論文 - 詳細
| RRC ID | 56030 |
|---|---|
| 著者 | Pan Z, Di S, Shi B, Jiang H, Shi Z, Liu Y, Wang Y, Luo H, Yu M, Wu X, Li Z. |
| タイトル | Increased antitumor activities of glypican-3-specific chimeric antigen receptor-modified T cells by coexpression of a soluble PD1-CH3 fusion protein. |
| ジャーナル | Cancer Immunol Immunother |
| Abstract |
Our recent clinical study demonstrated that glypican-3 (GPC3)-specific chimeric antigen receptor-modified T (CAR-T) cells are a promising treatment for hepatocellular carcinoma (HCC). However, the interaction of programmed cell death 1 (PD-1) and PD-L1-mediated T-cell inhibition is involved in immune evasion in a wide range of solid tumors, including HCC. To overcome this problem, we introduced a fusion protein composed of a PD-1 extracellular domain and CH3 from IgG4 into GPC3-specific CAR-T cells (GPC3-28Z) to block the PD-1/PD-L1 pathway. GPC3-specific CAR-T cells carrying the PD-1-CH3 fusion protein (sPD1) specifically recognized and lysed GPC3-positive HCC cells. The proliferation capacity of GPC3-28Z-sPD1 T cells after weekly stimulation with target cells was much higher than that of control GPC3-28Z T cells. Additionally, the coexpression of sPD1 could protect CAR-T cells from exhaustion when incubated with target cells, as phosphorylated AKT and Bcl-xL expression levels were higher in GPC3-28Z-sPD1 T cells than in GPC3-28Z cells. Importantly, in two HCC tumor xenograft models, GPC3-28Z-sPD1 T cells displayed a significantly higher tumor suppression capacity than GPC3-28Z T cells. In addition, an increased number of CD3+ T cells in the circulation and tumors and increased granzyme B levels and decreased Ki67 expression levels in the tumors were observed in the mice treated with GPC3-28Z-sPD1 T cells. Together, these data indicated that GPC3-specific CAR-T cells carrying sPD1 show promise as a treatment for patients with HCC. |
| 巻・号 | 67(10) |
| ページ | 1621-1634 |
| 公開日 | 2018-10-1 |
| DOI | 10.1007/s00262-018-2221-1 |
| PII | 10.1007/s00262-018-2221-1 |
| PMID | 30078052 |
| MeSH | Animals Carcinoma, Hepatocellular / immunology* Carcinoma, Hepatocellular / metabolism Carcinoma, Hepatocellular / prevention & control Cells, Cultured Glypicans / immunology* Glypicans / metabolism Humans Immunoglobulin G / immunology* Immunoglobulin G / metabolism Liver Neoplasms / immunology Liver Neoplasms / metabolism Liver Neoplasms / prevention & control Mice Mice, Inbred NOD Mice, SCID Programmed Cell Death 1 Receptor / immunology* Programmed Cell Death 1 Receptor / metabolism Protein Domains Receptors, Antigen, T-Cell / immunology* Receptors, Antigen, T-Cell / metabolism Recombinant Fusion Proteins / immunology* Recombinant Fusion Proteins / metabolism T-Lymphocytes / immunology* T-Lymphocytes / metabolism Xenograft Model Antitumor Assays |
| IF | 4.9 |
| 引用数 | 16 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 13 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | Huh-7 |