STAT3 antisense oligonucleotide AZD9150 in a subset of patients with heavily pretreated lymphoma: results of a phase 1b trial

Matthew J Reilley, Patricia McCoon, Carl Cook, Paul Lyne, Razelle Kurzrock, Youngsoo Kim, Richard Woessner, Anas Younes, John Nemunaitis, Nathan Fowler, Michael Curran, Qinying Liu, Tianyuan Zhou, Joanna Schmidt, Minji Jo, Samantha J Lee, Mason Yamashita, Steven G Hughes, Luis Fayad, Sarina Piha-Paul, Murali V P Nadella, Xiaokun Xiao, Jeff Hsu, Alexey Revenko, Brett P Monia, A Robert MacLeod, David S Hong, Matthew J Reilley, Patricia McCoon, Carl Cook, Paul Lyne, Razelle Kurzrock, Youngsoo Kim, Richard Woessner, Anas Younes, John Nemunaitis, Nathan Fowler, Michael Curran, Qinying Liu, Tianyuan Zhou, Joanna Schmidt, Minji Jo, Samantha J Lee, Mason Yamashita, Steven G Hughes, Luis Fayad, Sarina Piha-Paul, Murali V P Nadella, Xiaokun Xiao, Jeff Hsu, Alexey Revenko, Brett P Monia, A Robert MacLeod, David S Hong

Abstract

Background: The Janus kinase (JAK) and signal transduction and activation of transcription (STAT) signaling pathway is an attractive target in multiple cancers. Activation of the JAK-STAT pathway is important in both tumorigenesis and activation of immune responses. In diffuse large B-cell lymphoma (DLBCL), the transcription factor STAT3 has been associated with aggressive disease phenotype and worse overall survival. While multiple therapies inhibit upstream signaling, there has been limited success in selectively targeting STAT3 in patients. Antisense oligonucleotides (ASOs) represent a compelling therapeutic approach to target difficult to drug proteins such as STAT3 through of mRNA targeting. We report the evaluation of a next generation STAT3 ASO (AZD9150) in a non-Hodgkin's lymphoma population, primarily consisting of patients with DLBCL.

Methods: Patients with relapsed or treatment refractory lymphoma were enrolled in this expansion cohort. AZD9150 was administered at 2 mg/kg and the 3 mg/kg (MTD determined by escalation cohort) dose levels with initial loading doses in the first week on days 1, 3, and 5 followed by weekly dosing. Patients were eligible to remain on therapy until unacceptable toxicity or progression. Blood was collected pre- and post-treatment for analysis of peripheral immune cells.

Results: Thirty patients were enrolled, 10 at 2 mg/kg and 20 at 3 mg/kg dose levels. Twenty-seven patients had DLBCL. AZD9150 was safe and well tolerated at both doses. Common drug-related adverse events included transaminitis, fatigue, and thrombocytopenia. The 3 mg/kg dose level is the recommended phase 2 dose. All responses were seen among DLBCL patients, including 2 complete responses with median duration of response 10.7 months and 2 partial responses. Peripheral blood cell analysis of three patients without a clinical response to therapy revealed a relative increase in proportion of macrophages, CD4+, and CD8+ T cells; this trend did not reach statistical significance.

Conclusions: AZD9150 was well tolerated and demonstrated efficacy in a subset of heavily pretreated patients with DLBCL. Studies in combination with checkpoint immunotherapies are ongoing.

Trial registration: Registered at ClinicalTrials.gov: NCT01563302 . First submitted 2/13/2012.

Keywords: Anti-sense oligonucleotide; Clinical trial; DLBCL; Diffuse large B-cell lymphoma; Immunotherapy; JAK-STAT; Lymphoma; STAT3.

Conflict of interest statement

Ethics approval and consent to participate

This study was reviewed and approved by the Institutional Review Board at the University of Texas MD Anderson Cancer Center. Written informed consent was obtained from the patients prior to treatment.

Consent for publication

Written informed consent was obtained from the patients for publication of their individual details and accompanying images in this manuscript. The consent form is held by the authors and is available for review by the Editor-in-Chief.

Competing interests

PM, CC, PL, RW, and MVPN are employees of Astrazeneca. YK, TZ, JS, MJ, SJL, MY, SGH, XX, JH, AR, BPM, and ARM are employees of Ionis Pharmaceuticals. The remaining authors declare no potential conflicts of interest.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Spider plot of percentage change in tumor size during treatment
Fig. 2
Fig. 2
Waterfall plot of best responses seen in 24 evaluable patients. Blue dotted lines are reference for partial response (− 30%) and progressive disease (+ 20%)
Fig. 3
Fig. 3
Changes in patient PBMC profiles following AZD9150 therapy (PBMC subpopulations with frequencies of less than 2% are not shown). a Surface markers analyzed. b-e Patient PBMC populations before (blue) and after 1 (orange) or 2 (green) cycles of therapy

References

    1. Darnell JE, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science [Internet] 1994;264(5164):1415–1421.
    1. Zhong Z, Wen Z, Darnell JE. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science [Internet] 1994;264(5155):95–98.
    1. Lütticken C, Wegenka UM, Yuan J, Buschmann J, Schindler C, Ziemiecki A, et al. Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. Science [Internet] 1994;263(5143):89–92.
    1. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer [Internet] 2009;9(11):798–809. doi: 10.1038/nrc2734.
    1. Denley SM, Jamieson NB, McCall P, Oien KA, Morton JP, Carter CR, et al. Activation of the IL-6R/Jak/stat pathway is associated with a poor outcome in resected pancreatic ductal adenocarcinoma. J Gastrointest Surg [Internet] 2013;17(5):887–898. doi: 10.1007/s11605-013-2168-7.
    1. Kleppe M, Kwak M, Koppikar P, Riester M, Keller M, Bastian L, et al. JAK-STAT pathway activation in malignant and nonmalignant cells contributes to MPN pathogenesis and therapeutic response. Cancer Discov [Internet] 2015;5(3):316–331. doi: 10.1158/-14-0736.
    1. Bromberg J, Darnell JE. The role of STATs in transcriptional control and their impact on cellular function. Oncogene [Internet] 2000;19(21):2468–2473. doi: 10.1038/sj.onc.1203476.
    1. Yu H, Jove R. The STATs of cancer--new molecular targets come of age. Nat Rev Cancer [Internet] 2004;4(2):97–105. doi: 10.1038/nrc1275.
    1. Haura EB, Turkson J, Jove R. Mechanisms of disease: Insights into the emerging role of signal transducers and activators of transcription in cancer. Nat Clin Pract Oncol [Internet] 2005;2(6):315–324. doi: 10.1038/ncponc0195.
    1. Woodfield SE, Graves HK, Hernandez JA, Bergmann A. De-regulation of JNK and JAK/STAT signaling in ESCRT-II mutant tissues cooperatively contributes to neoplastic tumorigenesis. Singh SR, editor. PLoS One [Internet] 2013;8(2):e56021. doi: 10.1371/journal.pone.0056021.
    1. Kroon P, Berry PA, Stower MJ, Rodrigues G, Mann VM, Simms M, et al. JAK-STAT blockade inhibits tumor initiation and clonogenic recovery of prostate cancer stem-like cells. Cancer Res [Internet] 2013;73(16):5288–5298. doi: 10.1158/0008-5472.CAN-13-0874.
    1. McCann GA, Naidu S, Rath KS, Bid HK, Tierney BJ, Suarez A, et al. Targeting constitutively-activated STAT3 in hypoxic ovarian cancer, using a novel STAT3 inhibitor. Oncoscience [Internet] 2014;1(3):216–228. doi: 10.18632/oncoscience.26.
    1. Kowshik J, Baba AB, Giri H, Deepak Reddy G, Dixit M, Nagini S. Astaxanthin inhibits JAK/STAT-3 signaling to abrogate cell proliferation, invasion and angiogenesis in a hamster model of oral cancer. Singh SR, editor. PLoS One [Internet] 2014;9(10):e109114. doi: 10.1371/journal.pone.0109114.
    1. Sen M, Pollock NI, Black J, DeGrave KA, Wheeler S, Freilino ML, et al. JAK kinase inhibition abrogates STAT3 activation and head and neck squamous cell carcinoma tumor growth. Neoplasia [Internet] 2015;17(3):256–264. doi: 10.1016/j.neo.2015.01.003.
    1. Liu Y, Li P-K, Li C, Lin J. Inhibition of STAT3 signaling blocks the anti-apoptotic activity of IL-6 in human liver cancer cells. J Biol Chem [Internet] 2010;285(35):27429–27439. doi: 10.1074/jbc.M110.142752.
    1. Azare J, Leslie K, Al-Ahmadie H, Gerald W, Weinreb PH, Violette SM, et al. Constitutively activated Stat3 induces tumorigenesis and enhances cell motility of prostate epithelial cells through integrin beta 6. Mol Cell Biol [Internet] 2007;27(12):4444–4453. doi: 10.1128/MCB.02404-06.
    1. Lam LT, Wright G, Davis RE, Lenz G, Farinha P, Dang L, et al. Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor- B pathways in subtypes of diffuse large B-cell lymphoma. Blood [Internet] 2008;111(7):3701–3713. doi: 10.1182/blood-2007-09-111948.
    1. Masuda M, Suzui M, Yasumatu R, Nakashima T, Kuratomi Y, Azuma K, et al. Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma. Cancer Res [Internet] 2002;62(12):3351–3355.
    1. Buettner R, Mora LB, Jove R. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res [Internet] 2002;8(4):945–954.
    1. Danoch H, Kalechman Y, Albeck M, Longo DL, Sredni B. Sensitizing B- and T- cell Lymphoma Cells to Paclitaxel/Abraxane-Induced Death by AS101 via Inhibition of the VLA-4-IL10-Survivin Axis. Mol Cancer Res [Internet] 2015;13(3):411–422. doi: 10.1158/1541-7786.MCR-14-0459.
    1. Kortylewski M, Kujawski M, Wang T, Wei S, Zhang S, Pilon-Thomas S, et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med [Internet] 2005;11(12):1314–1321. doi: 10.1038/nm1325.
    1. Li HS, Liu C, Xiao Y, Chu F, Liang X, Peng W, et al. Bypassing STAT3-mediated inhibition of the transcriptional regulator ID2 improves the antitumor efficacy of dendritic cells. Sci Signal [Internet] 2016;9(447):ra94. doi: 10.1126/scisignal.aaf3957.
    1. Mace TA, Ameen Z, Collins A, Wojcik S, Mair M, Young GS, et al. Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. Cancer Res [Internet] 2013;73(10):3007–3018. doi: 10.1158/0008-5472.CAN-12-4601.
    1. Seth PP, Vasquez G, Allerson CA, Berdeja A, Gaus H, Kinberger GA, et al. Synthesis and biophysical evaluation of 2′,4′-constrained 2’O-methoxyethyl and 2′,4′-constrained 2’O-ethyl nucleic acid analogues. J Org Chem [Internet] 2010;75(5):1569–1581. doi: 10.1021/jo902560f.
    1. Hong D, Kurzrock R, Kim Y, Woessner R, Younes A, Nemunaitis J, et al. AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer. Sci Transl Med [Internet] 2015;7(314):314ra185. doi: 10.1126/scitranslmed.aac5272.
    1. Frampton GM, Fichtenholtz A, Otto GA, Wang K, Downing SR, He J, et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol [Internet] 2013;31(11):1023–1031. doi: 10.1038/nbt.2696.
    1. Ok C. Y., Chen J., Xu-Monette Z. Y., Tzankov A., Manyam G. C., Li L., Visco C., Montes-Moreno S., Dybkaer K., Chiu A., Orazi A., Zu Y., Bhagat G., Richards K. L., Hsi E. D., Choi W. W. L., van Krieken J. H., Huh J., Zhao X., Ponzoni M., Ferreri A. J. M., Bertoni F., Farnen J. P., Moller M. B., Piris M. A., Winter J. N., Medeiros L. J., Young K. H. Clinical Implications of Phosphorylated STAT3 Expression in De Novo Diffuse Large B-cell Lymphoma. Clinical Cancer Research. 2014;20(19):5113–5123. doi: 10.1158/1078-0432.CCR-14-0683.
    1. Davis RE, Ngo VN, Lenz G, Tolar P, Young RM, Romesser PB, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature [Internet] 2010;463(7277):88–92. doi: 10.1038/nature08638.
    1. Song TL, Nairismägi M-L, Laurensia Y, Lim J-Q, Tan J, Li Z-M, et al. Oncogenic activation of the STAT3 pathway drives PD-L1 expression in natural killer/T-cell lymphoma. Blood [Internet] 2018;132(11):1146–1158. doi: 10.1182/blood-2018-01-829424.
    1. Manso R, Sánchez-Beato M, González-Rincón J, Gómez S, Rojo F, Mollejo M, et al. Mutations in the JAK/STAT pathway genes and activation of the pathway, a relevant finding in nodal Peripheral T-cell lymphoma. Br J Haematol [Internet]. 2017; Available from: . [cited 7 Oct 2018].
    1. Nairismägi M-L, Gerritsen ME, Li ZM, Wijaya GC, Chia BKH, Laurensia Y, et al. Oncogenic activation of JAK3-STAT signaling confers clinical sensitivity to PRN371, a novel selective and potent JAK3 inhibitor, in natural killer/T-cell lymphoma. Leukemia [Internet] 2018;32(5):1147–1156. doi: 10.1038/s41375-017-0004-x.
    1. Woessner R, Sah V, McCoon P, Grosskurth S, Deng N, DuPont R, et al. Proceedings of the 110th Annual Meeting of the American Association for Cancer Research; 2017 Apr 1–5. Washington DC and Philadephia: AACR; 2017. Inhibition of STAT3 by antisense oligonucleotide treatment decreases the immune suppressive tumor microenvironment in syngeneic and GEM tumor models [abstract] p. Abstract nr 3684.
    1. Yang Z-Z, Grote DM, Xiu B, Ziesmer SC, Price-Troska TL, Hodge LS, et al. TGF-β upregulates CD70 expression and induces exhaustion of effector memory T cells in B-cell non-Hodgkin’s lymphoma. Leukemia [Internet] 2014;28(9):1872–1884. doi: 10.1038/leu.2014.84.
    1. Horikawa N, Abiko K, Matsumura N, Hamanishi J, Baba T, Yamaguchi K, et al. Expression of Vascular Endothelial Growth Factor in Ovarian Cancer Inhibits Tumor Immunity through the Accumulation of Myeloid-Derived Suppressor Cells. Clin Cancer Res [Internet] 2017;23(2):587–599. doi: 10.1158/1078-0432.CCR-16-0387.
    1. Sade-Feldman M, Kanterman J, Klieger Y, Ish-Shalom E, Olga M, Saragovi A, et al. Clinical Significance of Circulating CD33+CD11b+HLA-DR- Myeloid Cells in Patients with Stage IV Melanoma Treated with Ipilimumab. Clin Cancer Res [Internet] 2016;22(23):5661–5672. doi: 10.1158/1078-0432.CCR-15-3104.
    1. Jayaraman P, Parikh F, Lopez-Rivera E, Hailemichael Y, Clark A, Ma G, et al. Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release. J Immunol [Internet] 2012;188(11):5365–5376. doi: 10.4049/jimmunol.1103553.
    1. Rosborough BR, Mathews LR, Matta BM, Liu Q, Raïch-Regué D, Thomson AW, et al. Cutting edge: Flt3 ligand mediates STAT3-independent expansion but STAT3-dependent activation of myeloid-derived suppressor cells. J Immunol [Internet] 2014;192(8):3470–3473. doi: 10.4049/jimmunol.1300058.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner