Freitag Patrick C, Kaulfuss Meike, Flühler Lea, Mietz Juliane, Weiss Fabian, Brücher Dominik, Kolibius Jonas, Hartmann K Patricia, Smith Sheena N, Münz Christian, Chijioke Obinna, Plückthun Andreas
Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Cellular Immunotherapy, Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Mol Ther Methods Clin Dev. 2023 Feb 26;29:120-132. doi: 10.1016/j.omtm.2023.02.012. eCollection 2023 Jun 8.
Clinical success in T cell therapy has stimulated widespread efforts to increase safety and potency and to extend this technology to solid tumors. Yet progress in cell therapy remains restricted by the limited payload capacity, specificity of target cell transduction, and transgenic gene expression efficiency of applied viral vectors. This renders complex reprogramming or direct applications difficult. Here, we developed a synergistic combination of trimeric adapter constructs enabling T cell-directed transduction by the human adenoviral vector serotype C5 and . Rationally chosen binding partners showed receptor-specific transduction of otherwise non-susceptible human T cells by exploiting activation stimuli. This platform remains compatible with high-capacity vectors for up to 37 kb DNA delivery, increasing payload capacity and safety because of the removal of all viral genes. Together, these findings provide a tool for targeted delivery of large payloads in T cells as a potential avenue to overcome current limitations of T cell therapy.
T细胞疗法的临床成功激发了人们为提高安全性和效力以及将该技术扩展至实体瘤而做出的广泛努力。然而，细胞疗法的进展仍然受到所应用病毒载体的有限载量能力、靶细胞转导特异性和转基因表达效率的限制。这使得复杂的重编程或直接应用变得困难。在此，我们开发了一种三聚体衔接子构建体的协同组合，可实现人C5血清型腺病毒载体对T细胞的定向转导。通过合理选择结合伙伴，利用激活刺激实现了对原本不敏感的人T细胞的受体特异性转导。该平台与用于递送长达37 kb DNA的高容量载体兼容，由于去除了所有病毒基因，提高了载量能力和安全性。总之，这些发现为在T细胞中靶向递送大量载荷提供了一种工具，作为克服当前T细胞疗法局限性的潜在途径。
