Hunter Theresa L, Bao Yanjie, Zhang Yan, Matsuda Daiki, Riener Romina, Wang Annabel, Li John J, Soldevila Ferran, Chu David S H, Nguyen Duy P, Yong Qian-Chen, Ross Brittany, Nguyen Michelle, Vestal James, Roberts Scott, Galvan Diana, Vega Jerel Boyd, Jhung Donald, Butcher Matthew, Nguyen Josephine, Zhang Stanley, Fernandez Claudia, Chen Jeffrey, Herrera Carolina, Kuo Yi, Pica E Michael, Mondal Goutam, Mammen Andrew L, Scholler John, Tanis Steven P, Sievers Stuart A, Frantz Aric M, Adams Gregor B, Shawver Laura, Farzaneh-Far Ramin, Rosenzweig Michael, Karmali Priya P, Bot Adrian I, June Carl H, Aghajanian Haig
Capstan Therapeutics, San Diego, CA, USA.
Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Science. 2025 Jun 19;388(6753):1311-1317. doi: 10.1126/science.ads8473.
Chimeric antigen receptor (CAR) T cell therapies have transformed treatment of B cell malignancies. However, their broader application is limited by complex manufacturing processes and the necessity for lymphodepleting chemotherapy, restricting patient accessibility. We present an in vivo engineering strategy using targeted lipid nanoparticles (tLNPs) for messenger RNA delivery to specific T cell subsets. These tLNPs reprogrammed CD8 T cells in both healthy donor and autoimmune patient samples, and in vivo dosing resulted in tumor control in humanized mice and B cell depletion in cynomolgus monkeys. In cynomolgus monkeys, the reconstituted B cells after depletion were predominantly naïve, suggesting an immune system reset. By eliminating the requirements for complex ex vivo manufacturing, this tLNP platform holds the potential to make CAR T cell therapies more accessible and applicable across additional clinical indications.
嵌合抗原受体（CAR）T细胞疗法已经改变了B细胞恶性肿瘤的治疗方式。然而，它们的更广泛应用受到复杂制造工艺和淋巴细胞清除化疗必要性的限制，从而限制了患者的可及性。我们提出了一种体内工程策略，使用靶向脂质纳米颗粒（tLNPs）将信使核糖核酸递送至特定的T细胞亚群。这些tLNPs在健康供体和自身免疫患者样本中对CD8 T细胞进行了重编程，体内给药导致人源化小鼠的肿瘤得到控制，食蟹猴的B细胞被清除。在食蟹猴中，清除后重新构建的B细胞主要是幼稚型的，这表明免疫系统被重置。通过消除对复杂体外制造的需求，这个tLNP平台有可能使CAR T细胞疗法更容易获得，并适用于更多的临床适应症。
