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Title: Nanobody-based chimeric antigen receptor T cells designed by CRISPR/Cas9 technology for solid tumor immunotherapy.

Authors: Mo, Fengzhen; Duan, Siliang; Jiang, Xiaobing; Yang, Xiaomei; Hou, Xiaoqiong; Shi, Wei; Carlos, Cueva Jumbo Juan; Liu, Aiqun; Yin, Shihua; Wang, Wu; Yao, Hua; Yu, Zihang; Tang, Zhuoran; Xie, Shenxia; Ding, Ziqiang; Zhao, Xinyue; Hammock, Bruce D; Lu, Xiaoling

Published In Signal Transduct Target Ther, (2021 02 25)

Abstract: Chimeric antigen receptor-based T-cell immunotherapy is a promising strategy for treatment of hematological malignant tumors; however, its efficacy towards solid cancer remains challenging. We therefore focused on developing nanobody-based CAR-T cells that treat the solid tumor. CD105 expression is upregulated on neoangiogenic endothelial and cancer cells. CD105 has been developed as a drug target. Here we show the generation of a CD105-specific nanobody, an anti-human CD105 CAR-T cells, by inserting the sequences for anti-CD105 nanobody-linked standard cassette genes into AAVS1 site using CRISPR/Cas9 technology. Co-culture with CD105+ target cells led to the activation of anti-CD105 CAR-T cells that displayed the typically activated cytotoxic T-cell characters, ability to proliferate, the production of pro-inflammatory cytokines, and the specific killing efficacy against CD105+ target cells in vitro. The in vivo treatment with anti-CD105 CAR-T cells significantly inhibited the growth of implanted CD105+ tumors, reduced tumor weight, and prolonged the survival time of tumor-bearing NOD/SCID mice. Nanobody-based CAR-T cells can therefore function as an antitumor agent in human tumor xenograft models. Our findings determined that the strategy of nanobody-based CAR-T cells engineered by CRISPR/Cas9 system has a certain potential to treat solid tumor through targeting CD105 antigen.

PubMed ID: 33627635 Exiting the NIEHS site

MeSH Terms: Animals; CRISPR-Cas Systems/genetics; Cell Line, Tumor; Endoglin/immunology*; Endoglin/therapeutic use; Humans; Immunotherapy*; Immunotherapy, Adoptive/methods; Male; Mice; Neoplasms/immunology; Neoplasms/therapy*; Receptors, Antigen, T-Cell/genetics; Receptors, Antigen, T-Cell/immunology; Receptors, Chimeric Antigen/genetics; Receptors, Chimeric Antigen/immunology*; Single-Domain Antibodies/immunology; Single-Domain Antibodies/pharmacology; T-Lymphocytes, Cytotoxic/immunology; Xenograft Model Antitumor Assays

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