肿瘤细胞治疗研究
英文原题：Beyond immune checkpoint blockade: T cell engagers and antibody-drug conjugates in cancer and autoimmune disease.
免疫检查点抑制剂已经改变了癌症治疗；然而，耐药性、靶向毒性和在自身免疫性疾病中有限的疗效推动了下一代免疫疗法的发展。
免疫检查点抑制剂已经改变了癌症治疗格局；然而，耐药性、靶向毒性和在自身免疫性疾病中疗效有限，推动了下一代免疫疗法的发展。T 细胞衔接器（TCE）能够将细胞毒性 T 细胞重定向以杀伤致病细胞，且不依赖 MHC 限制；而抗体药物偶联物（ADC）则通过受体介导的内吞作用将强效载荷直接递送至靶细胞。本综述综合了 TCE 和 ADC 在肿瘤学及免疫介导炎症性疾病（IMID）中的临床前和临床数据。CD47/SIRP 固有免疫检查点作为下一代免疫药理学的一个案例被简要审视，其中 evorpacept 和 BYON4228 等药物在与利妥昔单抗联合治疗非霍奇金淋巴瘤时显示出令人鼓舞的客观缓解率（50% ORR），下一代设计降低了血液学毒性。近期自身免疫性疾病中的同情用药研究结果表明，CD19 CD3 TCE（blinatumomab）和 B 细胞成熟抗原（BCMA）CD3 TCE（teclistamab）可在难治性抗合成酶综合征和系统性硬化症中迅速引起临床改善，并伴随细胞因子释放综合征（CRS）（分别有 40% 和 100% 的患者为 3 级），且无神经毒性。在 CD3 亲和力减弱的工程化 TCE 中，1-2 级 CRS 发生率 < 20%。除细胞清除策略外，靶向 OX40L/TNF 的双特异性抗体和抗 TL1A 抗体正在化脓性汗腺炎和风湿性疾病中推进。相反，ADC 策略结果不一；一种抗 TNF-糖皮质激素受体调节剂 ADC 在 2b 期试验中未能优于阿达木单抗。安全性特征存在差异：TCE主要引起细胞因子释放综合征，而ADC则带来脱靶载荷毒性风险。新兴的双靶向TCE、半衰期延长形式及合理联合方案体现了关键免疫药理学原理，可能拓宽癌症和自身免疫性疾病的治疗格局。
Immune checkpoint inhibitors have transformed cancer treatment; however, resistance, on-target toxicity, and limited efficacy in autoimmune disorders have motivated next-generation immunotherapies. T cell engagers (TCEs) redirect cytotoxic T cells to kill pathogenic cells independently of MHC restriction, whereas antibody-drug conjugates (ADCs) deliver potent payloads directly into target cells via receptor-mediated internalization. This review synthesizes preclinical and clinical data on TCEs and ADCs in oncology and immune-mediated inflammatory disorders (IMIDs). The CD47/SIRP innate immune checkpoint is briefly examined as a case study in next-generation immunopharmacology, with agents like evorpacept and BYON4228 showing encouraging objective response rates (50% ORR) in non-hodgkin lymphoma when combined with rituximab, with next-generation designs reducing hematologic toxicity. Recent compassionate use findings in autoimmunity demonstrate that CD19 CD3 TCE (blinatumomab) and (B-cell maturation antigen) BCMA CD3 TCE (teclistamab) elicit rapid clinical improvement in refractory antisynthetase syndrome and systemic sclerosis, accompanied by cytokine release syndrome (CRS) (grade 3 in 40% and 100% of patients, respectively) and no neurotoxicity. In engineered TCEs with attenuated CD3 affinity, grade 1-2 CRS occurs in < 20% of patients. Beyond cell-depleting strategies, bispecific antibodies targeting OX40L/TNF and anti-TL1A antibodies are advancing in hidradenitis suppurativa and rheumatic diseases. Conversely, ADC strategies have yielded mixed results; an anti-TNF-glucocorticoid receptor modulator ADC failed to outperform adalimumab in a phase 2b trial. Safety profiles differ: TCEs predominantly cause cytokine release syndrome, whereas ADCs pose off-target payload toxicity risks. Emerging dual-targeting TCEs, half-life-extended formats, and rational combinations illustrate key immunopharmacological principles that may broaden the therapeutic landscape for cancer and autoimmune diseases.
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