肿瘤细胞治疗研究
英文原题：Early intrathecal dexamethasone and methotrexate as an effective approach for immune effector cell-associated neurotoxicity syndrome after CAR-T cell therapies.
我们的数据提示，早期给予 IDM 可能有助于快速缓解 CAR-T 细胞治疗后的重度或类固醇难治性 ICANS，这可能为这些患者的后续治疗创造机会。
引言：CAR-T（CAR-T）细胞疗法已在复发/难治性（R/R）B细胞血液恶性肿瘤治疗中取得显著成功。尽管CAR-T在急性髓系白血病（AML）中的应用仍受限，本团队及其他机构已证明，靶向C型凝集素样分子1（CLL1）的CAR-T治疗R/R AML可取得较高完全缓解率。然而，CAR-T相关毒性（如糖皮质激素难治性重度免疫效应细胞相关神经毒性综合征[ICANS]）可能危及生命。既往病例提示，鞘内糖皮质激素单用或联合化疗可能有效；理论上，鞘内糖皮质激素联合鞘内化疗可更快速、充分地控制ICANS。但鞘内地塞米松和甲氨蝶呤（IDM）能否使糖皮质激素难治性或重度ICANS患者获益，尚不清楚。方法：回顾性分析13例重度或糖皮质激素难治性ICANS患者临床资料，通过ICANS分级、ICE评分及实验室指标变化评估IDM疗效。3–4级ICANS降至1级，或1–2级ICANS恢复至ICE评分10分，定义为ICANS缓解。结果：13例患者中，AML 7例、ALL 3例、多发性骨髓瘤1例、B细胞淋巴瘤1例、母细胞性浆细胞样树突细胞肿瘤1例；年龄中位数39岁（11–65岁）。既往治疗线数中位数为7（1–16）。患者分别接受靶向CD19、CLL1、CD7、CD123、BCMA或CD19-CD22的6种CAR-T产品；CAR-T细胞输注剂量中位数为2.0×10⁶/kg。淋巴清除前骨髓原始细胞中位比例为33.23%（5.34%–78.50%），9例有中枢神经系统受累。所有患者均发生1–2级CRS。13例中，5例发生3–4级ICANS，8例发生1–2级ICANS。CAR-T治疗后ICANS发生时间中位数为11天（3–20天）。ICANS发生后首次IDM给药中位时间不超过12小时，IDM给药次数中位数为1次（1–3次）。ICANS缓解中位时间为1天（1–7天），应答率为92.3%（12/13）。IDM显著降低CAR-T细胞水平，并有降低脑脊液蛋白和IL-6水平的趋势。截至2025年6月30日，中位OS为6个月、中位PFS为5个月。结论：数据提示，早期给予IDM可能有助于快速缓解CAR-T治疗后的重度或糖皮质激素难治性ICANS，为患者后续治疗创造机会。仍需更大样本、多中心临床试验进一步验证。
INTRODUCTION: Chimeric antigen receptor T (CAR-T) cell therapies have demonstrated remarkable success in treating relapsed and refractory (R/R) B-cell hematological malignancies. Although the application of CAR-T therapy in acute myeloid leukemia (AML) is still restricted, we and other institutions have also demonstrated high complete remission rate of CAR-T targeting C-type lectin-like molecule 1 (CLL1) for R/R AML. However, CAR-T cell related toxicities such as steroid-refractory and severe immune effector cell-associated neurotoxicity syndrome (ICANS) can be life-threatening. Previous cases have reported potential efficacy of intrathecal corticosteroids alone or in combination with chemotherapy. Theoretically, intrathecal corticosteroids combined with intrathecal chemotherapy can control ICANS faster and better. Whether intrathecal dexamethasone and methotrexate (IDM) is beneficial for the patient with steroid-refractory or severe ICANS remains unclear. METHODS: We retrospectively analyzed the clinical data of 13 patients with severe or steroid-refractory ICANS, and evaluated the effect of IDM in the treatment of severe ICANS or steroid-refractory ICANS by analyzing the changes in ICANS grade, ICE score, and laboratory indicators. Grade 3-4 ICANS downgraded to grade 1 and grade 1-2 ICANS recovery to an ICE score of 10 points is considered ICANS remission. RESULTS: Among the 13 patients, there were 7 cases of AML, 3 cases of ALL, 1 case of MM, 1 case of B-cell lymphoma, and 1 case of blastic plasmacytoid dendritic cell neoplasm, with a median age of 39 (11-65) years. The median number of prior lines of therapy was 7(1-16). There were 6 CAR-T products targeting CD19, CLL1, CD7, CD123, BCMA, and CD19-CD22, respectively. The median CAR-T cell infusion dose was 2.0 10 6 /kg. The median bone marrow blasts before lymphocyte depletion was 33.23%(5.34%-78.50%) and 9 patients had CNS involvement. All patients developed grade 1-2 CRS. Of the 13 patients, 5 had grade 3-4 ICANS and 8 had grade 1-2 ICANS. The median onset time of ICANS after CAR-T was 11(3-20) days. The median time of first IDM after ICANS was within 12 hours, and the median number of IDM was 1(1-3). The median time to ICANS remission was 1(1-7) days, with a response rate of 92.3% (12/13 patients). IDM significantly reduced CAR-T cells and tended to reduce protein and IL-6 levels in cerebrospinal fluid. As of June 30, 2025, the median OS and median PFS were 6 months and 5 months, respectively. CONCLUSION: Our data suggest that early administration of IDM may contribute to a rapid resolution of severe or steroid-refractory ICANS after CAR-T cell therapies, which may create opportunities for subsequent treatments in these patients. Larger sample and multicenter clinical trials are warranted to further validate these findings.
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