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
リソース情報
ヒト・動物細胞 Huh-7