Novel gene-modified effector T cells for mogamulizumab

Purpose:Mogamulizumab (Mog), a humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody (mAb) that mediates antibody-dependent cellular cytotoxicity (ADCC) using FcR 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 Design:We lentivirally gene-modified peripheral blood T cells from healthy volunteers and ATL patients expressing the affinity-increased chimeric CD16-CD3 receptor (cCD16-T cells). Subsequently we examined the ADCC effect mediated by those cCD16-T cells in the presence of Mog against ATL tumor cells both in vitro and in vivo. Results:cCD16-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. cCD16-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), co-administration of Mog and human cCD16-T cells successfully suppressed tumor growth in xenografted immunodeficient mice, and significantly prolonged their survival (p<0.01 and p=0.02, respectively). Conclusions:These data strongly suggest clinical feasibility of the novel combined adoptive immunotherapy using cCD16-T cells and Mog for treatment of aggressive ATL, particularly in patients who are ineligible for allo-HSCT.

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