Eliciting anti-cancer immunity by genetically engineered multifunctional exosomes

Qinqin Cheng; Zhefu Dai; Goar Smbatyan; Alan L Epstein; Heinz-Josef Lenz; Yong Zhang

doi:10.1016/j.ymthe.2022.06.013

Eliciting anti-cancer immunity by genetically engineered multifunctional exosomes

Mol Ther. 2022 Sep 7;30(9):3066-3077. doi: 10.1016/j.ymthe.2022.06.013. Epub 2022 Jun 22.

Authors

Qinqin Cheng¹, Zhefu Dai¹, Goar Smbatyan², Alan L Epstein³, Heinz-Josef Lenz², Yong Zhang⁴

Affiliations

¹ Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.
² Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
³ Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
⁴ Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA; Department of Chemistry, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA 90089, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA; Research Center for Liver Diseases, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: yongz@usc.edu.

Abstract

Exosomes are cell-derived nanovesicles involved in regulating intercellular communications. In contrast to conventional nanomedicines, exosomes are characterized by unique advantages for therapeutic development. Despite their major successes in drug delivery, the full potential of exosomes for immunotherapy remains untapped. Herein we designed genetically engineered exosomes featured with surfaced-displayed antibody targeting groups and immunomodulatory proteins. Through genetic fusions with exosomal membrane proteins, Expi293F cell-derived exosomes were armed with monoclonal antibodies specific for human T-cell CD3 and epidermal growth factor receptor (EGFR) as well as immune checkpoint modulators, programmed death 1 (PD-1) and OX40 ligand (OX40L). The resulting genetically engineered multifunctional immune-modulating exosomes (GEMINI-Exos) can not only redirect and activate T cells toward killing EGFR-positive triple negative breast cancer (TNBC) cells but also elicit robust anti-cancer immunity, giving rise to highly potent inhibition against established TNBC tumors in mice. GEMINI-Exos represent candidate agents for immunotherapy and may offer a general strategy for generating exosome-based immunotherapeutics with desired functions and properties.

Keywords: exosomes; extracellular vesicles; immunotherapy; protein engineering; synthetic biology; triple negative breast cancer.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antineoplastic Agents, Immunological* / pharmacology
Antineoplastic Agents, Immunological* / therapeutic use
ErbB Receptors / genetics
ErbB Receptors / metabolism
Exosomes* / metabolism
Humans
Immunotherapy
Mice
Triple Negative Breast Neoplasms* / genetics
Triple Negative Breast Neoplasms* / therapy

Substances

Antineoplastic Agents, Immunological
ErbB Receptors

Abstract

Publication types

MeSH terms

Substances

Grants and funding