CAR-T治疗B-NHL导致局部严重CRS机制与干预策略研究

CAR-T疗法在复发/难治性恶性血液系统疾病的治疗中取得了显著的进步，但同时也存在特异甚至致命性的毒副作用，其中以CRS反应最常见。在本团队在前期CAR-T治疗淋巴瘤患者的临床工作中，我们发现大负荷的肿瘤会在病灶局部引发显著的炎症反应，我们将其定义为局部的CRS。持续进展的局部CRS反应会诱发严重的系统性CRS，并导致器官不可逆性损伤甚至危及生命。但是，此类患者若仅遵循现有CRS管理指南救治，难以平稳过渡，比如使用anti-IL-6R会导致局部CRS加重。这提示我们局部CRS的发生机制可能不同于系统性CRS。因此，本研究拟通过在免疫健全小鼠中构建局部CRS模型，结合临床样本，探索局部CRS的进展规律和细胞分子机制。在此基础上，筛选并评价潜在干预策略对控制局部CRS反应的可行性和有效性。相关研究结果将为临床上局部CRS的管理提供新的治疗策略和重要的理论依据。

CAR-T therapy has made remarkable progress in the treatment of relapse/refractory malignant hematologic diseases, but it also has specific, or fatal adverse effects, among which, the CRS is the most common one. In our team's previous CAR-T cells clinical work in the treatment of lymphoma, we found that large load of tumors would cause significant inflammatory responses in the local sites, which we defined as local CRS. Progressive local CRS responses can induce severe systemic CRS and lead to irreversible or life-threatening organ damages. However, it is difficult for such patients to make a smooth transition if they only follow the existing CRS management guidelines. For example, the use of anti IL-6R had lead to local aggravaing CRS. This suggests that the mechanism of local CRS may be different from systematic CRS. Therefore, this study intends to explore the progression in cellular and molecular mechanisms of local CRS by constructing local CRS models in immune-healthy mice and combining with clinical samples. On this basis, the feasibility and effectiveness of potential intervention strategies for controlling local CRS responses were screened and evaluated. Relevant research results will provide new therapeutic strategies and important theoretical basis for the management of local CRS in clinical practice.