Qinqin Cheng1, Xiaojing Shi1, Menglu Han1, Goar Smbatyan2, Heinz-Josef Lenz2, Yong Zhang1,3,4,5. 1. Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy , University of Southern California , Los Angeles , California 90089 , United States. 2. Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine , University of Southern California , Los Angeles , California 90089 , United States. 3. Department of Chemistry, Dornsife College of Letters, Arts and Sciences , University of Southern California , Los Angeles , California 90089 , United States. 4. Norris Comprehensive Cancer Center , University of Southern California , Los Angeles , California 90089 , United States. 5. Research Center for Liver Diseases , University of Southern California , Los Angeles , California 90089 , United States.
Abstract
Exosomes are naturally occurring membranous vesicles secreted by various types of cells. Given their unique and important biological and pharmacological properties, exosomes have been emerging as a promising form of nanomedicine acting via efficient delivery of endogenous and exogenous therapeutics. Here we explore a new concept of utilizing endogenously derived exosomes as artificial controllers of cellular immunity to redirect and activate cytotoxic T cells toward cancer cells for killing. This was achieved through genetically displaying two distinct types of antibodies on exosomal surface. The resulting synthetic multivalent antibodies retargeted exosomes (SMART-Exos), which express monoclonal antibodies specific for T-cell CD3 and cancer cell-associated epidermal growth factor receptor (EGFR), were shown to not only induce cross-linking of T cells and EGFR-expressing breast cancer cells but also elicit potent antitumor immunity both in vitro and in vivo. This proof-of-concept study demonstrates a novel application of exosomes in cancer immunotherapy and may provide a general and versatile approach for the development of a new class of cell-free therapy.
Exosomes are naturally occurring membranous vesicles secreted by various types of cells. Given their unique and important biological and pharmacological properties, exosomes have been emerging as a promising form of nanomedicine acting via efficient delivery of endogenous and exogenous therapeutics. Here we explore a new concept of utilizing endogenously derived exosomes as artificial controllers of cellular immunity to redirect and activate cytotoxic T cells toward cancer cells for killing. This was achieved through genetically displaying two distinct types of antibodies on exosomal surface. The resulting synthetic multivalent antibodies retargeted exosomes (SMART-Exos), which express monoclonal antibodies specific for T-cell CD3 and n class="Disease">cancer cell-associated epidermal growth factor receptor (EGFR), were shown to not only induce cross-linking of T cells and EGFR-expressing breast cancer cells but also elicit potent antitumor immunity both in vitro and in vivo. This proof-of-concept study demonstrates a novel application of exosomes in cancer immunotherapy and may provide a general and versatile approach for the development of a new class of cell-free therapy.
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