肿瘤细胞治疗研究
英文原题：Bispecific CAR T and CAR NK cells in dual-threat immunotherapy: opportunities and challenges.
抗原逃逸和瘤内异质性仍是基于嵌合抗原受体（CAR）的肿瘤免疫治疗实现持久缓解的主要障碍。
抗原逃逸和肿瘤内异质性仍是嵌合抗原受体（CAR）癌症免疫疗法实现持久应答的主要障碍。单抗原CAR-T细胞疗法虽在血液系统恶性肿瘤中取得显著成功，但由抗原丢失、谱系可塑性和肿瘤演化所致复发仍常见，实体瘤疗效也有限。双特异性抗体等其他靶向免疫疗法同样受到抗原依赖性局限，凸显持久免疫控制这一更广泛挑战。为应对这些问题，双特异性及组合型CAR策略逐渐出现，以扩大抗原覆盖范围、提高肿瘤选择性并减少免疫逃逸。本综述考察抗原逃逸的生物学机制，并批判性评估双靶向CAR架构，包括串联CAR、双CAR系统、逻辑门控设计及抑制性CAR。我们区分机制上的合理性与经临床验证的获益，指出各研究结局异质，且支持其始终优于优化单特异性策略的证据有限。我们总结支持双特异性CAR-T策略的临床前及临床证据，尤其是B细胞恶性肿瘤中的研究，同时讨论毒性、制造复杂性及转化规模化等挑战。我们还评估工程化NK 细胞（CAR-NK）这一互补平台。其先天细胞毒性、良好安全性和适配异基因制造的特点带来重要转化优势，但持久性、肿瘤浸润及临床验证仍有限。最后，我们将CAR疗法置于不断演变的免疫治疗格局中，强调治疗排序、联合策略、潜在交叉耐药，以及依据肿瘤特异性抗原表达和免疫逃逸模式匹配CAR设计及平台选择的必要性。
Antigen escape and intratumoral heterogeneity remain major barriers to durable responses in chimeric antigen receptor (CAR)-based cancer immunotherapies. While single-antigen CAR-T cell therapies have achieved notable success in hematologic malignancies, relapse driven by antigen loss, lineage plasticity, and tumor evolution remains common, and efficacy in solid tumors is limited. Similar antigen-dependent limitations are also observed in other targeted immunotherapies, including bispecific antibodies, underscoring the broader challenge of achieving durable immune control. To address these challenges, bispecific and combinatorial CAR strategies have emerged to broaden antigen coverage, enhance tumor selectivity, and reduce immune evasion. This review examines the biological mechanisms underlying antigen escape and critically evaluates dual-targeting CAR architectures, including tandem CARs, dual-CAR systems, logic-gated designs, and inhibitory CARs. We distinguish between mechanistic rationale and clinically validated benefit, highlighting the heterogeneity of outcomes across studies and the limited evidence supporting consistent superiority over optimized monospecific approaches. We summarize preclinical and clinical evidence supporting bispecific CAR-T strategies, particularly in B-cell malignancies, while discussing challenges related to toxicity, manufacturing complexity, and translational scalability. We further evaluate CAR-engineered natural killer (CAR-NK) cells as a complementary platform. Their innate cytotoxicity, favorable safety profile, and compatibility with allogeneic manufacturing offer important translational advantages, although limitations in persistence, tumor infiltration, and clinical validation remain. Finally, we position CAR-based therapies within the evolving immunotherapy landscape, emphasizing therapeutic sequencing, combination strategies, potential cross-resistance, and the need to align CAR design and platform selection with tumor-specific patterns of antigen expression and immune escape.
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