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  3. IL-12 nanochaperone-engineered CAR T cell for robust tumor-immunotherapy

IL-12 nanochaperone-engineered CAR T cell for robust tumor-immunotherapy

  • Biomaterials. 2022 Feb;281:121341. doi: 10.1016/j.biomaterials.2021.121341.
Yingmei Luo 1,  Ze Chen 2,  Mingjian Sun 3,  Baohong Li 4,  Fan Pan 2,  Aiqing Ma 4,  Jianhong Liao 2,  Ting Yin 4,  Xiaofan Tang 2,  Guojun Huang 2,  Baozhen Zhang 2,  Hong Pan 5,  Mingbin Zheng 6,  Lintao Cai 7
Affiliations

Affiliations

  • 1 Guangdong Key Laboratory of Nanomedicine, CAS Key Laboratory of Health Informatics, CAS-HK Joint Lab of Biomaterials, Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen, 518055, PR China; Key Laboratory for Nanomedicine, Department of Histology and Embryology and School of Pharmacy, Guangdong Medical University, Dongguan, 523808, PR China.
  • 2 Guangdong Key Laboratory of Nanomedicine, CAS Key Laboratory of Health Informatics, CAS-HK Joint Lab of Biomaterials, Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen, 518055, PR China.
  • 3 School of Information Science and Engineering, Harbin Institute of Technology, Weihai, Shandong, 264209, China.
  • 4 Key Laboratory for Nanomedicine, Department of Histology and Embryology and School of Pharmacy, Guangdong Medical University, Dongguan, 523808, PR China.
  • 5 Guangdong Key Laboratory of Nanomedicine, CAS Key Laboratory of Health Informatics, CAS-HK Joint Lab of Biomaterials, Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen, 518055, PR China. Electronic address: hong.pan@siat.ac.cn.
  • 6 Guangdong Key Laboratory of Nanomedicine, CAS Key Laboratory of Health Informatics, CAS-HK Joint Lab of Biomaterials, Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen, 518055, PR China; National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital, Southern University of Science and Technology Shenzhen, 518112, PR China; Key Laboratory for Nanomedicine, Department of Histology and Embryology and School of Pharmacy, Guangdong Medical University, Dongguan, 523808, PR China; Zhuhai Institute of Advanced Technology Chinese Academy of Sciences, 519000, Zhuhai, PR China. Electronic address: mb.zheng@siat.ac.cn.
  • 7 Guangdong Key Laboratory of Nanomedicine, CAS Key Laboratory of Health Informatics, CAS-HK Joint Lab of Biomaterials, Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen, 518055, PR China; Zhuhai Institute of Advanced Technology Chinese Academy of Sciences, 519000, Zhuhai, PR China. Electronic address: lt.cai@siat.ac.cn.
PMID: 34995901 DOI: 10.1016/j.biomaterials.2021.121341
Abstract

Although chimeric antigen receptor T (CAR T) cell immunotherapy has demonstrated remarkable success in clinical, therapeutic effects are still limited in solid tumor due to lack of activated T cell infiltration in immunosuppression of tumor microenvironment. Herein, we develop IL-12 nanostimulant-engineered CAR T cell (INS-CAR T) biohybrids for boosting antitumor immunity of CAR T cells via immunofeedback. As stimulating nanochaperone, IL-12-loaded human serum albumin (HSA) nanoparticles are effectively conjugated onto CAR T cells via bioorthogonal chemistry without influencing their antitumor capabilities. IL-12 is responsively released from INS-CAR T biohybrids in presence of the increased thiol groups on cell-surface triggered by tumor antigens. In return, released IL-12 obviously promotes the secretion of CCL5, CCL2 and CXCL10, which further selectively recruits and expands CD8+ CAR T cells in tumors. Ultimately, the immune-enhancing effects of IL-12 nanochaperone significantly boost CAR T cell antitumor capabilities, dramatically eliminated solid tumor and minimized unwanted side effects. Hence, immunofeedback INS-CAR T biohybrids, which include INS that serves as an intelligent 'nanochaperone', could provide a powerful tool for efficient and safe antitumor immunotherapy.

Keywords

CAR T cell therapy; Immunofeedback pathway; Immunosuppression; Interleukin 12; Nanochaperone.

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