Chimeric Antigen Receptor T-Cell Therapies for Aggressive B-Cell Lymphomas: Current and Future State of the Art.
Chimeric Antigen Receptor T-Cell Therapies for Aggressive B-Cell Lymphomas: Current and Future State of the Art.
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DOI：
10.1200/edbk_238693
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发表时间：
2019-01-01
期刊：
影响因子：
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通讯作者：
Palomba, M Lia
中科院分区：
文献类型：
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作者：
Abramson, Jeremy S;Lunning, Matthew;Palomba, M Lia
对于一线化学免疫疗法原发难治或在一线化学免疫疗法后复发的侵袭性 B 细胞淋巴瘤，采用常规疗法的治愈率较低。尽管高剂量化疗仍然是足够年轻和健康的患者首次复发时的标准治疗方法，但只有不到四分之一的复发/难治性疾病患者通过这种方法得到治愈。抗 CD19 嵌合抗原受体 (CAR) T 细胞已成为治疗多种复发/难治性疾病患者的有效疗法，能够诱导化疗难治性疾病患者的持久缓解。三种用于侵袭性 B 细胞淋巴瘤的抗 CD19 CAR T 细胞（axicabtagene ciloleucel、tisagenlecleucel 和 lisocabtagene ciloleucel）已获得美国食品和药物管理局批准或处于后期开发阶段。所有三种 CAR T 细胞都能在 33%-40% 的治疗患者中产生持久缓解。这些产品之间的差异包括特定的 CAR 结构、共刺激域、制造工艺、剂量和关键试验的资格标准。值得注意的毒性包括细胞因子释放综合征和神经毒性，这些毒性通常是可治疗和可逆的，以及血细胞减少症和低丙种球蛋白血症。不同 CAR T 细胞产品的细胞因子释放综合征和神经毒性的发生率不同，部分与共刺激域的类型有关。潜在的耐药机制包括 CAR T 细胞耗竭和免疫逃避、CD19 抗原丢失以及缺乏持久性。 CAR T细胞的合理组合策略正在评估中，包括免疫检查点抑制剂、免疫调节剂和酪氨酸激酶抑制剂。新型细胞产品也在开发中，包括针对多种肿瘤抗原的 CAR T 细胞、分泌细胞因子的 CAR T 细胞和基因编辑的 CAR T 细胞等。
Aggressive B-cell lymphomas that are primary refractory to, or relapse after, frontline chemoimmunotherapy have a low cure rate with conventional therapies. Although high-dose chemotherapy remains the standard of care at first relapse for sufficiently young and fit patients, fewer than one-quarter of patients with relapsed/refractory disease are cured with this approach. Anti-CD19 chimeric antigen receptor (CAR) T cells have emerged as an effective therapy in patients with multiple relapsed/refractory disease, capable of inducing durable remissions in patients with chemotherapy-refractory disease. Three anti-CD19 CAR T cells for aggressive B-cell lymphoma (axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene ciloleucel) are either U.S. Food and Drug Administration approved or in late-stage development. All three CAR T cells produce durable remissions in 33%-40% of treated patients. Differences among these products include the specific CAR constructs, costimulatory domains, manufacturing process, dose, and eligibility criteria for their pivotal trials. Notable toxicities include cytokine release syndrome and neurologic toxicities, which are usually treatable and reversible, as well as cytopenias and hypogammaglobulinemia. Incidences of cytokine release syndrome and neurotoxicity differ across CAR T-cell products, related in part to the type of costimulatory domain. Potential mechanisms of resistance include CAR T-cell exhaustion and immune evasion, CD19 antigen loss, and a lack of persistence. Rational combination strategies with CAR T cells are under evaluation, including immune checkpoint inhibitors, immunomodulators, and tyrosine kinase inhibitors. Novel cell products are also being developed and include CAR T cells that target multiple tumor antigens, cytokine-secreting CAR T cells, and gene-edited CAR T cells, among others.