Intravenous infusion of engineered megakaryocytes to produce oncolytic platelets in vivo for enhanced cancer immunotherapy
Abstract
Tumor-targeted delivery of oncolytic viruses (OVs) via systemic administration could not only expand virotherapy beyond primary tumors to widespread metastases, but also improve clinical adherence and convenience. We here engineer megakaryocytes encapsulating oncolytic adenovirus type 5 (M-Ad5) to produce oncolytic platelets in vivo by leveraging the thrombopoiesis process. Upon intravenous administration, M-Ad5 travels through the lungs, where it can release OVs-harbored therapeutic platelets into circulation under pulmonary turbulence microenvironments. Under the shelter of platelets, OVs resist inactivation by neutralizing antibodies and actively target widespread noninjectable cancer lesions. Intravenous infusion of M-Ad5 to mice with A549 lung cancer could significantly inhibit tumor growth and prolong survival. In multiple mouse tumor models, M-Ad5 induced a robust antitumor immune response by reprogramming the immunosuppressive tumor microenvironment, and potentiated the response to immune checkpoint inhibitors by recruiting more immune cells. We demonstrated that M-Ad5 in combination with PDL1 inhibitors activated tumor antigen-specific CD8 + T cells and memory T cells, thereby suppressing the growth of CT26 colorectal cancer metastasis, and preventing postsurgical B16F10 cancer recurrence and metastatic spread, as well as providing long-term immune protection against the rechallenged tumors.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (14)
Yinxian Yang
State Key Laboratory of Advanced Drug Delivery and Release Systems, School of Pharmacy, Zhejiang University
Shenqiang Wang
State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences
Xueying Shi
State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University
Xudong Chen
Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University
Ruyi Zhou
State Key Laboratory of Advanced Drug Delivery and Release Systems, School of Pharmacy, Zhejiang University
Tao Sheng
Department of Chemistry
Xiaofeng Chen
School of Chemical Engineering
Jinpeng Han
State Key Laboratory of Advanced Drug Delivery and Release Systems, School of Pharmacy, Zhejiang University
Yan Xu
Qing Wu
Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University
Yuqi Zhang
State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Collaborative Innovation Centre of Radiological Medicine of Jiangsu Higher Education Institutions
Hongjun Li
State Key Laboratory of Advanced Drug Delivery and Release Systems, School of Pharmacy, Zhejiang University
Jicheng Yu
State Key Laboratory of Advanced Drug Delivery and Release Systems, School of Pharmacy, Zhejiang University
Zhen Gu