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

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

TAREG OMER MOHAMMED,¹ HAORILE CHAGAN-YASUTAN,^1,2 YUGO ASHINO,^1,2 WAKANA NAKAYAMA,³ YAYOI TAKAHASHI,⁴ TAIZO SHIMOMURA,⁵ TETSUHIRO FUJIMOTO,⁵ YUKO WATANABE,⁵ TOSHIRO NIKI,⁶ HITOSHI SUZUSHIMA⁵ and TOSHIO HATTORI^1,7

¹Division of Emerging Infectious Diseases, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan
²Disaster-related Infectious Disease, International Research Institute of Disaster Science, Tohoku University, Sendai, Miyagi, Japan
³Department of Dermatology, Kumamoto Shinto General Hospital, Kumamoto, Kumamoto, Japan
⁴Department of Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan
⁵Department of Hematology, Kumamoto Shinto General Hospital, Kumamoto, Kumamoto, Japan
⁶Department of Immunology, Faculty of Medicine, Kagawa University, Takamatsu, Kagawa, Japan
⁷Graduate School of Health Science and Social Welfare, KIBI International University, Takahashi, Okayama, Japan

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.

keywords —— Adult T-cell leukemia/lymphoma; galectin-9; immune reconstitution inflammatory syndrome; mogamulizumab; skin eruption

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Tohoku J. Exp. Med., 2017, 241, 201-208

Correspondence: Haorile Chagan-Yasutan, Disaster-related Infectious Disease, International Research Institute of Disaster Science, Tohoku University, Sendai, Miyagi 980-8575, Japan.

e-mail: haorile831@yahoo.co.jp