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.

3rd Department of Surgery 1st Faculty of Medicine Charles University and University Hospital Motol Prague Czechia

Department of Immunology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czechia

Department of Urology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czechia

See more in PubMed

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 PubMed DOI PMC

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

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 PubMed DOI

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

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 PubMed DOI

Cohn A. L., Tabernero J., Maurel J., Nowara E., Sastre J., Chuah B. Y. S. (2013). A randomized, placebo-controlled phase 2 study of ganitumab or conatumumab in combination with FOLFIRI for second-line treatment of mutant metastatic colorectal cancer. Ann. Oncol. 24 (7), 1777–1785. 10.1093/annonc/mdt057 PubMed DOI

Dai X., Zhang J., Arfuso F., Chinnathambi A., Zayed M. E., Alharbi S. A., et al. (2015). Targeting TNF-related apoptosis-inducing ligand (TRAIL) receptor by natural products as a potential therapeutic approach for cancer therapy. Exp. Biol. Med. 240 (6), 760–773. 10.1177/1535370215579167 PubMed DOI PMC

de Miguel D., Lemke J., Anel A., Walczak H., Martinez-Lostao L. (2016). Onto better TRAILs for cancer treatment. Cell Death Differ 23 (5), 733–747. 10.1038/cdd.2015.174 PubMed DOI PMC

Dobson C. L., Main S., Newton P., Chodorge M., Cadwallader K., Humphreys R., et al. (2009). Human monomeric antibody fragments to TRAIL-R1 and TRAIL-R2 that display potent in vitro agonism. mAbs. 1 (6), 552–562. 10.4161/mabs.1.6.10057 PubMed DOI PMC

Dubuisson A., Micheau O. (2017). Antibodies and derivatives targeting DR4 and DR5 for cancer therapy. Antibodies 6 (4).16. 10.3390/antib6040016 PubMed DOI PMC

Dufva O., Koski J., Maliniemi P., Ianevski A., Klievink J., Leitner J., et al. (2020). Integrated drug profiling and CRISPR screening identify essential pathways for CAR T-cell cytotoxicity. Blood. 135 (9), 597–609. 10.1182/blood.2019002121 PubMed DOI PMC

Ehrlich S., Infante-Duarte C., Seeger B., Zipp F. (2003). Regulation of soluble and surface-bound TRAIL in human T cells, B cells, and monocytes. Cytokine. 24 (6), 244–253. 10.1016/s1043-4666(03)00094-2 PubMed DOI

Elmore S. (2007). Apoptosis: a review of programmed cell death. Toxicol. Pathol. 35 (4), 495–516. 10.1080/01926230701320337 PubMed DOI PMC

Fang F., Wang A. P., Yang S. F. (2005). Antitumor activity of a novel recombinant mutant human tumor necrosis factor-related apoptosis-inducing ligand. Acta Pharmacol. Sin. 26 (11), 1373–1381. 10.1111/j.1745-7254.2005.00206.x PubMed DOI

Feins S., Kong W., Williams E. F., Milone M. C., Fraietta J. A. (2019). An introduction to chimeric antigen receptor (CAR) T-cell immunotherapy for human cancer. Am. J. Hematol. 94 (S1), S3–s9. 10.1002/ajh.25418 PubMed DOI

Forero-Torres A., Infante J. R., Waterhouse D., Wong L., Vickers S., Arrowsmith E., et al. (2013). Phase 2, multicenter, open-label study of tigatuzumab (CS-1008), a humanized monoclonal antibody targeting death receptor 5, in combination with gemcitabine in chemotherapy-naive patients with unresectable or metastatic pancreatic cancer. Cancer Med. 2 (6), 925–932. 10.1002/cam4.137 PubMed DOI PMC

Fuchs C. S., Fakih M., Schwartzberg L., Cohn A. L., Yee L., Dreisbach L., et al. (2013). TRAIL receptor agonist conatumumab with modified FOLFOX6 plus bevacizumab for first-line treatment of metastatic colorectal cancer: a randomized phase 1b/2 trial. Cancer 119 (24), 4290–4298. 10.1002/cncr.28353 PubMed DOI

Gasparini C., Vecchi Brumatti L., Monasta L., Zauli G. (2013). TRAIL-based therapeutic approaches for the treatment of pediatric malignancies. Curr. Med. Chem. 20 (17), 2254–2271. 10.2174/0929867311320170009 PubMed DOI

He Y., Hendriks D., van Ginkel R., Samplonius D., Bremer E., Helfrich W. (2016). Melanoma-directed activation of apoptosis using a bispecific antibody directed at MCSP and TRAIL receptor-2/death receptor-5. J. Invest. Dermatol. 136 (2), 541–544. 10.1016/j.jid.2015.11.009 PubMed DOI

Hendriks D., He Y., Koopmans I., Wiersma V. R., van Ginkel R. J., Samplonius D. F., et al. (2016). Programmed Death Ligand 1 (PD-L1)-targeted TRAIL combines PD-L1-mediated checkpoint inhibition with TRAIL-mediated apoptosis induction. Oncoimmunology 5 (8), e1202390. 10.1080/2162402X.2016.1202390 PubMed DOI PMC

Hirata E., Sahai E. (2017). Tumor microenvironment and differential responses to therapy. Cold Spring Harb Perspect. Med. 7 (7), a026781. 10.1101/cshperspect.a026781 PubMed DOI PMC

Jeong G. M., Lee Y. J., Kim Y. S., Jeong K. J. (2014). High-level production of Fc-fused kringle domain in Pichia pastoris. J. Ind. Microbiol. Biotechnol. 41 (6), 989–996. 10.1007/s10295-014-1435-2 PubMed DOI

Kindler H. L., Richards D. A., Garbo L. E., Garon E. B., Stephenson J. J., Jr., Rocha-Lima C. M., et al. (2012). A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer. Ann. Oncol. 23 (11), 2834–2842. 10.1093/annonc/mds142 PubMed DOI

Kobayashi E., Kishi H., Ozawa T., Hamana H., Nakagawa H., Jin A., et al. (2014). A chimeric antigen receptor for TRAIL-receptor 1 induces apoptosis in various types of tumor cells. Biochem. Biophys. Res. Commun. 453 (4), 798–803. 10.1016/j.bbrc.2014.10.024 PubMed DOI

Lemke J., von Karstedt S., Zinngrebe J., Walczak H. (2014). Getting TRAIL back on track for cancer therapy. Cell Death Differ 21 (9), 1350–1364. 10.1038/cdd.2014.81 PubMed DOI PMC

Lim B., Greer Y., Lipkowitz S., Takebe N. (2019). Novel apoptosis-inducing agents for the treatment of cancer, a new arsenal in the toolbox. Cancers 11 (8), 1087. 10.3390/cancers11081087 PubMed DOI PMC

Liu F., Si Y., Liu G., Li S., Zhang J., Ma Y. (2015). The tetravalent anti-DR5 antibody without cross-linking direct induces apoptosis of cancer cells. Biomed. Pharmacother. 70, 41–45. 10.1016/j.biopha.2014.12.024 PubMed DOI

Lopez J., Tait S. W. (2015). Mitochondrial apoptosis: killing cancer using the enemy within. Br. J. Cancer 112 (6), 957–962. 10.1038/bjc.2015.85 PubMed DOI PMC

MacFarlane M., Kohlhaas S. L., Sutcliffe M. J., Dyer M. J., Cohen G. M. (2005). TRAIL receptor-selective mutants signal to apoptosis via TRAIL-R1 in primary lymphoid malignancies. Cancer Res. 65 (24), 11265–11270. 10.1158/0008-5472.CAN-05-2801 PubMed DOI

McCarthy M. M., Sznol M., DiVito K. A., Camp R. L., Rimm D. L., Kluger H. M. (2005). Evaluating the expression and prognostic value of TRAIL-R1 and TRAIL-R2 in breast cancer. Clin. Cancer Res. 11 (14), 5188–5194. 10.1158/1078-0432.CCR-05-0158 PubMed DOI

Medler J., Nelke J., Weisenberger D., Steinfatt T., Rothaug M., Berr S., et al. (2019). TNFRSF receptor-specific antibody fusion proteins with targeting controlled FcγR-independent agonistic activity. Cell Death Dis. 10 (3), 224. 10.1038/s41419-019-1456-x PubMed DOI PMC

Micheau O., Shirley S., Dufour F. (2013). Death receptors as targets in cancer. Br. J. Pharmacol. 169 (8), 1723–1744. 10.1111/bph.12238 PubMed DOI PMC

Mika T., Maghnouj A., Klein-Scory S., Ladigan-Badura S., Baraniskin A., Thomson J., et al. (2020). Digital-droplet PCR for quantification of CD19-directed CAR T-cells. Front. Mol. Biosci. 7, 84. 10.3389/fmolb.2020.00084 PubMed DOI PMC

Min Y. J., Lee J. H., Choi S. J., Chi H. S., Lee J. S., Kim W. K., et al. (2004). Prognostic significance of Fas (CD95) and TRAIL receptors (DR4/DR5) expression in acute myelogenous leukemia. Leuk. Res. 28 (4), 359–365. 10.1016/j.leukres.2003.08.015 PubMed DOI

Nagai H., Kim Y. H. (2017). Cancer prevention from the perspective of global cancer burden patterns. J. Thorac. Dis. 9 (3), 448–451. 10.21037/jtd.2017.02.75 PubMed DOI PMC

Natoni A., MacFarlane M., Inoue S., Walewska R., Majid A., Knee D., et al. (2007). TRAIL signals to apoptosis in chronic lymphocytic leukaemia cells primarily through TRAIL-R1 whereas cross-linked agonistic TRAIL-R2 antibodies facilitate signalling via TRAIL-R2. Br. J. Haematol. 139 (4), 568–577. 10.1111/j.1365-2141.2007.06852.x PubMed DOI

Ouyang X., Shi M., Jie F., Bai Y., Shen P., Yu Z., et al. (2018). Phase III study of dulanermin (recombinant human tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand) combined with vinorelbine and cisplatin in patients with advanced non-small-cell lung cancer. Invest. New Drugs. 36 (2), 315–322. 10.1007/s10637-017-0536-y PubMed DOI

Pal S., Amin P. J., Sainis K. B., Shankar B. S. (2016). Potential role of TRAIL in metastasis of mutant KRAS expressing lung adenocarcinoma. Cancer Microenviron. 9 (2-3), 77–84. 10.1007/s12307-016-0184-3 PubMed DOI PMC

Pan L. Q., Zhao W. B., Lai J., Ding D., Wei X. Y., Li Y. Y., et al. (2015). Hetero-modification of TRAIL trimer for improved drug delivery and in vivo antitumor activities. Sci. Rep. 5 (1), 14872. 10.1038/srep14872 PubMed DOI PMC

Papadopoulos K. P., Isaacs R., Bilic S., Kentsch K., Huet H. A., Hofmann M., et al. (2015). Unexpected hepatotoxicity in a phase I study of TAS266, a novel tetravalent agonistic Nanobody® targeting the DR5 receptor. Cancer Chemother. Pharmacol. 75 (5), 887–895. 10.1007/s00280-015-2712-0 PubMed DOI

Pehlivan K. C., Duncan B. B., Lee D. W. (2018). CAR-T cell therapy for acute lymphoblastic leukemia: transforming the treatment of relapsed and refractory disease. Curr. Hematol. Malig Rep. 13 (5), 396–406. 10.1007/s11899-018-0470-x PubMed DOI

Pieczykolan J. S., Kubiński K., Masłyk M., Pawlak S. D., Pieczykolan A., Rózga P. K., et al. (2014). AD-O53.2--a novel recombinant fusion protein combining the activities of TRAIL/Apo2L and Smac/Diablo, overcomes resistance of human cancer cells to TRAIL/Apo2L. Invest. New Drugs. 32 (6), 1155–1166. 10.1007/s10637-014-0153-y PubMed DOI

Qiu Y., Zhang Z., Shi J., Liu S., Liu Y., Zheng D. (2012). A novel anti-DR5 chimeric antibody and epirubicin synergistically suppress tumor growth. IUBMB Life. 64 (9), 757–765. 10.1002/iub.1064 PubMed DOI

Quintavalle C., Condorelli G. (2012). Dulanermin in cancer therapy: still much to do. Transl. Lung Cancer Res. 1 (2), 158–159. 10.3978/j.issn.2218-6751.2012.02.03 PubMed DOI PMC

Ratain M. J., Doi T., De Jonge M. J., LoRusso P., Dunbar M., Chiney M., et al. (2019). Phase 1, first-in-human study of TRAIL receptor agonist fusion protein ABBV-621. Jco 37 (15), 3013. 10.1200/jco.2019.37.15_suppl.3013 DOI

Reck M., Krzakowski M., Chmielowska E., Sebastian M., Hadler D., Fox T., et al. (2013). A randomized, double-blind, placebo-controlled phase 2 study of tigatuzumab (CS-1008) in combination with carboplatin/paclitaxel in patients with chemotherapy-naïve metastatic/unresectable non-small cell lung cancer. Lung Cancer 82 (3), 441–448. 10.1016/j.lungcan.2013.09.014 PubMed DOI

Schirrmacher V. (2019). From chemotherapy to biological therapy: a review of novel concepts to reduce the side effects of systemic cancer treatment (Review). Int. J. Oncol. 54 (2), 407–419. 10.3892/ijo.2018.4661 PubMed DOI PMC

Soria J. C., Márk Z., Zatloukal P., Szima B., Albert I., Juhász E., et al. (2011). Randomized phase II study of dulanermin in combination with paclitaxel, carboplatin, and bevacizumab in advanced non-small-cell lung cancer. J. Clin. Oncol. 29 (33), 4442–4451. 10.1200/JCO.2011.37.2623 PubMed DOI

Surget S., Chiron D., Gomez-Bougie P., Descamps G., Ménoret E., Bataille R., et al. (2012). Cell death via DR5, but not DR4, is regulated by p53 in myeloma cells. Cancer Res. 72 (17), 4562–4573. 10.1158/0008-5472.CAN-12-0487 PubMed DOI

von Karstedt S., Walczak H. (2020). An unexpected turn of fortune: targeting TRAIL-Rs in KRAS-driven cancer. Cell Death Discov. 6 (1), 14. 10.1038/s41420-020-0249-4 PubMed DOI PMC

Wajant H. (2019). Molecular mode of action of TRAIL receptor agonists-common principles and their translational exploitation. Cancers 11 (7). 10.3390/cancers11070954 PubMed DOI PMC

Wajant H. (2004). TRAIL and NFkappaB signaling--a complex relationship. Vitam Horm. 67, 101–132. 10.1016/S0083-6729(04)67007-5 PubMed DOI

Willms A., Schittek H., Rahn S., Sosna J., Mert U., Adam D., et al. (2019). Impact of p53 status on TRAIL-mediated apoptotic and non-apoptotic signaling in cancer cells. PLoS One 14 (4), e0214847. 10.1371/journal.pone.0214847 PubMed DOI PMC

Yang J., Leblanc F. R., Dighe S., Nyland S. B., Feith D. J., Loughran T. P., Jr (2016). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediates and sustains NF-κb constitutive activation in LGL leukemia cells. Blood 128 (22), 2762. 10.1182/blood.v128.22.2762.2762 DOI

Younes A., Vose J. M., Zelenetz A. D., Smith M. R., Burris H. A., Ansell S. M., et al. (2010). A Phase 1b/2 trial of mapatumumab in patients with relapsed/refractory non-Hodgkin's lymphoma. Br. J. Cancer 103 (12), 1783–1787. 10.1038/sj.bjc.6605987 PubMed DOI PMC

Yuan X., Gajan A., Chu Q., Xiong H., Wu K., Wu G. S. (2018). Developing TRAIL/TRAIL death receptor-based cancer therapies. Cancer Metastasis Rev. 37 (4), 733–748. 10.1007/s10555-018-9728-y PubMed DOI PMC

Zhang H. Y., Man J. H., Liang B., Zhou T., Wang C. H., Li T., et al. (2010). Tumor-targeted delivery of biologically active TRAIL protein. Cancer Gene Ther. 17 (5), 334–343. 10.1038/cgt.2009.76 PubMed DOI PMC

Zhang Y., Zhang Z. (2020). The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol. Immunol. 17 (8), 807–821. 10.1038/s41423-020-0488-6 PubMed DOI PMC

Harnessing p53 for targeted cancer therapy: new advances and future directions