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Split chimeric antigen receptor-modified T cells targeting glypican-3 suppress hepatocellular carcinoma growth with reduced cytokine release
| Content Provider | SAGE Publishing |
|---|---|
| Author | Liu, Xuan Wen, Jianyun Yi, Honglei Hou, Xiaorui Yin, Yue Ye, Guofu Wu, Xuedong Jiang, Xiaotao |
| Copyright Year | 2020 |
| Abstract | Human glypican-3 (hGPC3) is a protein highly expressed in hepatocellular carcinoma (HCC) but limited in normal tissues, making it an ideal target for immunotherapy. The adoptive transfer of hGPC3-specific chimeric antigen receptor T (CAR-T) cells for HCC treatment has been conducted in clinical trials. Due to the rigid construction, conventional CAR-T cells have some intrinsic limitations, like uncontrollable overactivation and inducing severe cytokine release syndrome.Methods:We redesigned the hGPC3-specific CAR by splitting the traditional CAR into two parts. By using coculturing assays and a xenograft mouse model, the in vitro and in vivo cytotoxicity and cytokine release of the split anti-hGPC3 CAR-T cells were evaluated against various HCC cell lines and compared with conventional CAR-T cells.Results:In vitro data demonstrated that split anti-hGPC3 CAR-T cells could recognize and lyse hGPC3+ HepG2 and Huh7 cells in a dose-dependent manner. Impressively, split anti-hGPC3 CAR-T cells produced and released a significantly lower amount of proinflammatory cytokines, including IFN-γ, TNF-α, IL-6, and GM-CSF, than conventional CAR-T cells. When injected into immunodeficient mice inoculated subcutaneously with HepG2 cells, our split anti-hGPC3 CAR-T cells could suppress HCC tumor growth, but released significantly lower levels of cytokines than conventional CAR-T cells.Conclusions:We describe here for the first time the use of split anti-hGPC3 CAR-T cells to treat HCC; split anti-hGPC3 CAR-T cells could suppress tumor growth and reduce cytokine release, and represent a more versatile and safer alternative to conventional CAR-T cells treatment. |
| Related Links | https://journals.sagepub.com/doi/pdf/10.1177/1758835920910347?download=true |
| ISSN | 17588359 |
| Volume Number | 12 |
| Journal | Therapeutic Advances in Medical Oncology (TAM) |
| e-ISSN | 17588359 |
| DOI | 10.1177/1758835920910347 |
| Language | English |
| Publisher | Sage Publications UK |
| Publisher Date | 2020-03-09 |
| Publisher Place | London |
| Access Restriction | Open |
| Rights Holder | © The Author(s), 2020 |
| Subject Keyword | immunotherapy CAR-T cell therapy adoptive cellular therapy hepatocellular carcinoma cytokine release syndrome glypican-3 |
| Content Type | Text |
| Resource Type | Article |
| Subject | Oncology |
