• Hiroki Tanaka, Hiroshi Fujiwara, Fumihiro Ochi, Kazushi Tanimoto, Nicholas Casey, Sachiko Okamoto, Junichi Mineno, Kiyotaka Kuzushima, Hiroshi Shiku, Takashi Sugiyama, A John Barrett, and Masaki Yasukawa.
• Department of Obstetrics and Gynecology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan. Department of Hematology, Clinical Immunology and Infectious Disease, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
• Clin Cancer Res. 2016 Sep 1; 22 (17): 4405-16.

PurposeMogamulizumab (Mog), a humanized anti-CC chemokine receptor 4 (CCR4) mAb that mediates antibody-dependent cellular cytotoxicity (ADCC) using FcγR IIIa (CD16)-expressing effector cells, has recently been approved for treatment of CCR4-positive adult T-cell leukemia (ATL) in Japan. However, Mog failure has sometimes been observed in patients who have accompanying chemotherapy-associated lymphocytopenia. In this study, we examined whether adoptive transfer of artificial ADCC effector cells combined with Mog would overcome this drawback.Experimental DesignWe lentivirally gene-modified peripheral blood T cells from healthy volunteers and ATL patients expressing the affinity-increased chimeric CD16-CD3ζ receptor (cCD16ζ-T cells). Subsequently, we examined the ADCC effect mediated by those cCD16ζ-T cells in the presence of Mog against ATL tumor cells both in vitro and in vivoResultscCD16ζ-T cells derived from healthy donors killed in vitro Mog-opsonized ATL cell line cells (n = 7) and primary ATL cells (n = 4) depending on both the number of effector cells and the dose of the antibody. cCD16ζ-T cells generated from ATL patients (n = 3) also exerted cytocidal activity in vitro against Mog-opsonized autologous ATL cells. Using both intravenously disseminated model (n = 5) and subcutaneously inoculated model (n = 4), coadministration of Mog and human cCD16ζ-T cells successfully suppressed tumor growth in xenografted immunodeficient mice, and significantly prolonged their survival (P < 0.01 and P = 0.02, respectively).ConclusionsThese data strongly suggest clinical feasibility of the novel combined adoptive immunotherapy using cCD16ζ-T cells and Mog for treatment of aggressive ATL, particularly in patients who are ineligible for allogeneic hematopoietic stem cell transplantation. Clin Cancer Res; 22(17); 4405-16. ©2016 AACR.©2016 American Association for Cancer Research.

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