Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia.
Division of Medical and Biological Sciences, Academy of Sciences of the Republic of Tatarstan, 420111 Kazan, Russia.
Cells. 2024 Nov 16;13(22):1892. doi: 10.3390/cells13221892.
CAR-T therapy has revolutionized the field of oncology, offering a promising treatment option for cancer patients. However, the significant morbidity associated with therapy-related toxicity presents a major challenge to its widespread use. Despite extensive research into the underlying mechanisms of CAR-T therapy-related toxicity, there are still many unknowns. Furthermore, the lack of adequate in vitro models for assessing immunotoxicity and neurotoxicity further complicates the development of safer cellular therapies. Previously in our laboratory, we developed cancer-stroma spheres (CSS) composed of prostate adenocarcinoma PC3 cells and mesenchymal stem cells (MSC). Herein we present evidence that multicellular CSS could serve as a valuable in vitro model for toxicity studies related to CAR-T therapy. CSS containing CD19-overexpressing PC3M cells exhibited increased secretion of CAR-T cell toxicity-associated IL-8, MCP-1, and IP-10 in the presence of anti-CD19 CAR-T cells, compared to spheres derived from single cell types.
嵌合抗原受体 T 细胞（CAR-T）疗法彻底改变了肿瘤学领域，为癌症患者提供了一种有前景的治疗选择。然而，与治疗相关的毒性所带来的高发病率对其广泛应用构成了重大挑战。尽管对 CAR-T 治疗相关毒性的潜在机制进行了广泛研究，但仍有许多未知因素。此外，缺乏评估免疫毒性和神经毒性的充分体外模型，进一步使更安全的细胞疗法的开发复杂化。此前，我们实验室开发了由前列腺腺癌 PC3 细胞和间充质干细胞（MSC）组成的肿瘤基质球体（CSS）。在此，我们提出证据表明，多细胞 CSS 可以作为与 CAR-T 治疗相关的毒性研究的有价值的体外模型。与源自单细胞类型的球体相比，含有过表达 CD19 的 PC3M 细胞的 CSS 在存在抗 CD19 CAR-T 细胞时，表现出 CAR-T 细胞毒性相关的 IL-8、MCP-1 和 IP-10 的分泌增加。
