Clinical activity of 9-ING-41, a small molecule selective glycogen synthase kinase-3 beta (GSK-3β) inhibitor, in refractory adult T-Cell leukemia/lymphoma

Andrew Hsu, Kelsey E Huntington, Andre De Souza, Lanlan Zhou, Adam J Olszewski, Nirav P Makwana, Diana O Treaba, Ludimila Cavalcante, Francis J Giles, Howard Safran, Wafik S El-Deiry, Benedito A Carneiro, Andrew Hsu, Kelsey E Huntington, Andre De Souza, Lanlan Zhou, Adam J Olszewski, Nirav P Makwana, Diana O Treaba, Ludimila Cavalcante, Francis J Giles, Howard Safran, Wafik S El-Deiry, Benedito A Carneiro

Abstract

GSK-3β is a serine/threonine kinase implicated in tumorigenesis and chemotherapy resistance. GSK-3β blockade downregulates the NF-κB pathway, modulates immune cell PD-1 and tumor cell PD-L1 expression, and increases CD8 + T cell and NK cell function. We report a case of adult T-cell leukemia/lymphoma (ATLL) treated with 9-ING-41, a selective GSK-3β inhibitor in clinical development, who achieved a durable response. A 43-year-old male developed diffuse lymphadenopathy, and biopsy of axillary lymph node showed acute-type ATLL. Peripheral blood flow cytometry revealed a circulating clonal T cell population, and CSF was positive for ATLL involvement. After disease progression on the 3rd line of treatment, he started treatment with 9-ING-41 monotherapy in a clinical trial (NCT03678883). CT imaging after seven months showed a partial response. Sustained reduction of peripheral blood ATLL cells lasted 15 months. Treatment of patient-derived CD8 + T cells with 9-ING-41 increased the secretion of IFN-γ, granzyme B, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In conclusion, treatment of a patient with refractory ATLL with the GSK-3β inhibitor 9-ING-41 resulted in a prolonged response. Ongoing experiments are investigating the hypothesis that 9-ING-41-induced T cell activation and immunomodulation contributes to its clinical activity. Further clinical investigation of 9-ING-41 for treatment of ATLL is warranted.

Keywords: 9-ING-41; ATLL; GSK-3; GSK-3b; glycogen synthase kinase 3.

Conflict of interest statement

LC and FJG are consultants to Actuate Therapeutics. BAC has received institutional support from Actuate Therapeutics related to ongoing clinical trial with 9-ING-41. All other authors have no conflicts of interest to declare.

Figures

Figure 1.
Figure 1.
Right axillary lymph node biopsy at diagnosis. (a) Diffuse polymorphic lymphoid population comprised of small to medium sized lymphocytes with irregular nuclei and indistinct nucleoli with a minor subset of large lymphoid cells with irregular nuclei and conspicuous nucleoli (hematoxylin and eosin stain x50 objective, immersion oil). (b) proliferation rate is approximately 70–80% (MIB1 antibody, x50 objective, immersion oil); (c-f) A predominant T-lymphoid population was detected by immunohistochemistry with expression of CD3, CD4 and with significant loss of CD7 and BCL2 (x50 objective, immersion oil) .
Figure 2.
Figure 2.
sIL-2 r Serum Concentration: sIL-2 r serum concentration (7,192 ng/ml) at first progression on 10/2018 leading to transition to second-line mogamulizumab; second progression (19,297 ng/ml) on 01/2019 leading to transition to third-line lenalidomide; sIL-2 r serum concentration (9,043 ng/ml) one month prior to initiation of 9-ING-41; and sIL-2 r serum concentration (2,094 ng/ml) at best response 15 months after initiation of 9-ING-41.
Figure 3.
Figure 3.
Timeline of Therapy with Correlating CT Imaging. (02/2018): Imaging at diagnosis showing enlarged bilateral axillary lymph nodes; (10/2018): progression of disease with increase in size of axillary and inguinal lymph nodes leading to transition to second-line mogamulizumab; (02/2019): Increase in size of axillary and inguinal lymph nodes leading to transition to third-line lenalidomide; (11/2019): persistently enlarged axillary and inguinal lymph nodes prior to start treatment with 9-ING-41, a selective small molecule inhibitor of GSK-3β; (12/2020): response with improvement of axillary and inguinal lymph nodes after 1 year of therapy with 9-ING-41.
Figure 4.
Figure 4.
Treatment of patient-derived CD8 + T cells with 9-ING-41 increases granzyme B, TRAIL, and IFN-gamma secretion while decreasing VEGF, TNF-alpha, and CCL5/RANTES concentrations in cell culture supernatant in comparison to control groups. Patient-derived CD8+ cytotoxic T cells were treated with 9-ING-41 for 48 hours (1 µM) or control (DMSO) and cytokine concentration was measured in cell culture supernatants. (a) Violin plots representing cytokine concentrations that increased post-treatment. (b) Violin plots representing cytokine concentrations that decreased post-treatment. Statistical significance was calculated with GraphPad Prism 9.3.1 using unpaired t tests and is denoted on each plot as follows: P > .05 = n.s., P ≤ .05 = *, P ≤ .01 = **, P ≤ .001 = ***, and P ≤ .0001 = **** (N = 3).

References

    1. Proietti FA, Carneiro-Proietti AB, Catalan-Soares BC, Murphy EL.. Global epidemiology of HTLV-I infection and associated diseases. Oncogene. 2005;24:6058–6068. doi:10.1038/sj.onc.1208968.
    1. Katsuya H, Ishitsuka K, Utsunomiya A, Hanada S, Eto T, Moriuchi Y, Saburi Y, Miyahara M, Sueoka E, Uike N, et al. Treatment and survival among 1594 patients with ATL. Blood. 2015;126:2570–2577. doi:10.1182/blood-2015-03-632489.
    1. Shimoyama M. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the lymphoma study group (1984-87). Br J Haematol. 1991;79:428–437. doi:10.1111/j.1365-2141.1991.tb08051.x.
    1. Araki K, Harada K, Nakamoto K, Shiroma M, Miyakuni T. Clinical significance of serum soluble IL-2R levels in patients with adult T cell leukaemia (ATL) and HTLV-1 carriers. Clin Exp Immunol. 2000;119:259–263. doi:10.1046/j.1365-2249.2000.01136.x.
    1. Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, et al. The 2016 revision of the world health organization classification of lymphoid neoplasms. Blood. 2016;127:2375–2390. doi:10.1182/blood-2016-01-643569.
    1. Wattel E, Vartanian JP, Pannetier C, Wain-Hobson S. Clonal expansion of human T-cell leukemia virus type I-infected cells in asymptomatic and symptomatic carriers without malignancy. J Virol. 1995;69:2863–2868. doi:10.1128/jvi.69.5.2863-2868.1995.
    1. Yoshida M. Multiple viral strategies of HTLV-1 for dysregulation of cell growth control. Annu Rev Immunol. 2001;19:475–496. doi:10.1146/annurev.immunol.19.1.475.
    1. Kfoury Y, Nasr R, Hermine O, de Thé H, Bazarbachi A. Proapoptotic regimes for HTLV-I-transformed cells: targeting tax and the NF-kappaB pathway. Cell Death Differ. 2005;12(Suppl 1):871–877. doi:10.1038/sj.cdd.4401624.
    1. Mori N, Fujii M, Cheng G, Ikeda S, Yamasaki Y, Yamada Y, Tomonaga M, Yamamoto N. Human T-cell leukemia virus type I tax protein induces the expression of anti-apoptotic gene Bcl-xL in human T-cells through nuclear factor-kappaB and c-AMP responsive element binding protein pathways. Virus Genes. 2001;22:279–287. doi:10.1023/A:1011158021749.
    1. Sakashita A, Hattori T, Miller CW, Suzushima H, Asou N, Takatsuki K, and Koeffler, H.P. Mutations of the p53 gene in adult T-cell leukemia. Blood. 1992;79:477–480. doi:10.1182/blood.V79.2.477.477.
    1. Kataoka K, Shiraishi Y, Takeda Y, Sakata S, Matsumoto M, Nagano S, Maeda T, Nagata Y, Kitanaka A, Mizuno S, et al. Aberrant PD-L1 expression through 3’-UTR disruption in multiple cancers. Nature. 2016;534:402–406. doi:10.1038/nature18294.
    1. Shimauchi T, Kabashima K, Nakashima D, Sugita K, Yamada Y, Hino R, and Tokura, Y. Augmented expression of programmed death-1 in both neoplastic and non-neoplastic CD4+ T-cells in adult T-cell leukemia/lymphoma. Int J Cancer. 2007;121:2585–2590. doi:10.1002/ijc.23042.
    1. Kozako T, Yoshimitsu M, Fujiwara H, Masamoto I, Horai S, White Y, Akimoto M, Suzuki S, Matsushita K, Uozumi K, et al. PD-1/PD-L1 expression in human T-cell leukemia virus type 1 carriers and adult T-cell leukemia/lymphoma patients. Leukemia. 2009;23:375–382. doi:10.1038/leu.2008.272.
    1. Maier H, Isogawa M, Freeman GJ, Chisari FV. PD-1:PD-L1 interactions contribute to the functional suppression of virus-specific CD8+ T lymphocytes in the liver. J Immunol. 2007;178:2714–2720. doi:10.4049/jimmunol.178.5.2714.
    1. Gill PS, Harrington W Jr., Kaplan MH, Ribeiro RC, Bennett JM, Liebman HA, Bernstein-Singer M, Espina BM, Cabral L, Allen S, et al. Treatment of adult T-cell leukemia-lymphoma with a combination of interferon alfa and zidovudine. N Engl J Med. 1995;332:1744–1748. doi:10.1056/NEJM199506293322603.
    1. Ishida T, Jo T, Takemoto S, Suzushima H, Uozumi K, Yamamoto K, Uike N, Saburi Y, Nosaka K, Utsunomiya A, et al. Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized phase II study. Br J Haematol. 2015;169:672–682. doi:10.1111/bjh.13338.
    1. Ishida T, Fujiwara H, Nosaka K, Taira N, Abe Y, Imaizumi Y, Moriuchi Y, Jo T, Ishizawa K, Tobinai K, et al. Multicenter phase II study of lenalidomide in relapsed or recurrent adult t-cell leukemia/lymphoma: ATLL-002. J Clin Oncol. 2016;34:4086–4093. doi:10.1200/JCO.2016.67.7732.
    1. Doble BW, Woodgett JR. GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci. 2003;116:1175–1186. doi:10.1242/jcs.00384.
    1. Sahin I, Eturi A, De Souza A, Pamarthy S, Tavora F, Giles FJ, and Carneiro, B.A. Glycogen synthase kinase-3 beta inhibitors as novel cancer treatments and modulators of antitumor immune responses. Cancer Biol Ther. 2019;20:1047–1056. doi:10.1080/15384047.2019.1595283.
    1. Krueger J, Rudd CE, Taylor A. Glycogen synthase 3 (GSK-3) regulation of PD-1 expression and and its therapeutic implications. Semin Immunol. 2019;42:101295. doi:10.1016/j.smim.2019.101295.
    1. Taylor A, Harker JA, Chanthong K, Stevenson PG, Zuniga EI, and Rudd CE. Glycogen synthase kinase 3 inactivation drives t-bet-mediated downregulation of co-receptor PD-1 to Enhance CD8(+) Cytolytic T cell responses. Immunity. 2016;44:274–286. doi:10.1016/j.immuni.2016.01.018.
    1. C-W L, Lim S-O, Xia W, Lee -H-H, Chan L-C, Kuo C-W, Khoo K-H, Chang -S-S, Cha J-H, Kim T, et al. Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity. Nat Commun. 2016;7:12632. doi:10.1038/ncomms12632.
    1. Shakoori A, Ougolkov A, Yu ZW, Zhang B, Modarressi MH, Billadeau DD, Mai M, Takahashi Y, Minamoto T. Deregulated GSK3beta activity in colorectal cancer: its association with tumor cell survival and proliferation. Biochem Biophys Res Commun. 2005;334:1365–1373. doi:10.1016/j.bbrc.2005.07.041.
    1. Walz A, Ugolkov A, Chandra S, Kozikowski A, Carneiro BA, O’Halloran TV, Giles FJ, Billadeau DD, Mazar AP. Molecular pathways: revisiting glycogen synthase kinase-3β as a target for the treatment of cancer. Clin Cancer Res. 2017;23:1891–1897. doi:10.1158/1078-0432.CCR-15-2240.
    1. Hoeflich KP, Luo J, Rubie EA, Tsao MS, Jin O, Woodgett JR. Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Nature. 2000;406:86–90. doi:10.1038/35017574.
    1. Busino L, Millman SE, Scotto L, Kyratsous CA, Basrur V, O’Connor O, Hoffmann A, Elenitoba-Johnson KS, Pagano M. Fbxw7α- and GSK3-mediated degradation of p100 is a pro-survival mechanism in multiple myeloma. Nat Cell Biol. 2012;14:375–385. doi:10.1038/ncb2463.
    1. Carneiro BA, Cavalcante L, Bastos BR, Powell SF, Ma WW, Sahebjam S, Harvey D, De Souza AL, Dhawan MS, Safran H, et al. Phase I study of 9-ING-41, a small molecule selective glycogen synthase kinase-3 beta (GSK-3β) inhibitor, as a single agent and combined with chemotherapy, in patients with refractory tumors. J Clin Oncol. 2020;38:3507. suppl; abstr 3507 doi:10.1200/JCO.2020.38.15_suppl.3507.
    1. Taylor A, Rothstein D, Rudd CE. Small-molecule inhibition of PD-1 transcription is an effective alternative to antibody blockade in cancer therapy. Cancer Res. 2018;78:706–717. doi:10.1158/0008-5472.CAN-17-0491.
    1. Rudd CE, Chanthong K, Taylor A. Small molecule inhibition of GSK-3 specifically inhibits the transcription of inhibitory co-receptor LAG-3 for enhanced anti-tumor immunity. Cell Rep. 2020;30:2075–82.e4. doi:10.1016/j.celrep.2020.01.076.
    1. Huntington KE, Zhang S, Carneiro BA, El-Deiry WS. GSK3β inhibition by small molecule 9-ING-41 decreases VEGF and other cytokines, and boosts NK and T cell-mediated killing of colorectal tumor cells. Cancer Res. 2021;81:2676. doi:10.1158/1538-7445.AM2021-2676.
    1. Huntington KE, Louie A, Zhou L, El-Deiry WS. A high-throughput customized cytokinome screen of colon cancer cell responses to small-molecule oncology drugs. Oncotarget. 2021;12:1980–1991. doi:10.18632/oncotarget.28079.
    1. Castro F, Cardoso AP, Gonçalves RM, Serre K, Oliveira MJ. Interferon-gamma at the crossroads of tumor immune surveillance or evasion. Front Immunol. 2018;9:847. doi:10.3389/fimmu.2018.00847.
    1. Maraskovsky E, Chen WF, Shortman K. IL-2 and IFN-gamma are two necessary lymphokines in the development of cytolytic T cells. J Immunol. 1989;143:1210–1214.
    1. Carneiro BA, El-Deiry WS. Targeting apoptosis in cancer therapy. Nat Rev Clin Oncol. 2020;17:395–417. doi:10.1038/s41571-020-0341-y.
    1. Zhang JS, Herreros-Villanueva M, Koenig A, Deng Z, de Narvajas AA, Gomez TS, Meng X, Bujanda L, Ellenrieder V, Li XK, et al. Differential activity of GSK-3 isoforms regulates NF-κB and TRAIL- or TNFα induced apoptosis in pancreatic cancer cells. Cell Death Dis. 2014;5:e1142. doi:10.1038/cddis.2014.102.
    1. Furman RR, Asgary Z, Mascarenhas JO, Liou HC, Schattner EJ. Modulation of NF-kappa B activity and apoptosis in chronic lymphocytic leukemia B cells. J Immunol. 2000;164:2200–2206. doi:10.4049/jimmunol.164.4.2200.
    1. Gasparini C, Celeghini C, Monasta L, Zauli G. NF-κB pathways in hematological malignancies. Cell Mol Life Sci. 2014;71:2083–2102. doi:10.1007/s00018-013-1545-4.
    1. Karmali R, Chukkapalli V, Gordon LI, Borgia JA, Ugolkov A, Mazar AP, and Giles, F.J. GSK-3β inhibitor, 9-ING-41, reduces cell viability and halts proliferation of B-cell lymphoma cell lines as a single agent and in combination with novel agents. Oncotarget. 2017;8:114924–114934. doi:10.18632/oncotarget.22414.
    1. Abd-Ellah A, Voogdt C, Krappmann D, Möller P, Marienfeld RB. GSK3β modulates NF-κB activation and RelB degradation through site-specific phosphorylation of BCL10. Sci Rep. 2018;8:1352. doi:10.1038/s41598-018-19822-z.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel