Inhibition of immune activation by a novel nuclear factor-kappa B inhibitor in HTLV-I–associated neurologic disease

Oh, Unsong; McCormick, Matthew; Datta, Dibyadeep; Turner, Richard V.; Bobb, Kathryn; Monie, Dileep D.; Sliskovic, Drago R.; Tanaka, Yuetsu; Zhang, Jie; Meshulam, Jeffrey; Jacobson, Steven

doi:10.1182/blood-2010-10-306571

Cited by 16 publications

(14 citation statements)

References 29 publications

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“…Therefore, bortezomib-induced cytotoxicity cannot be fully attributed to inhibition of canonical NF-κB activity in MM cells (19, 20). Since inhibition of both canonical and non-canonical pathways is required to efficiently block total NF-κB activity, we here characterize the anti-tumor activity of PBS-1086, an inhibitor of both canonical and non-canonical NF-κB pathways (21), in MM.…”

Section: Introductionmentioning

confidence: 99%

Dual Inhibition of Canonical and Noncanonical NF-κB Pathways Demonstrates Significant Antitumor Activities in Multiple Myeloma

Fabre

Mimura

Bobb

et al. 2012

Clinical Cancer Research

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Purpose NF-κB transcription factor plays a key role in the pathogenesis of multiple myeloma (MM) in the context of the bone marrow (BM) microenvironment. Both canonical and non-canonical pathways contribute to total NF-κB activity. Recent studies have demonstrated a critical role for the non-canonical pathway: selective inhibitors of the canonical pathway present a limited activity, mutations of the non-canonical pathway are frequent, and bortezomib-induced cytotoxicity cannot be fully attributed to inhibition of canonical NF-κB activity. Experimental design MM cell lines, primary patient cells, and the human MM xenograft murine model were used to examine the biologic impact of dual inhibition of both canonical and non-canonical NF-κB pathways. Results We show that PBS-1086 induces potent cytotoxicity in MM cells, but not in peripheral blood mononuclear cells. PBS-1086 overcomes the proliferative and anti-apoptotic effects of the BM milieu, associated with inhibition of NF-κB activity. Moreover, PBS-1086 strongly enhances the cytotoxicity of bortezomib in bortezomib-resistant MM cell lines and patient MM cells. PBS-1086 also inhibits osteoclastogenesis through an inhibition of RANKL-induced NF-κB activation. Finally, in a xenograft model of human MM in the BM milieu, PBS-1086 shows significant in vivo anti-MM activity and prolongs host survival, associated with apoptosis and inhibition of both NF-κB pathways in tumor cells. Conclusions Our data demonstrate that PBS-1086 is a promising dual inhibitor of the canonical and non-canonical NF-κB pathways. Our preclinical study therefore provides the framework for clinical evaluation of PBS-1086 in combination with bortezomib for the treatment of MM and related bone lesions.

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Section: Introductionmentioning

confidence: 99%

Dual Inhibition of Canonical and Noncanonical NF-κB Pathways Demonstrates Significant Antitumor Activities in Multiple Myeloma

Fabre

Mimura

Bobb

et al. 2012

Clinical Cancer Research

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“…Of note, treatment with IMD-0354 alone suppressed the proliferation of not only ATL cell lines, but also HTLV-I-infected cell lines established by infection in vitro, which express the viral oncoprotein, Tax, suggesting that IMD-0354 could eventually prevent the emergence of leukemic cell clones in asymptomatic carriers, (36) and also be useful in con-trolling NF-jB activity of HTLV-I antigen-expressing cells in human T-cell leukemia virus type I-associated myelopathy/ tropical spastic paraparesis (HAM ⁄ TSP) patients. (37) In conclusion, IMD-0354 effectively suppressed the survival of primary and established ATL cells in vitro and in vivo. These results raise the possibility of small molecularweight IKK inhibitors, such as IMD-0354, as a novel therapeutic agent for ATL treatment.…”

Section: Discussionmentioning

confidence: 82%

An IκB kinase 2 inhibitor IMD‐0354 suppresses the survival of adult T‐cell leukemia cells

et al. 2011

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Adult T-cell leukemia (ATL) is a fatal T-cell malignancy associated with human T-cell leukemia virus type I infection. The aberrant expression of nuclear factor-jB (NF-jB) is considered to contribute to the malignant phenotype and chemo-resistance of ATL cells. Because of the poor prognosis of ATL, the development of new therapeutic strategies is direly needed. In the present study, we show that an IjB kinase 2 (IKK2) inhibitor, IMD-0354, efficiently inhibits the survival of CD4 + CD25+ primary ATL cells and prevents the growth of or induces apoptosis of patient-derived ATL cell lines. Assays of transcription with integrated forms of reporter genes revealed that IMD-0354 suppresses NF-jB-dependent transcriptional activity. Moreover, the daily administration of IMD-0354 prevents the growth of tumors in mice inoculated with ATL cells. Our results suggest that targeting IKK2 with a small molecule inhibitor, such as IMD-0354, is an attractive strategy for the treatment of ATL. (Cancer Sci 2012; 103: 100-106) H uman T-cell leukemia virus type I (HTLV-I) is the etiological agent of adult T-cell leukemia (ATL) and is known to transform T lymphocytes.(1-3) While the majority of infected individuals remain asymptomatic during their lifetime, 2-5% of carriers develop an aggressive form of CD4-positive T-cell leukemia after a long latency period of 50-60 years, and another 0.25-3% of carriers develop a chronic neuro-inflammatory disorder termed HTLV-I-associated myelopathy ⁄ tropical spastic paraparesis.(4-7) At present, there are few established regimens for ATL treatment, mainly because of the intrinsic resistance to conventional drug therapies.(8) Thus, novel therapeutic interventions are urgently required. Although the viral oncoprotein Tax is believed to play a central role in HTLV-I-induced leukemogenesis, (9,10) the expression levels of Tax and other viral proteins are extremely low in leukemic cells freshly isolated from ATL patients and ATL-derived cell lines. (11,12) The tax gene is even mutated or truncated in some ATL cases. (13,14) Thus, Tax might not necessarily be required at later stages of disease progression, and Tax-independent mechanisms are likely to contribute to the proliferation and resistance to apoptosis of leukemic cells. The constitutive activation of nuclear factor-jB (NF-jB) was found in peripheral ATL cells and ATL-derived cell lines, (15) implying important prosurvival roles of NF-jB in ATL cells. Nuclear factor-jB activation has long been implicated in association with multiple processes of oncogenesis, including cell-cycle progression, control of apoptosis, migration, and metastasis.(16) Thus, the inhibition of NF-jB was suggested to be a potential means for cancer therapy in tumors highly expressing NF-jB. (17) We previously reported that a reduction of NF-jB activity by the forced expression of a dominantnegative form of IjBa strongly suppresses the survival of ATL cell lines, and that abrogation of NF-jB activity by a protease inhibitor, ritonavir, significantly prevented the growth ...

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“…It has been reported that PBMCs from HAM/TSP patients showed increased STAT5 activation, as indicated by STAT5 phosphorylation, in short‐term (20 h) culture, which was partially inhibited by Hu‐Mikβ1 . In the current study, we examined pSTAT5 in CD4 + and CD8 + T cells of HVs and HAM/TSP patients using fresh whole blood.…”

Section: Resultsmentioning

confidence: 93%

“…Among the five HAM/TSP patients that demonstrated CD122 saturation, three patients demonstrated sustained saturation of CD122 on NK cells and CD8 + T cells during the Hu‐Mikβ1 treatment period and then lost saturation of CD122 by 6 weeks after the final dose. Importantly, the higher doses of Hu‐Mikβ1 administration provided more inhibitory effects on activated T cell functions of HAM/TSP patients, which are the characteristic features of T cell dysregulation in HAM/TSP patients . In addition, HAM/TSP patients with longer disease duration (such as HAM#5, #6, and #8) seemed to show more effects of Hu‐Mikβ1 on CD122 saturation and inhibition of activated CD8 + T cells compared to HAM/TSP patients with shorter disease duration (such as HAM#7), which might be related to chronic activation and/or expansion of CD8 + T cells in the patients.…”

Section: Discussionmentioning

confidence: 93%

“…Hu‐Mikβ1 was shown to block IL‐15 transpresentation and IL‐15‐induced cell proliferation and was evaluated in a phase I clinical trial in patients with T cell large granular lymphocyte leukemia . Previous ex vivo studies demonstrated that Hu‐Mikβ1 inhibited abnormal T cell proliferation and HTLV‐1‐specific cellular immune responses of HAM/TSP patients, suggesting that Hu‐Mikβ1 might contribute to blocking IL‐15 action in HAM/TSP patients. Based on its effects, we hypothesized that the administration of Hu‐Mikβ1 in HAM/TSP patients would lead to inhibition of abnormal T cell functions.…”

Section: Introductionmentioning

confidence: 99%

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Clinical trial of a humanized anti‐IL‐2/IL‐15 receptor β chain in HAM/TSP

Enose-Akahata

Ohayon

et al. 2019

Ann Clin Transl Neurol

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Objective Human T cell lymphotropic virus 1 (HTLV‐1)‐associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive, neurological disease. Chronic activation of CD8+ T cells, as evidenced by increased spontaneous lymphoproliferation and HTLV‐1‐specific cytotoxic T cells, has been demonstrated in HAM/TSP patients. Since IL‐2 and IL‐15 stimulate memory CD8+ T cell activity, these cytokines have been implicated in the immunopathogenesis of HAM/TSP. In this phase I trial, we evaluated the safety, pharmacokinetics, and ability of Hu‐Mikβ1, a humanized monoclonal antibody directed toward the IL‐2/IL‐15 receptor β‐chain (IL‐2/IL‐15Rβ: CD122), to saturate CD122 and regulate abnormal immune responses in patients with HAM/TSP by inhibition of IL‐15 action. Methods Hu‐Mikβ1 was administered intravenously at doses of 0.5 mg/kg, 1.0 mg/kg, or 1.5 mg/kg in a total of nine HAM/TSP patients. Five doses of Hu‐Mikβ1 were administered at 3‐week intervals. The clinical response was evaluated using standardized scales. Viral and immunologic outcome measures were examined including HTLV‐1 proviral load, T cell phenotypic analysis and spontaneous lymphoproliferation in HAM/TSP patients. Results There was no significant toxicity associated with Hu‐Mikβ1 administration in HAM/TSP patients. Saturation of CD122 by Hu‐Mikβ1 was achieved in five out of nine HAM/TSP patients. Administration of Hu‐Mikβ1 was associated with inhibition of aberrant CD8+ T cell function including spontaneous lymphoproliferation and degranulation and IFN‐γ expression, especially in HAM/TSP patients that achieved CD122 saturation. Interpretation The treatment with Hu‐Mikβ1 had a number of immunological effects on HAM/TSP patients although no clinical efficacy was observed. We also did not see any dose‐related toxicity.

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Inhibition of immune activation by a novel nuclear factor-kappa B inhibitor in HTLV-I–associated neurologic disease

Cited by 16 publications

References 29 publications

Dual Inhibition of Canonical and Noncanonical NF-κB Pathways Demonstrates Significant Antitumor Activities in Multiple Myeloma

Dual Inhibition of Canonical and Noncanonical NF-κB Pathways Demonstrates Significant Antitumor Activities in Multiple Myeloma

An IκB kinase 2 inhibitor IMD‐0354 suppresses the survival of adult T‐cell leukemia cells

Clinical trial of a humanized anti‐IL‐2/IL‐15 receptor β chain in HAM/TSP

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