CAR exosomes derived from effector CAR-T cells have potent antitumour effects and low toxicity

Wenyan Fu,Min Ding,Fangxing Lin,Mingzhu Pan,Tian Li,Xuting Ye,Changhai Lei,Yafeng Shen,Chuqi Wang,Kewen Qian,Shi Hu,Yongji Yang,Shuowu Liu,Xiaoyan Fan,Yingshu Cui

doi:10.1038/s41467-019-12321-3

Abstract

Genetically engineered T cells expressing a chimeric antigen receptor (CAR) are rapidly emerging a promising new treatment for haematological and non-haematological malignancies. CAR-T therapy can induce rapid and durable clinical responses but is associated with unique acute toxicities. Moreover, CAR-T cells are vulnerable to immunosuppressive mechanisms. Here, we report that CAR-T cells release extracellular vesicles, mostly in the form of exosomes that carry CAR on their surface. The CAR-containing exosomes express a high level of cytotoxic molecules and inhibit tumour growth. Compared with CAR-T cells, CAR exosomes do not express Programmed cell Death protein 1 (PD1), and their antitumour effect cannot be weakened by recombinant PD-L1 treatment. In a preclinical in vivo model of cytokine release syndrome, the administration of CAR exosomes is relatively safe compared with CAR-T therapy. This study supports the use of exosomes as biomimetic nanovesicles that may be useful in future therapeutic approaches against tumours.

Highlights

Engineered T cells expressing a chimeric antigen receptor (CAR) are rapidly emerging a promising new treatment for haematological and non-haematological malignancies
The targeting specificity of CARs is usually achieved by antigen-recognition regions in the form of a single-chain variable fragment or a binding receptor/ ligand in the extracellular domains, while the T-cell-activating function is achieved by the intracellular domain, including a region of the T-cell receptors (TCRs) CD3ζ chain that provides ‘signal 1’ and one or more domains from co-stimulatory receptors, such as CD28, OX40 (CD134), and/or 4-1BB (CD137), to provide ‘signal 2’
The two most commonly noticed toxic effects in CAR-T immunotherapy are cytokine release syndrome (CRS), which is characterized by high fever, hypotension, hypoxia, and/or multiorgan toxicity, and CAR-T-related encephalopathy syndrome (CRES), which is typically characterized by a toxic encephalopathic state with symptoms of delirium, confusion and, occasionally, cerebral oedema and seizures[5,6,7]

Summary

Introduction

Engineered T cells expressing a chimeric antigen receptor (CAR) are rapidly emerging a promising new treatment for haematological and non-haematological malignancies. Data from numerous phase I/II clinical trials conducted at single institutions have indicated that this approach is typically associated with an overall response rate of 50–90% in patients with B-cell malignancies refractory to standard therapies[3,4]. Despite their efficiency, adoptive T-cell therapies show unique toxicities, which are distinct from those seen with conventional chemotherapies, monoclonal antibodies (mAbs), and smallmolecule-targeted therapies. TCR activation boosts the production of CTL-derived exosomes, and the presence of the TCR/CD3ζ complex was demonstrated in the membranes of human-CTL-derived exosomes in another relevant study[21]

Methods

Results

Conclusion