Reference - Detail
| RRC ID | 44404 |
|---|---|
| Author | Ochi F, Fujiwara H, Tanimoto K, Asai H, Miyazaki Y, Okamoto S, Mineno J, Kuzushima K, Shiku H, Barrett J, Ishii E, Yasukawa M. |
| Title | Gene-modified human α/β-T cells expressing a chimeric CD16-CD3ζ receptor as adoptively transferable effector cells for anticancer monoclonal antibody therapy. |
| Journal | 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. |
| Volume | 2(3) |
| Pages | 249-62 |
| Published | 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 |
| Times Cited | 40 |
| WOS Category | ENDOCRINOLOGY & METABOLISM BIOCHEMISTRY & MOLECULAR BIOLOGY |
| Altmetric score |
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| The most frequently cited source | Patent(IFI CLAIMS) |
| Total number of mentions | 9 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | 293T(RCB2202) |