Mukhametshin Sabir A, Gilyazova Elvina M, Davletshin Damir R, Ganeeva Irina A, Zmievskaya Ekaterina A, Chasov Vitaly V, Petukhov Alexsei V, Valiullina Aigul Kh, Spada Sheila, Bulatov Emil R
Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia.
Laboratory of Molecular Oncology, National Laboratory Astana, Astana 010000, Kazakhstan.
Biomedicines. 2025 Sep 22;13(9):2314. doi: 10.3390/biomedicines13092314.
Chimeric Antigen Receptor (CAR)-T cell therapy has transformed the treatment landscape of cancer, yet major challenges remain in enhancing efficacy, reducing adverse effects, and expanding accessibility. Autologous CAR-T cells, derived from individual patients, have achieved remarkable clinical success in hematologic malignancies; however, their highly personalized nature limits scalability, increases costs, and delays timely treatment. Allogeneic CAR-T cells generated from healthy donors provide an "off-the-shelf" alternative but face two critical immune barriers: graft-versus-host disease (GvHD), caused by donor T-cell receptor (TCR) recognition of host tissues, and host-versus-graft rejection, mediated by recipient immune responses against donor HLA molecules. Recent advances in genome engineering, particularly Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9, allow precise modification of donor T cells to overcome these limitations. For example, TRAC gene knockout eliminates TCR expression, preventing GvHD, while disruption of HLA molecules reduces immunogenicity without impairing cytotoxicity. Beyond hematologic cancers, CRISPR-edited allogeneic CAR-T cells targeting the NKG2D receptor have shown promise in preclinical studies and early-phase trials. NKG2D CAR-T cells recognize stress ligands (MICA/B, ULBP1-6) expressed on over 80% of diverse solid tumors, including pancreatic and ovarian cancers, thereby broadening therapeutic applicability. Nevertheless, the genomic editing process carries risks of off-target effects, including potential disruption of tumor suppressor genes and oncogenes, underscoring the need for stringent safety and quality control. This review examines the distinguishing features of allogeneic versus autologous CAR-T therapy, with a particular focus on NKG2D-based allogeneic CAR-T approaches for solid tumors. We summarize current strategies to mitigate immune barriers, discuss practical manufacturing challenges, and analyze available clinical data on NKG2D CAR-T trials. Collectively, these insights underscore both the promise and the hurdles of developing safe, universal, and scalable allogeneic CAR-T therapies for solid malignancies.
嵌合抗原受体（CAR）-T细胞疗法已经改变了癌症的治疗格局，但在提高疗效、减少不良反应和扩大可及性方面仍存在重大挑战。源自个体患者的自体CAR-T细胞在血液系统恶性肿瘤中取得了显著的临床成功；然而，其高度个性化的性质限制了可扩展性，增加了成本，并延误了及时治疗。从健康供体产生的同种异体CAR-T细胞提供了一种“现货”替代方案，但面临两个关键的免疫障碍：由供体T细胞受体（TCR）识别宿主组织引起的移植物抗宿主病（GvHD），以及由受体针对供体HLA分子的免疫反应介导的宿主抗移植物排斥。基因组工程的最新进展，特别是成簇规律间隔短回文重复序列（CRISPR）/Cas9，允许对供体T细胞进行精确修饰以克服这些限制。例如，TRAC基因敲除消除了TCR表达，预防了GvHD，而HLA分子的破坏降低了免疫原性而不损害细胞毒性。除了血液系统癌症，靶向NKG2D受体的CRISPR编辑的同种异体CAR-T细胞在临床前研究和早期试验中已显示出前景。NKG2D CAR-T细胞识别超过80%的各种实体瘤（包括胰腺癌和卵巢癌）上表达的应激配体（MICA/B、ULBP1-6），从而拓宽了治疗适用性。然而，基因组编辑过程存在脱靶效应的风险，包括潜在的肿瘤抑制基因和癌基因的破坏，这突出了严格的安全和质量控制的必要性。本综述探讨了同种异体与自体CAR-T疗法的区别特征，特别关注基于NKG2D的实体瘤同种异体CAR-T方法。我们总结了当前减轻免疫障碍的策略，讨论了实际生产挑战，并分析了NKG2D CAR-T试验的现有临床数据。总的来说，这些见解强调了开发用于实体恶性肿瘤的安全、通用和可扩展的同种异体CAR-T疗法的前景和障碍。
