| RRC ID |
44404
|
| 著者 |
Ochi F, Fujiwara H, Tanimoto K, Asai H, Miyazaki Y, Okamoto S, Mineno J, Kuzushima K, Shiku H, Barrett J, Ishii E, Yasukawa M.
|
| タイトル |
Gene-modified human α/β-T cells expressing a chimeric CD16-CD3ζ receptor as adoptively transferable effector cells for anticancer monoclonal antibody therapy.
|
| ジャーナル |
Cancer Immunol Res
|
| Abstract |
The central tumoricidal activity of anticancer monoclonal antibodies (mAb) is exerted by FcγR IIIa (CD16)-expressing effector cells in vivo via antibody-dependent cell-mediated cytotoxicity (ADCC), as observed for natural killer (NK) cells. In practice, chemotherapy-induced leukopenia and exhaustion of NK cells resulting from ADCC often hamper the clinical efficacy of cancer treatment. To circumvent this drawback, we examined in vivo the feasibility of T cells, gene-modified to express a newly generated affinity-matured (158V/V) chimeric CD16-CD3ζ receptor (cCD16ζ-T cells), as a transferable alternative effector for cancer mAb therapy. cCD16ζ-T cells were readily expandable in ex vivo culture using anti-CD2/CD3/CD28 beads and recombinant human interleukin-2 (rhIL-2), and they successfully displayed ADCC-mediated tumoricidal activity in vitro. During ADCC, ligation of opsonized cancer cells to the introduced cCD16ζ-T cells stimulated the effector cells to produce proinflammatory cytokines and release toxic granules through the activation of the Nuclear factor of activated T cells (NFAT) pathway after phosphorylation of the CD3ζ chain. In parallel, these stimulated cCD16ζ-T cells transiently proliferated and differentiated into effector memory T cells. In contrast, NK cells activated by rhIL-2 displayed similar ADCC activity, but failed to proliferate. Human cCD16ζ-T cells infused concomitantly with anti-CD20 mAb synergistically inhibited the growth of disseminated Raji cells, a CD20(+) lymphoma cell line, in immunodeficient mice, whereas similarly infused rhIL-2-treated NK cells survived for a shorter time and displayed less effective tumor suppression. Our findings strongly suggest the clinical feasibility of cCD16ζ-T cells as adoptively transferable ADCC effector cells that could potentially enhance the clinical responses mediated by currently available anticancer mAbs.
|
| 巻・号 |
2(3)
|
| ページ |
249-62
|
| 公開日 |
2014-3-1
|
| DOI |
10.1158/2326-6066.CIR-13-0099-T
|
| PII |
2326-6066.CIR-13-0099-T
|
| PMID |
24778321
|
| MeSH |
Adoptive Transfer
Animals
Antibodies, Monoclonal / immunology
Antibodies, Monoclonal / pharmacology*
Antineoplastic Agents / pharmacology*
CD3 Complex / genetics*
CD3 Complex / metabolism
Cell Line, Tumor
Female
GPI-Linked Proteins / genetics
GPI-Linked Proteins / metabolism
Humans
Mice
Mice, SCID
Receptors, IgG / genetics*
Receptors, IgG / metabolism
Recombinant Fusion Proteins / immunology
Recombinant Fusion Proteins / metabolism
T-Lymphocytes / immunology*
|
| IF |
6.17
|
| 引用数 |
40
|
|
WOS 分野
|
ENDOCRINOLOGY & METABOLISM
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
293T(RCB2202) |
