肿瘤细胞治疗研究
英文原题：Cardiotoxic profiles of CAR-T therapy and bispecific T-cell engagers in hematological cancers.
Tisagenlecleucel与严重和致命的不良心脏事件相关，在DLBCL患者中，与axicabtagene ciloleucel相比，低血压的致死率更高，但在儿童ALL患者中，与blinatumomab相比，低血压致死率相似。
嵌合抗原受体（CAR）T 细胞疗法和双特异性 T 细胞衔接剂可将 T 细胞重定向至肿瘤抗原，已使复发/难治性 B 细胞癌症患者显著获益，但两类疗法的心脏毒性差异尚未充分研究。我们使用世界卫生组织药物警戒数据库 VigiBase，比较靶向 CD19 的 CAR-T 疗法与 blinatumomab（靶向 CD19/CD3 的双特异性 T 细胞衔接剂）的心脏毒性特征。方法：筛选 VigiBase 中弥漫大 B 细胞淋巴瘤（DLBCL，n=17,479）和急性淋巴细胞白血病（ALL，n=28,803）的所有不良反应安全报告，并进一步筛选接受 CAR-T 或 blinatumomab 的患者。比较 CAR-T 产品（如 tisagenlecleucel 和 axicabtagene ciloleucel）之间，以及 CAR-T 与 blinatumomab 之间的报告比值比（ROR）和病死率。结果：Tisagenlecleucel 与心力衰竭相关（IC 025=0.366），DLBCL 和儿童 ALL 患者中病死率分别为 85.7% 和 80.0%。对于 DLBCL 患者，axicabtagene ciloleucel 低血压报告比例高于 tisagenlecleucel（ROR 2.54；95% CI 1.28–5.03；p=0.012），但 tisagenlecleucel 相关低血压病死率更高［50.0% 对 5.6%；p<0.001］。在儿童 ALL 患者中，blinatumomab 和 tisagenlecleucel 相关低血压病死率相近［34.7% 对 20.0%；p=0.66］。结论：Tisagenlecleucel 与严重且致死性心脏不良事件相关；在 DLBCL 患者中，其低血压病死率高于 axicabtagene ciloleucel，而在儿童 ALL 患者中，与 blinatumomab 相关低血压病死率相近。有效管理需要由包括心脏肿瘤科医生在内、擅长跨学科处理此类毒性的资深医生参与。嵌合抗原受体（CAR）T 细胞疗法和 blinatumomab 是两种用于治疗常规化疗无效血液癌症的新疗法。我们旨在研究这些疗法对心脏影响是否存在重大差异。我们分析了大型全球患者数据库。结果发现，在弥漫大 B 细胞淋巴瘤中，两种 CAR-T 疗法均与心力衰竭和低血压相关；在另一种癌症急性淋巴细胞白血病中，CAR-T 疗法与心力衰竭和心脏骤停相关。本研究提示，鉴于此类副作用的发生频率和严重程度，临床照护应由有经验的跨学科团队共同开展。
BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy and bispecific T-cell engagers, which redirect T-cells to tumor antigens, have immensely benefitted patients with relapsed/refractory B-cell cancers. How these therapies differ in cardiotoxicity is underexplored. We used the World Health Organization pharmacovigilance database, VigiBase, to compare cardiotoxicity profiles between CD19-targeted CAR-T therapy and blinatumomab (a CD19/CD3-targeted bispecific T-cell engager). METHODS: Safety reports in VigiBase were filtered for diffuse large B-cell lymphoma (DLBCL, n = 17,479) and acute lymphocytic leukemia (ALL, n = 28,803) for all adverse reactions. Data were further filtered for patients taking CAR-T therapy or blinatumomab. Reporting odds ratios (ROR) and fatality rates were compared between CAR-T cell products (e.g. tisagenlecleucel and axicabtagene ciloleucel), and between CAR-T therapy and blinatumomab. RESULTS: Tisagenlecleucel is associated with cardiac failure (IC 025 = 0.366) with fatality rates of 85.7% and 80.0% in DLBCL and pediatric ALL patients respectively. For DLBCL patients, axicabtagene ciloleucel has greater reporting for hypotension than tisagenlecleucel (ROR: 2.54; 95% CI: 1.28-5.03; p = 0.012), but tisagenlecleucel has higher fatality rates for hypotension than axicabtagene ciloleucel [50.0% (tisagenlecleucel) vs 5.6% (axicabtagene ciloleucel); p < 0.001]. Blinatumomab and tisagenlecleucel have similar fatality rates for hypotension in pediatric ALL patients [34.7% (tisagenlecleucel) vs 20.0% (blinatumomab); p = 0.66]. CONCLUSIONS: Tisagenlecleucel is associated with severe and fatal adverse cardiac events, with higher fatality rates for hypotension compared to axicabtagene ciloleucel in DLBCL patients, but similar hypotension fatality rates compared to blinatumomab in pediatric ALL patients. Effective management necessitates experienced physicians, including cardio-oncologists, skilled in interdisciplinary approaches to manage these toxicities. Chimeric antigen receptor (CAR) T-cell therapy and blinatumomab are two new types of cancer therapies used to treat blood cancers that fail to respond to conventional chemotherapy. Our goal is to study if there are major differences in how these treatments affect the heart. We analyzed a large, global database of patients who had these treatments. We find that in a blood cancer called diffuse large B-cell lymphoma, two CAR-T cell therapies are linked to heart failure and low blood pressure. In another type of cancer, acute lymphocytic leukemia, CAR-T cell therapy is associated with heart failure and cardiac arrest. The study suggests that given the frequency and severity of these side effects, clinical care should involve an interdisciplinary team experienced in managing these serious side effects.
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