Bioorthognal Equipping CAR-T Cells with Hyaluronidase and Checkpoint Blocking Antibody for Enhanced Solid Tumor Immunotherapy
作者单位：South China University of Technology
会议名称：《第十四届全国免疫学学术大会》
会议日期：2021年
学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
关 键 词：Bioorthogonal reaction Chimeric antigen receptor T cell Immunotherapy Solid tumor
摘 要：Adoptive cellular therapy utilizing Chimeric antigen receptor-redirected T(CAR-T) cells has shown striking therapeutic effects on hematological malignancies. In contrast, the efficacy of treating solid tumors with CAR-T cell therapies is still poor, which is largely due to inefficient penetration into solid tumors and immunosuppressive tumor microenvironment. Herein, we engineered hyaluronidase(HAase) and the checkpoint blocking antibody α-PDL1 on the surface of CAR-T cells via highly efficient and biocompatible bioorthogonal click chemistry to improve the therapeutic effects of CAR-T cells on solid tumors. The modified HAase degrades hyaluronic acid and destroys the tumor extracellular matrix, allowing CAR-T cells penetrate deeply into solid tumors, as evidenced by in vitro infiltration experiments and in vivo biodistribution studies. In addition, in vitro cytotoxicity studies showed stronger antitumor activity of α-PDL1-decorated CAR-T cells than traditional CAR-T cells. Importantly, HAase-and α-PDL1-engineered CAR-T cells showed better therapeutic efficacy on A20 solid tumors, and did not cause significant systemic toxicity. In this work, we provided a simple, efficient, and biologically safe chemical strategy to engineer traditional CAR-T cells for enhanced therapeutic efficacy on solid tumors, which can be extended to other adoptive cellular immunotherapies and holds great potential for clinical application.