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


METHODS
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.
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.
Hiroki
H
Tanaka
Department of Hematology, Clinical Immunology and Infectious Disease, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
Hiroshi
H
Fujiwara
Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
Fumihiro
F
Ochi
Department of Hematology, Clinical Immunology and Infectious Disease, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
Kazushi
K
Tanimoto
Department of Hematology, Clinical Immunology and Infectious Disease, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
Nicholas
N
Casey
CDM Center, Takara Bio Inc., Ohtsu, Shiga, Japan.
Sachiko
S
Okamoto
CDM Center, Takara Bio Inc., Ohtsu, Shiga, Japan.
Junichi
J
Mineno
Division of Immunology, Aichi Cancer Center, Nagoya, Aichi, Japan.
Kiyotaka
K
Kuzushima
Department of Cancer Vaccine and Immuno-Gene Therapy, Mie University Graduate School of Medicine, Tsu, Mie, Japan. yunarief@m.ehime-u.ac.jp yasukawa@m.ehime-u.ac.jp.
Hiroshi
H
Shiku
Department of Obstetrics and Gynecology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
Takashi
T
Sugiyama
Hematology Branch, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland.
A John
AJ
Barrett
Department of Hematology, Clinical Immunology and Infectious Disease, Ehime University Graduate School of Medicine, Toon, Ehime, Japan. yunarief@m.ehime-u.ac.jp yasukawa@m.ehime-u.ac.jp.
Masaki
M
Yasukawa
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology; D017252:CD3 Complex / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D016219:Immunotherapy, Adoptive; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D051379:Mice; D054398:Receptors, CCR4 / Q000235:genetics / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics* / Q000378:metabolism; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D017252:CD3 Complex; D054398:Receptors, CCR4; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; C549035:mogamulizumab