决定异体 CAR T 细胞排斥与扩增的细胞和分子机制
Cellular and molecular mechanisms determining allogeneic CAR T cell rejection and expansion.
我们评估了11例接受单一批次cemacabtagene ansegedleucel(cema-cel)治疗的大B细胞淋巴瘤患者,cemacabtagene ansegedleucel是一种异体抗CD19 CAR T产品。
英文原题:Recognition and management of early complications in CAR-T cell therapy and virus-specific T-lymphocyte therapy: a practical clinical reference.
国际公认的标准对细胞免疫效应疗法的早期并发症进行分级。及时识别、早期药物干预和监测对于降低非复发死亡率至关重要。不断扩大的真实世界经验以及治疗前风险分层工具的整合,将继续完善这一快速发展领域中基于证据的实践,最终改善患者结局并降低非复发死亡率。
细胞免疫疗法——包括CAR-T 细胞疗法和病毒特异性T淋巴细胞(VSTs)的过继转移——已改变了难治性血液系统恶性肿瘤和移植后感染性并发症的治疗。目前欧洲药品管理局已批准八种产品,包括七种靶向CD19或BCMA的自体CAR-T产品以及tabelecleucel(Ebvallo),后者是首个获批的异体即用型EBV特异性T细胞产品,用于EBV阳性移植后淋巴增殖性疾病。尽管两者具有临床疗效,但这两种模式均具有不同于传统细胞毒性化疗的独特早期毒性特征。
本综述总结了识别、评估和治疗CAR-T细胞治疗及VST输注后可能出现的早期问题的当前建议。内容:讨论的CAR-T特异性并发症包括细胞因子释放综合征(CRS)、免疫效应细胞相关神经毒性综合征(ICANS)、免疫效应细胞相关血液毒性(ICAHT)和免疫效应细胞相关HLH样综合征(IEC-HS)。CRS按ASTCT共识标准分级,并以tocilizumab作为一线药物治疗;激素难治性ICANS最常采用高剂量静脉注射anakinra(最高12 mg/kg/天)治疗,这是目前研究最多的二线选择,尽管支持证据仍主要为观察性研究。ICAHT采用经过验证的EHA/EBMT分级框架进行分类,根据深度和持续时间区分早期(第0-30天)和晚期(第30天后)中性粒细胞减少,管理从预防性G-CSF逐步升级至造血细胞支持,最终选择为异基因HSCT。对于VST,主要的早期并发症为肿瘤 flare 反应(约20%的tabelecleucel受者)、GVHD(使用富集产品时低于5%)、急性输注反应和低级别CRS样细胞因子释放。我们总结了重叠综合征的鉴别诊断、儿科特异性调整、ICU升级标准和临床监测计划。
BACKGROUND: Cellular immunotherapies-including chimeric antigen receptor T-cell (CAR-T) therapies and adoptive transfer of virus-specific T lymphocytes (VSTs) - have transformed the treatment of refractory hematological malignancies and post-transplant infectious complications. Eight products are currently authorized by the European Medicines Agency, encompassing seven autologous CAR-T products targeting CD19 or BCMA and tabelecleucel (Ebvallo), the first approved allogeneic off-the-shelf EBV-specific T-cell product for EBV-positive post-transplant lymphoproliferative disease. Despite their clinical efficacy, both modalities carry distinct early toxicity profiles that differ from conventional cytotoxic chemotherapy. OBJECTIVE: This review summarizes current recommendations for identifying, assessing, and treating early problems that can occur after CAR-T cell therapy and VST administration. CONTENT: CAR-T-specific complications discussed include cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), immune effector cell-associated hematotoxicity (ICAHT), and immune effector cell-associated HLH-like syndrome (IEC-HS). CRS is graded by ASTCT consensus criteria and managed with tocilizumab as first-line pharmacological therapy; steroid-refractory ICANS is most commonly treated with high-dose intravenous anakinra (up to 12 mg/kg/day) which is currently the most studied second-line option, although the supporting evidence remains largely observational. ICAHT is classified using the validated EHA/EBMT grading framework, separating early (day 0-30) and late (post-day 30) neutropenia by depth and duration, with management escalating from prophylactic G-CSF through hematopoietic cell boost to allogeneic HSCT as the ultimate option. For VSTs, the principal early complications are tumor flare reaction (in approximately 20% of tabelecleucel recipients), GVHD (below 5% with enriched products), acute infusion reactions, and low-grade CRS-like cytokine release. We summarize a differential diagnosis of overlapping syndromes, pediatric-specific adaptations, ICU escalation criteria, and a clinical monitoring schedule. CONCLUSIONS: Internationally validated criteria grade the early complications of cellular immune effector therapies. Prompt recognition, early pharmacological intervention, and monitoring are essential to minimize non-relapse mortality. Expanding real-world experience and the integration of pre-treatment risk stratification tools will continue to refine evidence-based practice in this rapidly evolving field, ultimately leading to improved patient outcomes and reduced non-relapse mortality rates.
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