to understand how they can efficiently be targeted by specific antibodies (2). A direct killing of tumor cells by activation of apoptotic processes seems therefore unlikely to be the only effect attributed to this therapeutic approach. In this context we deem reasonable to hypothesize that the anti-tumor effect of TRAIL-based therapies might also depend on some previously unexpected consequences that these treatments play on immune cells. In fact, TRAIL is now emerging as a key player in regulating immune responses (3,4). Results are still controversial, but it seems that at certain stages of their activation process and especially under disease conditions, T cells gain sensitivity to TRAIL through the expression of cognate death receptors (5-7). In vivo administration of TRAIL receptor agonist antibodies could therefore involuntarily target immune cells, too, with different and unpredictable immunological outcomes depending on their functions and activation state. For instance, TRAIL triggering could contribute to the down-regulation of regulatory T cells leading to the recovery of anti-tumor T cell responses and immune mediated tumor regressions (8). On the other hand, TRAIL-mediated elimination of immune effectors, meaning tumor-specific CD8 T cells (3) or crucial mediators of antigen processing and presentation, like DCs (9), could instead contribute in tilting the balance thereby favouring disease progression due to depressed tumor immunity.
In view of this, we would like to encourage the introduction of studies aimed at evaluating potential effects of such therapies on immune cells. This may provide a more exhaustive picture of the mechanisms by which therapies targeting TRAIL death receptors may affect tumor growth in cancer patients.