Galectin-9 as a Predictive Marker for the Onset of Immune-Related Adverse Effects Associated with Anti-CCR4 MoAb Therapy in Patients with Adult T Cell Leukemia.
Adult T-cell leukemia/lymphoma (ATL/ATLL) is one of the most malignant lymphomas with poor prognosis. ATL/ATLL cells express CC chemokine receptor 4, and mogamulizumab (anti-CCR4 monoclonal antibody) exhibits strong cytotoxicity for ATL/ATLL cells. We analyzed plasma samples of 6 patients with ATL/ATLL treated with chemotherapy followed by mogamulizumab therapy (mogatherapy) for changes in the levels of biomarkers in relation to immune-related adverse effects. As treatment is often associated with skin eruptions, we investigated the profiles of inflammatory cytokines, including galectin-9 (Gal-9), which becomes increased in various infectious diseases and allergic patients. Gal-9, soluble interleukin (IL)-2 receptor, tumor necrosis factor-α, and IL-10 levels were increased before chemotherapy, and Gal-9 levels were associated with the sIL-2 receptor, which reflects tumor burden. Inflammatory levels decreased after chemotherapy. After mogatherapy, 5 of 6 patients attained complete remission (CR), whereas 1 patient showed no response (NR) and died. Among 5 patients with CR, the biomarkers remained low during mogatherapy, except for a 3-5-fold increment in Gal-9 (associated with skin eruptions). A skin biopsy showed infiltration by inflammatory cells and Gal-9 synthesis in areas with CD8 cell infiltration. In the patient with NR, increased levels of Gal-9 and the aforementioned biomarkers were noted 3 days after mogatherapy, followed by opportunistic infections resembling immune reconstitution inflammatory syndrome. Therefore, an increased Gal-9 plasma level in ATL/ATLL indicates tumor burden and reflects immune activation by mogatherapy. These findings may indicate that an increase in the Gal-9 level, a novel immune checkpoint molecule, can reflect immune-related adverse effects of various biotherapies.
Division of Emerging Infectious Diseases, Graduate School of Medicine, Tohoku University.
Tareg Omer
TO
Mohammed
Haorile
H
Chagan-Yasutan
Yugo
Y
Ashino
Wakana
W
Nakayama
Yayoi
Y
Takahashi
Taizo
T
Shimomura
Tetsuhiro
T
Fujimoto
Yuko
Y
Watanabe
Toshiro
T
Niki
Hitoshi
H
Suzushima
Toshio
T
Hattori
D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D037161:Galectins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000378:metabolism; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000276:immunology*; D009894:Opportunistic Infections / Q000139:chemically induced / Q000276:immunology; D054398:Receptors, CCR4 / Q000276:immunology*; D015375:Receptors, Interleukin-2; D012867:Skin / Q000473:pathology; D012995:Solubility; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D037161:Galectins; C508609:IL10 protein, human; C105032:LGALS9 protein, human; D054398:Receptors, CCR4; D015375:Receptors, Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C549035:mogamulizumab