Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Mar 10:8:628332.
doi: 10.3389/fmolb.2021.628332. eCollection 2021.

The TRAIL in the Treatment of Human Cancer: An Update on Clinical Trials

Martin Snajdauf  1 , Klara Havlova  2 , Jiri Vachtenheim Jr  1 , Andrej Ozaniak  1 , Robert Lischke  1 , Jirina Bartunkova  3 , Daniel Smrz  3 , Zuzana Strizova  3
Affiliations
Review

The TRAIL in the Treatment of Human Cancer: An Update on Clinical Trials

Martin Snajdauf et al. Front Mol Biosci. .

Abstract

TRAIL (tumor-necrosis factor related apoptosis-inducing ligand, CD253) and its death receptors TRAIL-R1 and TRAIL-R2 selectively trigger the apoptotic cell death in tumor cells. For that reason, TRAIL has been extensively studied as a target of cancer therapy. In spite of the promising preclinical observations, the TRAIL-based therapies in humans have certain limitations. The two main therapeutic approaches are based on either an administration of TRAIL-receptor (TRAIL-R) agonists or a recombinant TRAIL. These approaches, however, seem to elicit a limited therapeutic efficacy, and only a few drugs have entered the phase II clinical trials. To deliver TRAIL-based therapies with higher anti-tumor potential several novel TRAIL-derivates and modifications have been designed. These novel drugs are, however, mostly preclinical, and many problems continue to be unraveled. We have reviewed the current status of all TRAIL-based monotherapies and combination therapies that have reached phase II and phase III clinical trials in humans. We have also aimed to introduce all novel approaches of TRAIL utilization in cancer treatment and discussed the most promising drugs which are likely to enter clinical trials in humans. To date, different strategies were introduced in order to activate anti-tumor immune responses with the aim of achieving the highest efficacy and minimal toxicity.In this review, we discuss the most promising TRAIL-based clinical trials and their therapeutic strategies.

Keywords: TRAIL clinical trials; TRAIL-receptor agonists; cancer; dulanermin; mapatumumab; recombinant TRAIL.

PubMed Disclaimer

Conflict of interest statement

JB is a part‐time employee and a minority shareholder of SOTIO a.s., a biotech company developing cell-based immunotherapy. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
TRAIL signaling pathway. TRAIL binds to TRAIL-R1, R2, DcR1 and DcR2 receptors with a similarly high affinity. Death receptors TRAIL-R1 and TRAIL-R2 contain a conserved death domain (DD) motif and thus, binding of TRAIL transmits the apoptotic signal by causing a trimerization of the receptor and a formation of the death-inducing signaling complex (DISC). The recruitment of an adaptor molecule, FADD, is associated with the DISC formation and a subsequent binding and activation of caspases 8 and 10. This process allows the activation of other effector caspases, including the executor caspases, caspase-3 and caspase-7, triggering the final steps of apoptosis. TRAIL is known to trigger the extrinsic apoptotic pathway, while multiple other stimuli, such as chemotherapeutic agents or stimuli causing the DNA damage or ER stress, trigger the intrinsic (mitochondrial) apoptotic pathway. Depending on the cellular context, both intracellular inhibitors, such as c-FLIP and Nf-kB, and extracellular inhibitors, such as TRAILshort and DcR1/2 can restrain the caspase activation and contribute to the resistance to TRAIL-induced cell death.
See this image and copyright information in PMC

References

    1. Aboulnasr F., Krogman A., Graham R. P., Cummins N. W., Misra A., Garcia-Rivera E., et al. (2020). Human cancers express TRAILshort, a dominant negative TRAIL splice variant, which impairs immune effector cell killing of tumor cells. Clin. Cancer Res. 26 (21), 5759–5771. 10.1158/1078-0432.CCR-20-0251 - DOI - PMC - PubMed
    1. Calvo E., de Jonge M. J. A., Rasco D. W., Moreno V., Chang Y.-W., Chiney M., et al. (2019). First-in-human study of ABBV-621 in patients (pts) with previously treated sold tumours: dose-optimization cohorts. Ann. Oncol. 30, v169–v170. 10.1093/annonc/mdz244.019 - DOI
    1. Cheah C. Y., Belada D., Fanale M. A., Janikova A., Czucman M. S., Flinn I. W., et al. (2015). Dulanermin with rituximab in patients with relapsed indolent B-cell lymphoma: an open-label phase 1b/2 randomised study. Lancet Haematol. 2 (4), e166–e174. 10.1016/S2352-3026(15)00026-5 - DOI - PubMed
    1. Chen W., Qiu L., Hou J., Zhao Y., Pan L., Yang S., et al. (2012). Recombinant circularly permuted TRAIL (CPT) for the treatment of relapsed or refractory multiple myeloma: an open-label, multicenter phase II clinical trial. Blood. 120 (21), 78. 10.1182/blood.v120.21.78.78 - DOI
    1. Chuntharapai A., Dodge K., Grimmer K., Schroeder K., Marsters S. A., Koeppen H., et al. (2001). Isotype-dependent inhibition of tumor growth in vivo by monoclonal antibodies to death receptor 4. J. Immunol. 166 (8), 4891–4898. 10.4049/jimmunol.166.8.4891 - DOI - PubMed