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Clinical trial of a humanized anti-IL-2/IL-15 receptor ? chain in HAM/TSP.

ABSTRACT: 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-Mik?1, a humanized monoclonal antibody directed toward the IL-2/IL-15 receptor ?-chain (IL-2/IL-15R?: CD122), to saturate CD122 and regulate abnormal immune responses in patients with HAM/TSP by inhibition of IL-15 action. METHODS:Hu-Mik?1 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-Mik?1 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-Mik?1 administration in HAM/TSP patients. Saturation of CD122 by Hu-Mik?1 was achieved in five out of nine HAM/TSP patients. Administration of Hu-Mik?1 was associated with inhibition of aberrant CD8+ T cell function including spontaneous lymphoproliferation and degranulation and IFN-? expression, especially in HAM/TSP patients that achieved CD122 saturation. INTERPRETATION:The treatment with Hu-Mik?1 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.

SUBMITTER: Enose-Akahata Y

PROVIDER: S-EPMC6689682 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Enose-Akahata Yoshimi Y Oh Unsong U Ohayon Joan J Billioux Bridgette Jeanne BJ Massoud Raya R Bryant Bonita R BR Vellucci Ashley A Ngouth Nyater N Cortese Irene I Waldmann Thomas A TA Jacobson Steven S

Annals of clinical and translational neurology 20190705 8

<h4>Objective</h4>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<sup>+</sup> 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<sup>+</sup> T cell activity, these cytokines have been implicated in the immunopathogenesis of HAM/T ...[more]

PMID: 31402625

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Project description:BackgroundHTLV-1 causes proliferation of clonal populations of infected T cells in vivo, each clone defined by a unique proviral integration site in the host genome. The proviral load is strongly correlated with odds of the inflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is evidence that asymptomatic HTLV-1 carriers (ACs) have a more effective CD8 + T cell response, including a higher frequency of HLA class I alleles able to present peptides from a regulatory protein of HTLV-1, HBZ. We have previously shown that specific features of the host genome flanking the proviral integration site favour clone survival and spontaneous expression of the viral transactivator protein Tax in naturally infected PBMCs ex vivo. However, the previous studies were not designed or powered to detect differences in integration site characteristics between ACs and HAM/TSP patients. Here, we tested the hypothesis that the genomic environment of the provirus differs systematically between ACs and HAM/TSP patients, and between individuals with strong or weak HBZ presentation.MethodsWe used our recently described high-throughput protocol to map and quantify integration sites in 95 HAM/TSP patients and 68 ACs from Kagoshima, Japan, and 75 ACs from Kumamoto, Japan. Individuals with 2 or more HLA class I alleles predicted to bind HBZ peptides were classified 'strong' HBZ binders; the remainder were classified 'weak binders'.ResultsThe abundance of HTLV-1-infected T cell clones in vivo was correlated with proviral integration in genes and in areas with epigenetic marks associated with active regulatory elements. In clones of equivalent abundance, integration sites in genes and active regions were significantly more frequent in ACs than patients with HAM/TSP, irrespective of HBZ binding and proviral load. Integration sites in genes were also more frequent in strong HBZ binders than weak HBZ binders.ConclusionClonal abundance is correlated with integration in a transcriptionally active genomic region, and these regions may promote cell proliferation. A clone that reaches a given abundance in vivo is more likely to be integrated in a transcriptionally active region in individuals with a more effective anti-HTLV-1 immune response, such those who can present HBZ peptides or those who remain asymptomatic.

Dataset Information

Clinical trial of a humanized anti-IL-2/IL-15 receptor ? chain in HAM/TSP.

Publications

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

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