Xu et al. engineered PD-L1-deleted DCs to produce bispecific extracellular vesicles (EVs) that expressed anti-human CD19 scFv and mouse PD-1 (EV-PD1-aCD19). Upon i.v. injection of mice implanted s.c. with human CD19-overexpressing murine CT6 colorectal carcinoma, which generally responds poorly to anti-PD-1, the nano-sized EV-PD1-aCD19, but not anti-CD19 scFV-engineered DCs, infiltrated and were retained in huCD19+ solid tumors, reshaped the TME and tumor draining LN milieu from immunologically cold to reactive, and induced tumor regression. EV-PD1-aCD19 also targeted circulating tumor-derived (PD-L1+) EVs to reverse pre-metastatic lung niches.
Contributed by Paula Hochman
ABSTRACT: Advances in the development of therapeutic extracellular vesicles (EVs) for cancer immunotherapy have allowed them to emerge as an alternative to cell therapy. In this proof-of-concept work, we develop bispecific EVs (BsEVs) by genetically engineering EV-producing dendritic cells (DCs) with aCD19 scFv and PD1 for targeting tumor antigens and blocking immune checkpoint proteins simultaneously. We find that these bispecific EVs (EVs-PD1-aCD19) have an impressive ability to accumulate in huCD19-expressing solid tumors following intravenous injection. In addition, EVs-PD1-aCD19 can remarkably reverse the immune landscape of the solid tumor by blocking PD-L1. Furthermore, EVs-PD1-aCD19 can also target tumor-derived EVs in circulation, which prevents the formation of a premetastatic niche in other tissues. Our technology is a demonstration of bispecific EV-based cancer immunotherapy, which may inspire treatments against various types of tumors with different surface antigens and even a patient-tailored therapy.
Author Info: (1) Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devic
Author Info: (1) Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu 215123, China. (2) Institute of Blood and Marrow Transplantation, National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China. (3) Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu 215123, China. (4) Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu 215123, China. (5) Institute of Advanced Materials (IAM) and School of Materials Science and Engineering, Nanjing University of Posts & Telecommunications, Nanjing 210000, China. (6) Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu 215123, China. (7) Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu 215123, China. (8) Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu 215123, China. (9) Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu 215123, China. (10) Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu 215123, China. (11) Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu 215123, China. (12) Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA. (13) Institute of Blood and Marrow Transplantation, National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China. Electronic address: chujianhong@hotmail.com. (14) Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu 215123, China. Electronic address: cwang@suda.edu.cn.
