Engineered CD4 T cells for in vivo delivery of therapeutic proteins

• 成果类型: Article
• 署名作者: Radhakrishnan, Harikrishnan; Newmyer, Sherri L.; Javitz, Harold S.; Bhatnagar, Parijat
• 署名单位: SRI International; SRI International
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12314
• DOI: 10.1073/pnas.2318687121
• 发表日期: 2024-10-01
• 关键词: interferon-beta; tumor microenvironment; pegylated interferon; clonal expansion; chemokines; cd8(+); management; toxicity; efficacy; cancer

摘要

The CD4 T cell, when engineered with a chimeric antigen receptor (CAR) containing specific intracellular domains, has been transformed into a zero-order drug-delivery platform. This introduces the capability of prolonged, disease-specific engineered protein biologics production, at the disease site. Experimental findings demonstrate that CD4 T cells offer a solution when modified with a CAR that includes 4-1BB but excludes CD28 intracellular domain. In this configuration, they achieve similar to 3X transduction efficiency of CD8 T cells, similar to 2X expansion rates, generating similar to 5X more biologic, and exhibit minimal cytolytic activity. Cumulatively, this addresses two main hurdles in the translation of cell-based drug delivery: scaling the production of engineered T cell ex vivo and generating sufficient biologics in vivo. When programmed to induce IFN beta upon engaging the target antigen, the CD4 T cells outperforms CD8 T cells, effectively suppressing cancer cell growth in vitro and in vivo. In summary, this platform enables precise targeting of disease sites with engineered protein-based therapeutics while minimizing healthy tissue exposure. Leveraging CD4 T cells' persistence could enhance disease management by reducing drug administration frequency, addressing critical challenges in cell-based therapy.