Chicaybam Leonardo, Bonamino Martín H, Luckow Invitti Adriana, Bortman Rozenchan Patricia, de Luna Vieira Igor, Strauss Bryan E
Vice Presidência de Pesquisa e Coleções Biológicas, Fundação Instituto Oswaldo Cruz (FIOCRUZ), Rio de Janeiro 21040-900, Brazil.
Programa de Imunologia e Biologia de Tumores, Coordenação de Pesquisa, Instituto Nacional de Câncer (INCA), Rio de Janeiro 20231-050, Brazil.
Cancers (Basel). 2020 Aug 21;12(9):2360. doi: 10.3390/cancers12092360.
Gene therapy is now surpassing 30 years of clinical experience and in that time a variety of approaches has been applied for the treatment of a wide range of pathologies. While the promise of gene therapy was over-stated in the 1990's, the following decades were met with polar extremes between demonstrable success and devastating setbacks. Currently, the field of gene therapy is enjoying the rewards of overcoming the hurdles that come with turning new ideas into safe and reliable treatments, including for cancer. Among these modalities, the modification of T cells with chimeric antigen receptors (CAR-T cells) has met with clear success and holds great promise for the future treatment of cancer. We detail a series of considerations for the improvement of the CAR-T cell approach, including the design of the CAR, routes of gene transfer, introduction of CARs in natural killer and other cell types, combining the CAR approach with checkpoint blockade or oncolytic viruses, improving pre-clinical models as well as means for reducing cost and, thus, making this technology more widely available. While CAR-T cells serve as a prime example of translating novel ideas into effective treatments, certainly the lessons learned will serve to accelerate the current and future development of gene therapy drugs.
基因治疗如今已有超过30年的临床经验，在此期间，人们应用了多种方法来治疗各种各样的病症。虽然在20世纪90年代基因治疗的前景被过度夸大，但在接下来的几十年里，该领域经历了明显的成功与毁灭性挫折之间的两极分化。目前，基因治疗领域正在收获克服将新想法转化为安全可靠治疗方法（包括癌症治疗方法）所带来的障碍的成果。在这些治疗方式中，用嵌合抗原受体修饰T细胞（CAR-T细胞）已取得显著成功，并对未来癌症治疗具有巨大潜力。我们详细阐述了一系列改进CAR-T细胞方法的考虑因素，包括CAR的设计、基因转移途径、在自然杀伤细胞和其他细胞类型中引入CAR、将CAR方法与检查点阻断或溶瘤病毒相结合、改进临床前模型以及降低成本的方法，从而使这项技术更广泛地可用。虽然CAR-T细胞是将新想法转化为有效治疗方法的一个典型例子，但无疑所吸取的经验教训将有助于加速当前和未来基因治疗药物的发展。
