Drug- loaded bispecific T cell nanoengager overcomes T cell exhaustion for potent cancer immunotherapy

• 成果类型: Article
• 署名作者: Wang, Jinjin; Huang, Xisha; Shi, Qiangqiang; Swingle, Kelsey L.; Hamilton, Alex G.; Gong, Ningqiang; Mitchell, Michael J.
• 署名单位: University of Pennsylvania; Chinese Academy of Sciences; University of Science & Technology of China, CAS; University of Pennsylvania; University of Pennsylvania; Pennsylvania Medicine; University of Pennsylvania; Pennsylvania Medicine; University of Pennsylvania; Pennsylvania Medicine; University of Pennsylvania; Pennsylvania Medicine
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2409564122
• 发表日期: 2025-11-11
• 页码: e2409564122
• 关键词: nanomedicine; immunotherapy; cancer; T cell; blinatumomab; adenosine; antibodies

摘要

Bispecific T cell engager (BiTE) therapeutics that link T cells and tumor cells to induce tumor cell lysis have demonstrated great success in the clinic for the treatment of many cancers. However, T cell exhaustion in the tumor microenvironment leads to tumor cell escape and BiTE therapy resistance. Herein, we developed a drug-loaded bispecific T cell nanoengager (NanoBiTE) to overcome this obstacle. NanoBiTE is composed of a mesoporous silica nanoparticle encapsulating the adenosine A2A receptor antagonist PBF-509 as a core, with a lipid layer surface coating as a shell and modification with anti-CD19 and anti-CD3 antibodies for tumor and T cell binding, respectively. Like the traditional BiTE blinatumomab, NanoBiTE can engage T cells with CD19+ tumor cells to promote tumor cell lysis. However, unlike blinatumomab, which tends to induce T cell exhaustion, we showed that the release of PBF-509 from NanoBiTE suppressed the A2AR pathway and substantially improved tumor cell killing induced by NanoBiTE. Moreover, NanoBiTE treatment led to substantially reduced tumor burden in vivo in a humanized mouse model. Our results demonstrate that NanoBiTE is a safe and potent bispecific therapy that can also reduce T cell exhaustion for cancer immunotherapy.