肿瘤细胞治疗研究
英文原题：In vivo CAR T cell generation using retargeted and functionalized lentiviral vectors with reduced immunogenicity.
尽管针对血液系统恶性肿瘤疗效显著，CAR T制造的成本和复杂性仍是更广泛患者可及性的重大障碍。
尽管针对血液系统恶性肿瘤具有显著疗效，CAR T 的生产成本与复杂性仍是限制患者更广泛可及性的重大障碍。除生产方面的挑战外，T 细胞的体外扩增可能损害其功能与持久性。因此，将 CAR 递送至体内以重编程宿主细胞，将是朝着现成可用疗法迈出的重要一步，但一直受限于病毒载体的低效率、低特异性以及免疫原性。在此，我们描述了具有优越功能性和高靶向特异性的假型化慢病毒载体（LV）的设计。我们表明，用来自海豚麻疹病毒（DMV）的嵌合包膜糖蛋白进行假型化的 LV 可被改造为选择性感染人 T 细胞，并逃避麻疹疫苗接种者血清中的中和抗体反应。我们进一步证明，骆驼源纳米抗体是一种更优越的重靶向结构域，克服了使用单链可变区片段抗体所固有的局限。使用靶向 CD7 受体的嵌合 DMV 假型化病毒，我们证明了在体外和体内均能高效且高度特异性地感染 T 细胞，产生功能性 CAR T 细胞，并在临床前 B 细胞淋巴瘤模型中诱导治疗疗效。
Despite striking efficacy against hematologic malignancies, the cost and complexity of CAR T manufacturing present significant barriers to broader patient access. Beyond manufacturing challenges, ex vivo expansion of T cells may be detrimental to their function and persistence. Thus, delivery of CARs to reprogram host cells in vivo would represent a significant advance towards a readily available therapy, but has been limited by low efficiency, low specificity, and immunogenicity of viral vectors. Here, we describe the design of pseudotyped lentiviral vectors (LV) with superior functionality and high target specificity. We show that LV pseudotyped with chimeric envelope glycoproteins from dolphin morbillivirus (DMV) can be engineered to selectively infect human T cells and evade neutralizing antibody responses in measles-vaccinated human serum. We further demonstrate that camelid-derived nanobodies are a superior retargeting domain, overcoming limitations inherent to the use of single-chain variable fragment antibodies. Using a chimeric DMV-pseudotyped virus targeting the CD7 receptor, we demonstrate efficient and highly specific infection of T cells both in vitro and in vivo, generating functional CAR T cells and inducing therapeutic efficacy in a preclinical B cell lymphoma model.
MEMBER ACCOUNT
登录成功会直接打开下一页。
