|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 25, No 11 (April 10), 2007: pp. 1305-1307 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.9804
On the TRAIL Toward Death Receptor–Based Cancer TherapeuticsDepartment of Pathology and Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL Identifying targeted agents capable of selectively inducing death of cancer cells, while sparing normal host cells, has been the ultimate goal of cancer therapeutic drug development. In the late 1980s, monoclonal antibodies (mAbs) that were found to have antitumor activity via induction of tumor cell apoptosis were developed by several laboratories.1,2 These mAbs were found to ligate a tumor necrosis factor (TNF) receptor family member named Fas (APO-1/CD95), and investigation into the biochemical mechanism by which anti-Fas Abs induce cell death has revealed incredible detail regarding the apoptotic machinery.3 Unfortunately, agonistic antimurine Fas mAbs, when tested in preclinical models in vivo, were extremely toxic, because of rapid induction of hepatocyte apoptosis.4 In addition, a critical role for Fas/FasL interactions in the regulation of T-cell homeostasis was uncovered through genetic analyses of the autoimmune-prone mouse strains Lpr and Gld.5 It was, therefore, not possible to move nonspecific Fas-based therapeutics into the clinical arena, although engagement of Fas on tumor cells by Fas ligand expressed by specific CD8+ T cells can promote tumor cell death in an antigen-specific fashion,6 and alterations in Fas signaling pathways in cancer have been reported to contribute to tumor cell resistance to immune-mediated destruction.7 These observations support the notion that Fas engagement still may be an important component of antitumor immune effector mechanisms in patients. An additional TNF family member that also could promote apoptosis of tumor cells, called TNF-related apoptosis-inducing ligand (TRAIL), was subsequently identified. TRAIL can interact with five distinct receptors, two of which are death receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5). Ligation of these receptors initiates a caspase-driven apoptotic pathway that is similar to what is induced through Fas.8 In contrast to FasL-deficient mice, TRAIL-deficient mice generated by gene targeting do not show global perturbation in T-cell development and homeostasis.9 Preclinical in vivo experiments of tumor growth in TRAIL-deficient mice (or in mice with endogenous TRAIL blocked) indicated a critical role in immune surveillance, because increased susceptibility to tumor formation—both spontaneously and in response to carcinogens—was observed.10-12 Constitutive expression of TRAIL receptors has been observed in a wide variety of human tumor types. These observations thus provided a sound rationale for the development of therapeutic agents that engage or mimic the TRAIL pathway on cancer cells. Several approaches have been explored to target TRAIL receptors therapeutically. One avenue of research has been the use of trimeric TRAIL itself as a recombinant natural ligand. Preclinical mouse models have shown effective antitumor activity in vivo, without significant toxicity.13-15 However, clinical development was stalled when hepatotoxicity was observed with some TRAIL preparations. It was subsequently determined that hepatocyte apoptosis occurred only with polyhistidine-tagged versions of recombinant TRAIL, a manufacturing artifact that could be avoided, which then reopened the door toward clinical application.16 In addition to TRAIL itself, an alternative therapeutic strategy is based on agonistic mAbs that specifically target the TRAIL receptors DR4 or DR5. The existence of decoy receptors that can bind TRAIL, yet not deliver a death signal, suggests a potential disadvantage of using the recombinant ligand and indicates a theoretical advantage to the use of specific anti-DR4 or -DR5 mAbs. All of these strategies are currently in clinical testing. In this issue of the Journal of Clinical Oncology, Tolcher et al17 report a phase I clinical trial of a fully human mAb against human TRAIL-R1/DR4. A careful dose escalation was performed, in which patients first received a single dose of mAb, which was an important step for safety concerns, given the potential for hepatotoxicity. The dose and frequency of administration were increased to 10 mg/kg every 14 days. A terminal half-life (t1/2ß) of 18 days was observed, suggesting that dosing every 2 to 3 weeks is a reasonable schedule. The concentration of anti-TRAIL-R1 mAb that is effective for tumor apoptosis in vitro is approximately 1 µg/mL, and all dose levels above 1 mg/kg achieved this concentration as a trough level in this phase I study. Importantly, no grade 3 elevations in transaminases and no bilirubin elevation clearly attributable to the drug were observed, although several patients did show grade 1 to 2 transaminase elevation, and two patients with pre-existing liver metastases with elevated transaminase levels at baseline did increase to grade 3. Therefore, although the overwhelming hepatotoxicity previously observed with anti-Fas mAbs in murine studies did not occur, these detectable effects on the liver from this trial warrant caution in moving forward in combination with other anticancer agents having hepatic effects, or in the context of patients receiving hepatotoxic drugs for other indications. There were no global effects on lymphocyte subsets seen in this study. However, recent work has indicated a clear role for the activity of TRAIL in determining whether CD4+ T-cell help for CD8+ T-cell memory is successfully achieved.18 This is a subtle aspect of immune regulation that would not be detected with typical clinical laboratory measures, so observations regarding potential immunosuppressive effects and opportunistic infections, particularly with longer-term administration of this mAb, should continue to be accumulated in future clinical experiments. At the same time, care should be used when considering the optimal timing for combining TRAIL receptor-targeted agents with immunotherapeutic interventions. A recent murine study has shown that promoting initial tumor cell apoptosis with an anti-DR5 mAb combined with administration of immunopotentiating antibodies against CD40 and CD137 could cause complete tumor clearance in a T-cell–dependent fashion,19 indicating that successful combination with immunotherapy can indeed be achieved.
No clinical responses were observed in this phase I trial. Although antitumor activity was not a primary end point of the study, it is important to consider mechanisms of resistance to agents targeting TRAIL receptors. First, immunohistochemistry for TRAIL-R1 expression was performed in a retrospective fashion on paraffin-embedded tissue, and 13 of 19 samples tested showed expression in at least 10% of tumor cells. The level of receptor expression required for an antitumor effect is not clear, but certainly the patients with tumors that lack TRAIL-R1 expression would not be expected to respond. Second, preclinical experiments utilizing TRAIL mutants that selectively bind either TRAIL-R1 or TRAIL-R2 have suggested that TRAIL-R2 might be the more potent receptor for ligand-induced apoptosis of cancer cells.20 Third, numerous mechanisms of resistance to TRAIL-induced apoptosis that could explain escape from anti-TRAIL-R1–mediated death have been reported. These include overexpression of Bcl-2 family proteins, deletion of the Bax gene, upregulated Akt and nuclear factor kappa B (NF- Early results from clinical trials of other TRAIL receptor–targeted agents were reported at the 2006 Annual Meeting of the American Society of Clinical Oncology (June 2-6, Atlanta, GA). A phase I trial of an anti-TRAIL-R2/DR5 mAb, in which one patient with chemotherapy-refractory Hodgkin's disease experienced a clinical response, was presented (abstract 3012). A combination trial of carboplatin and paclitaxel with anti-TRAIL-R1 mAb was reported, which demonstrated the feasibility of delivering this combination and showed at least four clinical responses (abstract 2515). Early results of a study using recombinant TRAIL itself, in which one patient with a chondrosarcoma demonstrated a partial response, were also presented (abstract 3013). Importantly, no major dose-limiting toxicities were reported in any of these trials, suggesting that the period of anxiety over possible life-threatening toxicities with TRAIL receptor–targeted therapies in patients is now firmly behind us. The main goals ahead with these agents will be increasing our understanding of the biologic mechanisms underlying tumor response versus resistance, pursuing logical combinations that counter these resistance mechanisms, and considering appropriate patient selection to enrich for a responsive population. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author indicated no potential conflicts of interest. REFERENCES
1. Trauth BC, Klas C, Peters AM, et al: Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science 245:301-305, 1989 2. Yonehara S, Ishii A, Yonehara M: A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-downregulated with the receptor of tumor necrosis factor. J Exp Med 169:1747-1756, 1989 3. Peter ME, Krammer PH: Mechanisms of CD95 (APO-1/Fas)-mediated apoptosis. Curr Opin Immunol 10:545-551, 1998[CrossRef][Medline] 4. Ogasawara J, Watanabe-Fukunaga R, Adachi M, et al: Lethal effect of the anti-Fas antibody in mice. Nature 364:806-809, 1993[CrossRef][Medline] 5. Nagata S, Suda T: Fas and Fas ligand: Lpr and gld mutations. Immunol Today 16:39-43, 1995[CrossRef][Medline] 6. Kagi D, Vignaux F, Ledermann B, et al: Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity. Science 265:528-530, 1994 7. Liu K, Caldwell SA, Abrams SI: Immune selection and emergence of aggressive tumor variants as negative consequences of Fas-mediated cytotoxicity and altered IFN-gamma-regulated gene expression. Cancer Res 65:4376-4388, 2005 8. Schulze-Osthoff K, Ferrari D, Los M, et al: Apoptosis signaling by death receptors. Eur J Biochem 254:439-459, 1998[Medline] 9. Cretney E, Uldrich AP, Berzins SP, et al: Normal thymocyte negative selection in TRAIL-deficient mice. J Exp Med 198:491-496, 2003 10. Cretney E, Takeda K, Yagita H, et al: Increased susceptibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice. J Immunol 168:1356-1361, 2002 11. Takeda K, Smyth MJ, Cretney E, et al: Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development. J Exp Med 195:161-169, 2002 12. Zerafa N, Westwood JA, Cretney E, et al: Cutting edge: TRAIL deficiency accelerates hematological malignancies. J Immunol 175:5586-5590, 2005 13. Xiang H, Nguyen CB, Kelley SK, et al: Tissue distribution, stability, and pharmacokinetics of Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand in human colon carcinoma COLO205 tumor-bearing nude mice. Drug Metab Dispos 32:1230-1238, 2004 14. Hylander BL, Pitoniak R, Penetrante RB, et al: The anti-tumor effect of Apo2L/TRAIL on patient pancreatic adenocarcinomas grown as xenografts in SCID mice. J Transl Med 3:22, 2005[CrossRef][Medline] 15. Hao C, Song JH, Hsi B, et al: TRAIL inhibits tumor growth but is nontoxic to human hepatocytes in chimeric mice. Cancer Res 64:8502-8506, 2004 16. Lawrence D, Shahrokh Z, Marsters S, et al: Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions. Nat Med 7:383-385, 2001[CrossRef][Medline] 17. Tolcher AW, Mita M, Meropol NJ, et al: Phase I pharmacokinetic and biologic correlative study of mapatumumab, a fully human monoclonal antibody with agonist activity to tumor necrosis factor-related apoptosis-inducing ligand receptor-1. J Clin Oncol 25:1390-1395, 2007 18. Janssen EM, Droin NM, Lemmens EE, et al: CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death. Nature 434:88-93, 2005[CrossRef][Medline] 19. Uno T, Takeda K, Kojima Y, et al: Eradication of established tumors in mice by a combination antibody-based therapy. Nat Med 12:693-698, 2006[CrossRef][Medline] 20. Kelley RF, Totpal K, Lindstrom SH, et al: Receptor-selective mutants of apoptosis-inducing ligand 2/tumor necrosis factor-related apoptosis-inducing ligand reveal a greater contribution of death receptor (DR) 5 than DR4 to apoptosis signaling. J Biol Chem 280:2205-2212, 2005 21. Vogler M, Durr K, Jovanovic M, et al: Regulation of TRAIL-induced apoptosis by XIAP in pancreatic carcinoma cells. Oncogene 26:248-257, 2007[CrossRef][Medline] 22. Khanbolooki S, Nawrocki ST, Arumugam T, et al: Nuclear factor-kappaB maintains TRAIL resistance in human pancreatic cancer cells. Mol Cancer Ther 5:2251-2260, 2006 23. Cheng J, Hylander BL, Baer MR, et al: Multiple mechanisms underlie resistance of leukemia cells to Apo2 Ligand/TRAIL. Mol Cancer Ther 5:1844-1853, 2006 24. Zhu H, Guo W, Zhang L, et al: Enhancing TRAIL-induced apoptosis by Bcl-X(L) siRNA. Cancer Biol Ther 4:393-397, 2005[Medline] 25. Yang LQ, Fang DC, Wang RQ, et al: Effect of NF-kappaB, survivin, Bcl-2 and Caspase3 on apoptosis of gastric cancer cells induced by tumor necrosis factor related apoptosis inducing ligand. World J Gastroenterol 10:22-25, 2004[Medline] 26. Zhang XD, Borrow JM, Zhang XY, et al: Activation of ERK1/2 protects melanoma cells from TRAIL-induced apoptosis by inhibiting Smac/DIABLO release from mitochondria. Oncogene 22:2869-2881, 2003[CrossRef][Medline] 27. Chawla-Sarkar M, Bae SI, Reu FJ, et al: Downregulation of Bcl-2, FLIP or IAPs (XIAP and survivin) by siRNAs sensitizes resistant melanoma cells to Apo2L/TRAIL-induced apoptosis. Cell Death Differ 11:915-923, 2004[CrossRef][Medline] 28. Fulda S, Meyer E, Debatin KM: Inhibition of TRAIL-induced apoptosis by Bcl-2 overexpression. Oncogene 21:2283-2294, 2002[CrossRef][Medline] 29. Kandasamy K, Srivastava RK: Role of the phosphatidylinositol 3'-kinase/PTEN/Akt kinase pathway in tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in non-small cell lung cancer cells. Cancer Res 62:4929-4937, 2002 30. Hopkins-Donaldson S, Bodmer JL, Bourloud KB, et al: Loss of caspase-8 expression in neuroblastoma is related to malignancy and resistance to TRAIL-induced apoptosis. Med Pediatr Oncol 35:608-611, 2000[CrossRef][Medline] 31. Han J, Goldstein LA, Gastman BR, et al: Differential involvement of Bax and Bak in TRAIL-mediated apoptosis of leukemic T cells. Leukemia 18:1671-1680, 2004[CrossRef][Medline] 32. Muhlethaler-Mottet A, Flahaut M, Bourloud KB, et al: Histone deacetylase inhibitors strongly sensitise neuroblastoma cells to TRAIL-induced apoptosis by a caspases-dependent increase of the pro- to anti-apoptotic proteins ratio. BMC Cancer 6:214, 2006[CrossRef][Medline] 33. La Ferla-Bruhl K, Westhoff MA, Karl S, et al: NF-kappaB-independent sensitization of glioblastoma cells for TRAIL-induced apoptosis by proteasome inhibition. Oncogene 26:571-582, 2007[CrossRef][Medline] 34. Zhu H, Guo W, Zhang L, et al: Proteasome inhibitors-mediated TRAIL resensitization and Bik accumulation. Cancer Biol Ther 4:781-786, 2005[Medline] 35. Singh TR, Shankar S, Srivastava RK: HDAC inhibitors enhance the apoptosis-inducing potential of TRAIL in breast carcinoma. Oncogene 24:4609-4623, 2005[CrossRef][Medline] 36. Panner A, James CD, Berger MS, et al: mTOR controls FLIPS translation and TRAIL sensitivity in glioblastoma multiforme cells. Mol Cell Biol 25:8809-8823, 2005 37. Zhu H, Zhang L, Huang X, et al: Overcoming acquired resistance to TRAIL by chemotherapeutic agents and calpain inhibitor I through distinct mechanisms. Mol Ther 9:666-673, 2004[CrossRef][Medline] 38. Xiang H, Fox JA, Totpal K, et al: Enhanced tumor killing by Apo2L/TRAIL and CPT-11 co-treatment is associated with p21 cleavage and differential regulation of Apo2L/TRAIL ligand and its receptors. Oncogene 21:3611-3619, 2002[CrossRef][Medline] 39. Shankar S, Singh TR, Chen X, et al: The sequential treatment with ionizing radiation followed by TRAIL/Apo-2L reduces tumor growth and induces apoptosis of breast tumor xenografts in nude mice. Int J Oncol 24:1133-1140, 2004[Medline] 40. Panner A, Parsa AT, Pieper RO: Use of APO2L/TRAIL with mTOR inhibitors in the treatment of glioblastoma multiforme. Expert Rev Anticancer Ther 6:1313-1322, 2006[CrossRef][Medline]
Related Correspondence
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
B) signaling, increased XIAP expression, and caspase mutations, among others.
