Synthetic Immunology Laboratory, Cancer Research Division, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India; Mani pal Academy of Higher Education, Manipal 576104, Karnataka, India.
Synthetic Immunology Laboratory, Cancer Research Division, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India; Advanced Academic Program, Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore MD 21218, USA.
Cytokine. 2022 Aug;156:155920. doi: 10.1016/j.cyto.2022.155920. Epub 2022 Jun 7.
CAR therapy holds promise in treating aggressive hematological malignancies. Nonetheless, the present autologous CAR therapy regimen makes multiple patients ineligible for the therapy due to inadequate quantity, quality and purity of the product. Furthermore, timely manufacturing of benchmarked cell products is logistically challenging and unaffordable. Extensive genetic modifications may be required to overcome the biological, clinical and manufacturing limitations of the autologous CAR therapy. n the light of the numerous configurations of CAR therapy, engineering "off-the-shelf" universal CAR T cells (UCART) is emerging as a safer, effective and affordable alternative to conventional CAR T cells With UCART therapy, batch production of a quality-controlled product with multiplex genetic modification can be feasible in a shorter period of time. Currently vast majority of the UCART programs target CD19 followed by BCMA and CD70. In order to make universal CAR T cell therapy possible, it is imperative to have engineering strategies to curb graft versus host disease (GvHD) and graft rejection (GR). Moreover, approaches to offer alternate strategies for intense preparative chemotherapy, infection control and CAR T cell persistence need to be optimized. An ideal universal immune receptor (UIR) design should counter the antigen escape and further the therapeutic value and affordability. UIRs would allow flexibility to personalize the therapy based on the specific malignancy characteristics as well. With the innovations in the inducible molecular switch, split CAR design, CRISPR/Cas9 mediated gene targeting, rational subset composition and cryopreservation, the strategies to engineer universal CAR T therapy is fast advancing from bench to bedside.
嵌合抗原受体（CAR）疗法在治疗侵袭性血液恶性肿瘤方面具有广阔的前景。然而，目前的自体 CAR 疗法方案由于产品数量、质量和纯度不足，使许多患者不符合治疗条件。此外，及时制造具有基准的细胞产品在物流上具有挑战性且负担不起。为了克服自体 CAR 疗法的生物学、临床和制造限制，可能需要进行广泛的基因修饰。鉴于 CAR 疗法的多种构型，工程化“现成的”通用嵌合抗原受体 T 细胞（UCART）正在成为一种更安全、有效且负担得起的替代传统 CAR T 细胞的方法。使用 UCART 疗法，可以在更短的时间内实现具有多重基因修饰的质量控制产品的批量生产。目前，绝大多数 UCART 项目以 CD19 为靶点，其次是 BCMA 和 CD70。为了使通用 CAR T 细胞疗法成为可能，必须有工程化策略来抑制移植物抗宿主病（GvHD）和移植物排斥（GR）。此外，需要优化替代策略，以提供强化预处理化疗、感染控制和 CAR T 细胞持久性的方法。理想的通用免疫受体（UIR）设计应能对抗抗原逃逸，并进一步提高治疗价值和可负担性。UIR 还可以根据特定的恶性肿瘤特征灵活地个性化治疗。随着诱导分子开关、分裂 CAR 设计、CRISPR/Cas9 介导的基因靶向、合理的亚群组成和冷冻保存方面的创新，工程化通用 CAR T 疗法的策略正在从实验室快速推进到临床应用。
