DLL3: an emerging target in small cell lung cancer

Dwight H Owen, Michael J Giffin, Julie M Bailis, Marie-Anne Damiette Smit, David P Carbone, Kai He, Dwight H Owen, Michael J Giffin, Julie M Bailis, Marie-Anne Damiette Smit, David P Carbone, Kai He

Abstract

Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers. Despite high rates of response to first-line chemotherapy and radiotherapy, patients with extensive-stage disease eventually relapse, and very few patients survive more than 5 years from diagnosis. Treatment options for recurrent or refractory disease are limited, and the treatments that do exist are associated with significant treatment-related toxicities. Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is highly expressed in SCLC and other neuroendocrine tumors but minimally expressed in normal tissues. It is therefore being explored as a potential therapeutic target in SCLC. Here, we review the preclinical and clinical evidence for targeting DLL3 in SCLC and discuss several DLL3-specific therapies being developed for the treatment of SCLC: the antibody-drug conjugate rovalpituzumab tesirine, the bispecific T cell engager immuno-oncology therapy AMG 757, and the chimeric antigen receptor T cell therapy AMG 119.

Keywords: Antibody-drug conjugate (ADC); Bispecific T cell engager (BiTE®) antibody construct; Chimeric antigen receptor (CAR) T cell therapy; Delta-like ligand 3 (DLL3); Immuno-oncology therapy; Neuroendocrine; Small cell lung cancer (SCLC); Targeted therapy.

Conflict of interest statement

M.J.G. and J.M.B. are employed by and hold shares in Amgen Inc. M-A.D.S. is employed by Amgen Inc. D.H.O. and K.H. declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
DLL3-targeted investigational products utilize distinct mechanisms of action. a Rovalpituzumab tesirine is a DLL3-targeted antibody-drug conjugate (ADC) that consists of a humanized DLL3-specific IgG1 monoclonal antibody, a pyrrolobenzodiazepine (PDB) dimer toxin, and a protease-cleavable linker that covalently links the antibody to the toxin. Internalization of the ADC to lysosomes leads to the cleavage of the linker, release of the toxin, and apoptosis. b AMG 757 is a half-life extended bispecific T cell engager (HLE BiTE®) antibody construct that consists of a single-chain (sc) Fv domain that binds DLL3, an scFv domain that binds CD3ε (an invariable part of the T cell receptor complex), and a fragment crystallizable (Fc) region. AMG 757 is designed to transiently connect DLL3-positive cells to CD3-positive T cells and induce serial lysis of tumor cells and concomitant proliferation of T cells. c AMG 119 is an adoptive cellular therapy that consists of a patient’s own T cells that have been genetically modified ex vivo to express a chimeric antigen receptor (CAR) that targets DLL3 and redirects cytotoxic T cells to DLL3-positive cells. AMG 119 is designed to expand and persist in vivo and induce apoptosis of tumor cells

References

    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30. doi: 10.3322/caac.21442.
    1. Hirsch FR, Suda K, Wiens J, Bunn PA., Jr New and emerging targeted treatments in advanced non-small-cell lung cancer. Lancet. 2016;388(10048):1012–1024. doi: 10.1016/S0140-6736(16)31473-8.
    1. Powell HA, Tata LJ, Baldwin DR, Potter VA, Stanley RA, Khakwani A, et al. Treatment decisions and survival for people with small-cell lung cancer. Br J Cancer. 2014;110(4):908–915. doi: 10.1038/bjc.2013.812.
    1. Horn L, Mansfield AS, Szczesna A, Havel L, Krzakowski M, Hochmair MJ, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379(23):2220–2229. doi: 10.1056/NEJMoa1809064.
    1. Genentech, Inc. Tecentriq (atezolizumab) [package insert]. U.S. Food and Drug Administration . Revised June 2018.
    1. Byers LA, Rudin CM. Small cell lung cancer: where do we go from here? Cancer. 2015;121(5):664–672. doi: 10.1002/cncr.29098.
    1. Koinis F, Agelaki S, Karavassilis V, Kentepozidis N, Samantas E, Peroukidis S, et al. Second-line pazopanib in patients with relapsed and refractory small-cell lung cancer: a multicentre phase II study of the Hellenic Oncology Research Group. Br J Cancer. 2017;117(1):8–14. doi: 10.1038/bjc.2017.137.
    1. Gadgeel SM, Pennell NA, Fidler MJ, Halmos B, Bonomi P, Stevenson J, et al. Phase II study of maintenance pembrolizumab in patients with extensive-stage small cell lung cancer (SCLC) J Thorac Oncol. 2018;13(9):1393–1399. doi: 10.1016/j.jtho.2018.05.002.
    1. Saito M, Shiraishi K, Goto A, Suzuki H, Kohno T, Kono K. Development of targeted therapy and immunotherapy for treatment of small cell lung cancer. Jpn J Clin Oncol. 2018;48(7):603–608. doi: 10.1093/jjco/hyy068.
    1. Bristol-Myers Squibb. Opdivo (nivolumab) [package insert]. U.S. Food and Drug Administration . Revised April 2018.
    1. Ready N, Farago AF, de Braud F, Atmaca A, Hellmann MD, Schneider JG, et al. Third-line nivolumab monotherapy in recurrent SCLC: CheckMate 032. J Thorac Oncol. 2019;14(2):237–244. doi: 10.1016/j.jtho.2018.10.003.
    1. Reck M, Vicente D, Ciuleanu T, Gettinger S, Peters S, Horn L, et al. Efficacy and safety of nivolumab (nivo) monotherapy versus chemotherapy (chemo) in recurrent small cell lung cancer (SCLC): results from CheckMate 331. Ann Oncol. 2018;29(suppl_10). 10.1093/annonc/mdy511.004
    1. Owonikoko TK, Kim HR, Govindan R, Ready N, Reck M, Peters S, et al. Nivolumab (nivo) plus ipilimumab (ipi), nivo, or placebo (pbo) as maintenance therapy in patients (pts) with extensive disease small cell lung cancer (ED-SCLC) after first-line (1L) platinum-based chemotherapy (chemo): Results from the double-blind, randomized phase III CheckMate 451 study. Annals of Oncology. 2019;30(Supplement_2):mdz094.
    1. Kalemkerian GP, Akerley W, Bogner P, Borghaei H, Chow LQ, Downey RJ, et al. Small cell lung cancer. J Natl Compr Cancer Netw. 2013;11(1):78–98. doi: 10.6004/jnccn.2013.0011.
    1. von Pawel J, Jotte R, Spigel DR, O'Brien ME, Socinski MA, Mezger J, et al. Randomized phase III trial of amrubicin versus topotecan as second-line treatment for patients with small-cell lung cancer. J Clin Oncol. 2014;32(35):4012–4019. doi: 10.1200/JCO.2013.54.5392.
    1. Pietanza MC, Waqar SN, Krug LM, Dowlati A, Hann CL, Chiappori A, et al. Randomized, double-blind, phase II study of temozolomide in combination with either veliparib or placebo in patients with relapsed-sensitive or refractory small-cell lung cancer. J Clin Oncol. 2018;36(23):2386–2394. doi: 10.1200/JCO.2018.77.7672.
    1. Morimoto M, Nishinakamura R, Saga Y, Kopan R. Different assemblies of notch receptors coordinate the distribution of the major bronchial Clara, ciliated and neuroendocrine cells. Development. 2012;139(23):4365–4373. doi: 10.1242/dev.083840.
    1. Bray SJ. Notch signalling in context. Nat Rev Mol Cell Biol. 2016;17(11):722–735. doi: 10.1038/nrm.2016.94.
    1. Sabari JK, Lok BH, Laird JH, Poirier JT, Rudin CM. Unravelling the biology of SCLC: implications for therapy. Nat Rev Clin Oncol. 2017;14(9):549–561. doi: 10.1038/nrclinonc.2017.71.
    1. Saunders LR, Bankovich AJ, Anderson WC, Aujay MA, Bheddah S, Black K, et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med. 2015;7(302):302ra136. doi: 10.1126/scitranslmed.aac9459.
    1. Kunnimalaiyaan M, Chen H. Tumor suppressor role of Notch-1 signaling in neuroendocrine tumors. Oncologist. 2007;12(5):535–542. doi: 10.1634/theoncologist.12-5-535.
    1. Lehman JM, Gwin ME, Massion PP. Immunotherapy and targeted therapy for small cell lung cancer: there is hope. Curr Oncol Rep. 2017;19(7):49. doi: 10.1007/s11912-017-0609-2.
    1. Augustyn A, Borromeo M, Wang T, Fujimoto J, Shao C, Dospoy PD, et al. ASCL1 is a lineage oncogene providing therapeutic targets for high-grade neuroendocrine lung cancers. Proc Natl Acad Sci U S A. 2014;111(41):14788–14793. doi: 10.1073/pnas.1410419111.
    1. Borromeo MD, Savage TK, Kollipara RK, He M, Augustyn A, Osborne JK, et al. ASCL1 and NEUROD1 reveal heterogeneity in pulmonary neuroendocrine tumors and regulate distinct genetic programs. Cell Rep. 2016;16(5):1259–1272. doi: 10.1016/j.celrep.2016.06.081.
    1. Furuta M, Kikuchi H, Shoji T, Takashima Y, Kikuchi E, Kikuchi J, et al. DLL3 regulates the migration and invasion of small cell lung cancer by modulating snail. Cancer Sci. 2019;110(5):1599–1608. doi: 10.1111/cas.13997.
    1. Tanaka K, Isse K, Fujihira T, Takenoyama M, Saunders L, Bheddah S, et al. Prevalence of Delta-like protein 3 expression in patients with small cell lung cancer. Lung Cancer. 2018;115:116–120. doi: 10.1016/j.lungcan.2017.11.018.
    1. Geffers I, Serth K, Chapman G, Jaekel R, Schuster-Gossler K, Cordes R, et al. Divergent functions and distinct localization of the notch ligands DLL1 and DLL3 in vivo. J Cell Biol. 2007;178(3):465–476. doi: 10.1083/jcb.200702009.
    1. Chapman G, Sparrow DB, Kremmer E, Dunwoodie SL. Notch inhibition by the ligand DELTA-LIKE 3 defines the mechanism of abnormal vertebral segmentation in spondylocostal dysostosis. Hum Mol Genet. 2011;20(5):905–916. doi: 10.1093/hmg/ddq529.
    1. Sharma SK, Pourat J, Abdel-Atti D, Carlin SD, Piersigilli A, Bankovich AJ, et al. Noninvasive interrogation of DLL3 expression in metastatic small cell lung cancer. Cancer Res. 2017;77(14):3931–3941. doi: 10.1158/0008-5472.CAN-17-0299.
    1. Konstantakou EG, Velentzas AD, Anagnostopoulos AK, Litou ZI, Konstandi OA, Giannopoulou AF, et al. Deep-proteome mapping of WM-266-4 human metastatic melanoma cells: from oncogenic addiction to druggable targets. PLoS One. 2017;12(2):e0171512. doi: 10.1371/journal.pone.0171512.
    1. Spino Marissa, Kurz Sylvia C., Chiriboga Luis, Serrano Jonathan, Zeck Briana, Sen Namita, Patel Seema, Shen Guomiao, Vasudevaraja Varshini, Tsirigos Aristotelis, Suryadevara Carter M., Frenster Joshua D., Tateishi Kensuke, Wakimoto Hiroaki, Jain Rajan, Riina Howard A., Nicolaides Theodore P., Sulman Erik P., Cahill Daniel P., Golfinos John G., Isse Kumiko, Saunders Laura R., Zagzag David, Placantonakis Dimitris G., Snuderl Matija, Chi Andrew S. Cell Surface Notch Ligand DLL3 is a Therapeutic Target in Isocitrate Dehydrogenase–mutant Glioma. Clinical Cancer Research. 2018;25(4):1261–1271. doi: 10.1158/1078-0432.CCR-18-2312.
    1. Koshkin VS, Garcia JA, Reynolds J, Elson P, Magi-Galluzzi C, McKenney JK, et al. Transcriptomic and protein analysis of small-cell bladder cancer (SCBC) identifies prognostic biomarkers and DLL3 as a relevant therapeutic target. Clin Cancer Res. 2019;25(1):210–221. doi: 10.1158/1078-0432.CCR-18-1278.
    1. Puca L, Sailer V, Gayvert K, Isse K, Sigouros M, Nanus DM, et al. Rovalpituzumab tesirine (Rova-T) as a therapeutic agent for neuroendocrine prostate cancer (NEPC) J Clin Oncol. 2017;35(15_suppl):5029. doi: 10.1200/JCO.2017.35.15_suppl.5029.
    1. George J, Walter V, Peifer M, Alexandrov LB, Seidel D, Leenders F, et al. Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. Nat Commun. 2018;9(1):1048. doi: 10.1038/s41467-018-03099-x.
    1. Giffin M, Cooke K, Lobenhofer E, Friedrich M, Raum T, Coxon A. P3.12-03 targeting DLL3 with AMG 757, a BiTE® antibody construct, and AMG 119, a CAR-T, for the treatment of SCLC. J Thorac Oncol. 2018;13(10):S971. doi: 10.1016/j.jtho.2018.08.1826.
    1. Rudin CM, Pietanza MC, Bauer TM, Ready N, Morgensztern D, Glisson BS, et al. Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study. Lancet Oncol. 2017;18(1):42–51. doi: 10.1016/S1470-2045(16)30565-4.
    1. Carbone DP, Morgensztern D, Le Moulec S, Santana-Davila R, Ready N, Hann CL, et al. Efficacy and safety of rovalpituzumab tesirine in patients with DLL3-expressing, ≥ 3rd line small cell lung cancer: results from the phase 2 TRINITY study. J Clin Oncol. 2018;36(15_suppl):8507. doi: 10.1200/JCO.2018.36.15_suppl.8507.
    1. Phase 3 Trial of Rova-T as Second-line Therapy for Advanced Small-Cell Lung Cancer (TAHOE Study) Halted [press release]. North Chicago, IL: AbbVie. 2018.
    1. Giffin MJ, Lobenhofer EK, Cooke K, Raum T, Stevens J, Beltran PJ, et al. Abstract 3632: BiTE® antibody constructs for the treatment of SCLC. Cancer Res. 2017;77(13 Supplement):3632.
    1. Klinger M, Benjamin J, Kischel R, Stienen S, Zugmaier G. Harnessing T cells to fight cancer with BiTE®antibody constructs–past developments and future directions. Immunol Rev. 2016;270(1):193–208. doi: 10.1111/imr.12393.
    1. Topp MS, Gokbuget N, Stein AS, Zugmaier G, O'Brien S, Bargou RC, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16(1):57–66. doi: 10.1016/S1470-2045(14)71170-2.
    1. Kantarjian H, Stein A, Gokbuget N, Fielding AK, Schuh AC, Ribera JM, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836–847. doi: 10.1056/NEJMoa1609783.
    1. Giffin M. Targeting DLL3 with BiTE® antibody constructs and cell-based therapies for the treatment of SCLC. American Association for Cancer Research Annual Meeting. Chicago; 2018.
    1. Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak O, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med. 2017;377(26):2545–2554. doi: 10.1056/NEJMoa1708566.
    1. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439–448. doi: 10.1056/NEJMoa1709866.
    1. Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45–56. doi: 10.1056/NEJMoa1804980.
    1. Perica K, Varela JC, Oelke M, Schneck J. Adoptive T cell immunotherapy for cancer. Rambam Maimonides Med J. 2015;6(1):e0004. doi: 10.5041/RMMJ.10179.
    1. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531–2544. doi: 10.1056/NEJMoa1707447.
    1. Locke FL, Neelapu SS, Bartlett NL, Siddiqi T, Chavez JC, Hosing CM, et al. Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther. 2017;25(1):285–295. doi: 10.1016/j.ymthe.2016.10.020.
    1. Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(1):31–42. doi: 10.1016/S1470-2045(18)30864-7.
    1. Owonikoko T, Smit M, Borghaei H, Salgia R, Boyer M, Rasmussen E, et al. OA13.02 two novel immunotherapy agents targeting DLL3 in SCLC: trials in progress of AMG 757 and AMG 119. J Thorac Oncol. 2018;13(10):S351. doi: 10.1016/j.jtho.2018.08.307.

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