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TRAIL-R2-specific antibodies and recombinant TRAIL can synergise to kill cancer cells
Mark H Tuthill1,2, Antonella Montinaro1, Julia Zinngrebe1
1Tumour Immunology Unit, Imperial College London, London, UK.
Abstract:
Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells while sparing normal tissues. Despite promising preclinical results, few patients responded to treatment with recombinant TRAIL (Apo2L/Dulanermin) or TRAIL-R2-specific antibodies, such as conatumumab (AMG655). It is unknown whether this was due to intrinsic TRAIL resistance within primary human cancers or insufficient agonistic activity of the TRAIL-receptor (TRAIL-R)-targeting drugs. Fcγ receptors (FcγR)-mediated crosslinking increases the cancer-cell-killing activity of TRAIL-R2-specific antibodies in vivo. We tested this phenomenon using FcγR-expressing immune cells from patients with ovarian cancer. However, even in the presence of high numbers of FcγR-expressing immune cells, as found in ovarian cancer ascites, AMG655-induced apoptosis was not enabled to any significant degree, indicating that this concept may not translate into clinical use. On the basis of these results, we next set out to determine whether AMG655 possibly interferes with apoptosis induction by endogenous TRAIL, which could be expressed by immune cells. To do so, we tested how AMG655 affected apoptosis induction by recombinant TRAIL. This, however, resulted in the surprising discovery of a striking synergy between AMG655 and non-tagged TRAIL (Apo2L/TRAIL) in killing cancer cells. This combination was as effective in killing cancer cells as highly active recombinant isoleucine-zipper-tagged TRAIL (iz-TRAIL). The increased killing efficiency was due to enhanced formation of the TRAIL death-inducing signalling complex, enabled by concomitant binding of Apo2L/TRAIL and AMG655 to TRAIL-R2. The synergy of AMG655 with Apo2L/TRAIL extended to primary ovarian cancer cells and was further enhanced by combination with the proteasome inhibitor bortezomib or a second mitochondrial-derived activator of caspases (SMAC) mimetic. Importantly, primary human hepatocytes were not killed by the AMG655-Apo2L/TRAIL combination, also not when further combined with bortezomib or a SMAC mimetic. We therefore propose that clinical-grade non-tagged recombinant forms of TRAIL, such as dulanermin, could be combined with antibodies such as AMG655 to introduce a highly active TRAIL-R2-agonistic therapy into the cancer clinic.
Insights
Combining TRAIL (Tumour necrosis factor-related apoptosis-inducing ligand) with antibodies like AMG655 synergistically kills cancer cells. This combination therapy, which spares normal cells, offers a promising new approach for cancer treatment.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promise in cancer therapy by inducing apoptosis in cancer cells while sparing normal tissues.
- Clinical trials with recombinant TRAIL (Apo2L/Dulanermin) and TRAIL-R2-specific antibodies (e.g., conatumumab/AMG655) yielded limited patient responses, prompting investigation into resistance mechanisms.
- Fcγ receptor (FcγR)-mediated crosslinking was hypothesized to enhance TRAIL-R2 antibody efficacy, but this did not translate to significant apoptosis induction in ovarian cancer models.
Purpose of the Study:
- To investigate the efficacy of combining AMG655 with endogenous or recombinant TRAIL in overcoming cancer cell resistance.
- To explore the underlying mechanisms of synergy between AMG655 and TRAIL in cancer cell apoptosis.
- To evaluate the safety of the combination therapy in primary human hepatocytes.
Main Methods:
- Testing the effect of AMG655 on apoptosis induced by recombinant TRAIL (Apo2L/TRAIL) in cancer cells.
- Analyzing the formation of the TRAIL death-inducing signaling complex (DISC) upon combined treatment.
- Assessing the synergistic effects of AMG655 and Apo2L/TRAIL in primary ovarian cancer cells, with or without bortezomib or a SMAC mimetic.
- Evaluating the toxicity of the combination therapy on primary human hepatocytes.
Main Results:
- A striking synergy was observed between AMG655 and non-tagged TRAIL (Apo2L/TRAIL), significantly enhancing cancer cell killing.
- The combination's efficacy was comparable to highly active isoleucine-zipper-tagged TRAIL (iz-TRAIL), attributed to enhanced DISC formation.
- Synergy was confirmed in primary ovarian cancer cells and further augmented by bortezomib or a SMAC mimetic.
- Crucially, primary human hepatocytes remained unaffected by the AMG655-Apo2L/TRAIL combination, even with added agents.
Conclusions:
- The combination of AMG655 with non-tagged TRAIL (Apo2L/TRAIL) represents a potent strategy for inducing cancer cell apoptosis.
- This synergistic approach overcomes limitations of previous TRAIL-based therapies and demonstrates a favorable safety profile in hepatocytes.
- Clinical-grade non-tagged TRAIL combined with antibodies like AMG655 could form the basis of a highly active TRAIL-R2-agonistic therapy for cancer treatment.
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