肿瘤细胞治疗研究
英文原题：ICANS mitigation in high-risk elderly patients treated with CD28 co-stimulatory anti-CD19 CAR-T cells using a standardization protocol: a pilot study.
ICANS mitigation in high-risk elderly patients treated with CD28 co-stimulatory anti-CD19 CAR-T cells using a standardization protocol: a pilot study.
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使用 axicabtagene-ciloleucel 和 brexucabtagene-autoleucel 时，总体 ICANS 与重度 ICANS 的发生率分别达 78% 和 35%。
CAR-T 细胞已革新复发/难治性大B细胞淋巴瘤（LBCL）治疗；CD28共刺激型产品虽可快速诱导应答，但免疫效应细胞相关神经毒性综合征（ICANS）发生率较高。使用阿基仑赛或布瑞基奥仑赛时，任何级别和重度ICANS发生率分别可达78%和35%。老年人尤其脆弱，但目前缺少风险缓解策略。为填补这一重要空白，研究者旨在为接受CD28型抗CD19 CAR-T 的老年人开发并实施标准化ICANS缓解方案。本单臂前瞻性试点研究纳入≥75岁，或≥65岁且另有危险因素的患者。方案包括预防性使用左乙拉西坦和硫胺素、早期按级别使用皮质类固醇，以及对3级和难治性ICANS使用阿那白滞素；难治性定义为24小时内无改善。终点包括ICANS持续时间、难治性、应答及毒性。45例患者符合条件，中位年龄75岁（范围65–86岁）；78% ECOG体能状态为2，42%有神经系统合并症。总体中67%发生3级或难治性ICANS，其中3级占31%，难治性占20%。ICANS中位持续4天，短于既往队列。疾病和患者特征不能预测ICANS指标，乳酸脱氢酶除外，其与重度ICANS仅呈趋势关联（P=0.07）。修正的内皮活化与应激指数（mEASIX）及ICANS预后评分系统（PSS）均无预测价值，且CAR-T 扩增未受影响。累积类固醇使用与感染（P=0.002）和非复发死亡率（P<0.0001）相关。6个月无进展生存率和总生存率分别为46%和59%。在这一高危队列中，按级别使用阿那白滞素而非预防性或挽救性使用，并采用务实的难治定义，与ICANS持续时间缩短相关，尽管重度事件仍较常见。类固醇相关毒性仍是关注重点；未来应开发减少类固醇使用的缓解策略，以优化老年CAR-T 患者结局。
Chimeric antigen receptor T-cell therapy (CAR-T) has transformed the treatment of relapsed/refractory large B-cell lymphoma (LBCL), with CD28-based products yielding rapid responses but higher rates of immune effector cell-associated neurotoxicity syndrome (ICANS). With axicabtagene-ciloleucel and brexucabtagene-autoleucel, overall and severe ICANS reach 78% and 35%, respectively. Older adults are vulnerable, yet mitigation strategies are still lacking. To address this critical gap, we aimed to develop and implement a standardized ICANS mitigation protocol for older adults receiving CD28-based anti- CD19 CAR-T. We conducted a single-arm prospective pilot study in patients 75 or 65 years with additional risk factor receiving CD28-based CAR-T. The protocol included levetiracetam and thiamine prophylaxis, early grade-based corticosteroids and anakinra for grade 3 and refractory ICANS, which was defined as no improvement within 24 hours. Endpoints were ICANS duration, refractoriness, response, and toxicity. Forty-five patients met eligibility criteria. Median age was 75 years (range: 65-86 years); 78% had Eastern Cooperative Oncology Group (ECOG) 2 and 42% had neurologic comorbidity. Grade 3 and refractory ICANS developed in 67% overall, with grade 3 in 31%, and refractory ICANS in 20%. Median ICANS duration was four days, which was shorter than previous cohorts. Disease and patients' characteristics did not predict ICANS metrics, excluding lactate dehydrogenase which showed a trend for severe ICANS (P=0.07). modified Endothelial Activation and Stress Index (mEASIX) and ICANS-Prognostic Scoring System (PSS) scores were not predictive and expansion was not compromised. Cumulative steroids associated with infections (P=0.002) and non-relapse mortality (P<0.0001). Sixmonth progression-free survival and overall survival were 46% and 59%, respectively. In this high-risk cohort, the ICANS mitigation protocol using anakinra in a graded approach (vs. prophylaxis or salvage therapy) and a pragmatic definition of refractory disease was associated with shorter ICANS duration, despite severe event rates. Steroid-related toxicity remains a concern, and future efforts should focus on steroid-sparing mitigation to optimize outcomes in older adults undergoing CAR-T.
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