論文 - 詳細
| RRC ID | 51709 |
|---|---|
| 著者 | Tanaka H, Fujiwara H, Ochi F, Tanimoto K, Casey N, Okamoto S, Mineno J, Kuzushima K, Shiku H, Sugiyama T, Barrett AJ, Yasukawa M. |
| タイトル | Development of Engineered T Cells Expressing a Chimeric CD16-CD3ζ Receptor to Improve the Clinical Efficacy of Mogamulizumab Therapy Against Adult T-Cell Leukemia. |
| ジャーナル | Clin Cancer Res |
| Abstract |
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. |
| 巻・号 | 22(17) |
| ページ | 4405-16 |
| 公開日 | 2016-9-1 |
| DOI | 10.1158/1078-0432.CCR-15-2714 |
| PII | 1078-0432.CCR-15-2714 |
| PMID | 27091408 |
| MeSH | 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 |
| IF | 10.107 |
| 引用数 | 12 |
| リソース情報 | |
| ヒト・動物細胞 | 293T(RCB2202) |