Data from Development of Engineered T Cells Expressing a Chimeric CD16-CD3ζ Receptor to Improve the Clinical Efficacy of Mogamulizumab Therapy Against Adult T-Cell Leukemia

Abstract

<div>Abstract<p><b>Purpose:</b> Mogamulizumab (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.</p><p><b>Experimental Design:</b> We 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 <i>in vitro</i> and <i>in vivo</i>.</p><p><b>Results:</b> cCD16ζ-T cells derived from healthy donors killed <i>in vitro</i> Mog-opsonized ATL cell line cells (<i>n</i> = 7) and primary ATL cells (<i>n</i> = 4) depending on both the number of effector cells and the dose of the antibody. cCD16ζ-T cells generated from ATL patients (<i>n</i> = 3) also exerted cytocidal activity <i>in vitro</i> against Mog-opsonized autologous ATL cells. Using both intravenously disseminated model (<i>n</i> = 5) and subcutaneously inoculated model (<i>n</i> = 4), coadministration of Mog and human cCD16ζ-T cells successfully suppressed tumor growth in xenografted immunodeficient mice, and significantly prolonged their survival (<i>P</i> < 0.01 and <i>P</i> = 0.02, respectively).</p><p><b>Conclusions:</b> These 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. <i>Clin Cancer Res; 22(17); 4405–16. ©2016 AACR</i>.</p></div>