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

Clin Cancer Res. 2016 Sep 1;22(17):4405-16. doi: 10.1158/1078-0432.CCR-15-2714. Epub 2016 Apr 18.


Purpose: 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.

Experimental design: 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 in vitro and in vivo

Results: cCD16ζ-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).

Conclusions: 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. Clin Cancer Res; 22(17); 4405-16. ©2016 AACR.

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Antibody-Dependent Cell Cytotoxicity / immunology
  • Antineoplastic Agents, Immunological / pharmacology
  • CD3 Complex / genetics*
  • CD3 Complex / metabolism
  • Cell Line, Tumor
  • Combined Modality Therapy
  • Disease Models, Animal
  • Female
  • Gene Expression
  • Genetic Vectors / genetics
  • Humans
  • Immunotherapy, Adoptive
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Lentivirus / genetics
  • Leukemia-Lymphoma, Adult T-Cell / immunology*
  • Leukemia-Lymphoma, Adult T-Cell / metabolism*
  • Leukemia-Lymphoma, Adult T-Cell / pathology
  • Leukemia-Lymphoma, Adult T-Cell / therapy
  • Mice
  • Receptors, CCR4 / genetics
  • Receptors, CCR4 / metabolism
  • Receptors, IgG / genetics*
  • Receptors, IgG / metabolism
  • Recombinant Fusion Proteins / genetics*
  • Recombinant Fusion Proteins / metabolism
  • T-Cell Antigen Receptor Specificity / immunology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Transduction, Genetic
  • Xenograft Model Antitumor Assays


  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents, Immunological
  • CD3 Complex
  • Receptors, CCR4
  • Receptors, IgG
  • Recombinant Fusion Proteins
  • mogamulizumab