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Journal of Clinical Oncology, Vol 25, No 28 (October 1), 2007: pp. 4505-4506 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.1011
Barriers to Effective TRAIL-Targeted Therapy of MalignancyMedical Research Council Toxicology Unit, Leicester, United Kingdom To the Editor: We read with interest the report1 and the accompanying editorial2 in the Journal of Clinical Oncology about the use of tumor necrosis factor–related apoptosis inducing ligand (TRAIL)-R1 receptor monoclonal antibody (MAb) mapatumumab in patients with advanced malignancy. Following on from the serious adverse events observed with the CD28 agonistic MAb, it is encouraging to see that a TRAIL agonistic MAb can be administered at such high doses without significant adverse consequences. We note that mapatumumab and other TRAIL receptor MAbs and TRAIL ligands are now undergoing clinical assessment alone and in combination with chemotherapy. However, we consider that these studies overlook a number of significant biologic and clinical problems. Firstly, the optimal conditions for the use of these reagents have not been defined. Although many derived human tumor cell lines are sensitive to TRAIL-mediated apoptosis, many primary tumor cells may in fact be totally resistant, despite expressing the necessary receptors. In our own experience with B-cell malignancies, in particular chronic lymphocytic leukemia (CLL), we have not detected significant sensitivity to TRAIL-mediated apoptosis in any case (n = 109).3,4 This resistance applies to apoptosis induced not only by wild type TRAIL ligand, but also to agonistic MAbs specific for TRAIL-R1 and TRAIL-R2, as well as soluble receptor-specific ligands for TRAIL-R1 and TRAIL-R2.3-6 To date, few studies have been carried out using primary cells from human solid tumors. However, it has been shown that most but not all primary malignant glioma cells are similarly resistant to TRAIL-mediated apoptosis, although they could be sensitized to TRAIL by proteasomal inhibition.7,8 Furthermore, these authors also concluded that TRAIL sensitivity of tumor cell lines does not reliably predict the response of primary cells.8 Isolated cells from medulloblastoma and meningioma were also TRAIL resistant.9 To date, it would therefore appear that many primary tumor cells are resistant to TRAIL, so necessitating the use of some form of combination therapy. Inherent tumor resistance may be a major barrier to effective TRAIL-targeted therapy. The mechanisms underlying this resistance remain unknown, but in CLL cells, formation of the death initiating signaling complex may be limiting.3,4 Until the mechanisms of resistance are better understood, it is difficult to resolve this problem rationally, but we have found empirically that prior exposure to specific histone deacetylase inhibitors at low (nanomolar), and hopefully nontoxic concentrations, results in necessary sensitization in many instances.4,5,6,10 However, this has revealed a further unanticipated level of complexity, namely that malignant cells may express both forms of death-signaling TRAIL receptors at the cell surface, but signal to apoptosis through only one receptor and not the other. In the case of B-cell malignancies, selective induction of apoptosis via the TRAIL-R1 pathway has been observed with mapatumumab but not lexatumumab (an agonistic TRAIL-R2 MAb), and with TRAIL-R1 but not TRAIL-R2 receptor-specific TRAIL mutants.5,6 Importantly, sensitivity could not be predicted from the levels of receptor expression. TRAIL receptors are often expressed only at very low levels at the cell surface of malignant B cells and may be difficult to detect by flow cytometry. It is not clear how many receptors need to be successfully engaged by either agonistic MAbs or soluble TRAIL ligands to induce apoptosis, but once sensitized, low levels of either may be sufficient. Finally, it is noteworthy that no significant clinical response to mapatumumab was observed in any of the patients reported by Tolcher et al, despite serum levels of MAb that would have been anticipated to have been effective. (It should be noted that low levels of mapatumumab will be circulating in these patients for many months to come and therefore potential interactions with other drugs should be monitored.) Trials combining mapatumumab and other TRAIL-targeting MAbs and ligands with chemotherapy are now being undertaken. The rationale underlying such combinations has been based on the use of preclinical xenograft murine models utilizing sensitive human tumor cell lines and a human or mouse MAb to the human TRAIL receptors. However, as noted earlier, derived tumor cell lines may not reflect the resistance of most primary human malignancies and are therefore not likely to be predictive of clinical responses. Moreover, it is possible that the combination of chemotherapy and TRAIL agonistic MAbs may result in unanticipated toxicities in man. The major concern with all therapies targeting the TRAIL pathway remains hepatotoxicity. Prior to entering the clinic, it is important to assess the potential hepatotoxicity of combinations of TRAIL agonistic MAbs and chemotherapy drugs in models that most closely mimic the in vivo situation. We currently lack a good preclinical model with which to assess such combinations. Mouse models may not be adequate since there is only one TRAIL receptor in this species. In summary, we suspect that many significant barriers remain before we can successfully target the TRAIL pathway for therapy of malignant disease. MAbs that exert significant functional activity differ fundamentally from most MAbs used routinely in clinical practice today and should be used under carefully defined conditions in order to avoid toxicities. For most MAbs, the only necessary prerequisite before clinical use is to demonstrate expression by immunohistochemistry. These standards will not suffice for functional MAbs; it may be necessary to document induction of apoptosis in vitro before commencing therapy. Our data indicate that some form of sensitization to TRAIL-pathway mediated apoptosis will be required. Whether sensitization to TRAIL-targeted apoptosis in malignant cells can be successfully dissociated from sensitization of normal cells to the same apoptotic cascade remains to be determined. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. 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 2. Gajewski TF: On the TRAIL toward death receptor-based cancer therapeutics. J Clin Oncol 25:1305-1307, 2007 3. MacFarlane M, Harper N, Snowden RT, et al: Mechanisms of resistance to TRAIL-induced apoptosis in primary B cell chronic lymphocytic leukaemia. Oncogene 21:6809-6818, 2002[CrossRef][Medline] 4. Inoue S, MacFarlane M, Harper N, et al: Histone deacetylase inhibitors potentiate TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in lymphoid malignancies. Cell Death Differ 11:S193-206, 2004 (suppl 2) 5. MacFarlane M, Inoue S, Kohlhaas SL, et al: Chronic lymphocytic leukemic cells exhibit apoptotic signaling via TRAIL-R1. Cell Death Differ 12:773-782, 2005[CrossRef][Medline] 6. MacFarlane M, Kohlhaas SL, Sutcliffe MJ, et al: TRAIL receptor-selective mutants signal to apoptosis via TRAIL-R1 in primary lymphoid malignancies. Cancer Res 65:11265-11270, 2005 7. 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 8. Koschny R, Holland H, Sykora J, et al: Bortezomib sensitizes primary human astrocytoma cells of WHO grades I to IV for tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Clin Cancer Res 13:3403-3412, 2007 9. Koschny R, Walczak H, Ganten TM: The promise of TRAIL: Potential and risks of a novel anticancer therapy. J Mol Med doi:10.1007/s00109-007-0194-1 10. Inoue S, Mai A, Dyer MJS, et al: Inhibition of histone deacetylase class I but not class II is critical for the sensitization of leukemic cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Cancer Res 66:6785-6792, 2006 Related Articles
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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