针对B细胞急性淋巴细胞白血病（B-ALL）的CAR-T细胞治疗中免疫持久性与复发通路的数学建模
Mathematical modelling of immune persistence and relapse pathways in CAR T-cell therapy for B-ALL
中文总结 AI 辅助
本研究针对B-ALL的CAR-T细胞治疗，开发BEAM模型揭示记忆与效应CAR-T细胞持久性防复发的机制，明确毒性与监视的权衡及初始肿瘤负荷的作用，为定制CAR-T疗法提供框架。
中文摘要 AI 辅助
嵌合抗原受体（CAR）T细胞疗法已彻底改变了B细胞急性淋巴细胞白血病（B-ALL）的治疗方式。尽管初始应答率很高，但仍有相当一部分患者会复发，原因通常包括CAR-T细胞持久性丧失、抗原逃逸，或是保护肿瘤细胞的免疫豁免部位。CAR-T细胞的长期持久性在临床上与持久缓解相关，但其必要性的原因却鲜为人知。为解决这一问题，我们开发并分析了针对B-ALL中CAR-T细胞动力学的BEAM（母细胞、效应细胞、激活细胞、记忆细胞）模型。BEAM模型在捕食者-猎物模型的基础上进行了扩展，纳入了三种CAR-T细胞状态（记忆细胞、激活细胞、效应细胞），并结合了母细胞的逻辑增长方程，该模型参照了obecabtagene autoleucel用于成人B-ALL的FELIX试验数据进行校准。我们发现，记忆细胞和效应细胞的持久性均可预防复发，但原因不同：记忆细胞的持久性维持着对低负荷或缓慢增殖的残留疾病的监视，而效应细胞的持久性则清除从免疫豁免部位出现的孤立母细胞。该模型进一步预测了即时细胞毒性与持久监视之间存在权衡，并确定初始肿瘤负荷是减少抗原阴性复发的关键可调节因素。总体而言，这些结果为设计更持久、个性化的CAR-T细胞疗法提供了框架。
英文摘要
Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of B-cell acute lymphoblastic leukaemia (B-ALL). Despite high initial response rates, a substantial fraction of patients relapse, often due to loss of CAR T-cell persistence, antigen escape, or immune-privileged sites that shield tumour cells. Prolonged CAR T-cell persistence is clinically associated with durable remission, but why it is required remains poorly understood. To address this, we develop and analyse the BEAM (Blast, Effector, Activated, Memory) model of CAR T-cell dynamics in B-ALL. BEAM extends predator--prey models with three CAR T-cell states (memory, activated, effector) coupled to a logistic growth equation for the blasts, calibrated against the FELIX trial of obecabtagene autoleucel in adult B-ALL. We find that both memory and effector persistence prevent relapse, but for distinct reasons: memory persistence sustains surveillance against low-burden or slowly proliferating residual disease, while effector persistence clears isolated blasts emerging from immune-privileged sites. The model further predicts a trade-off between immediate cytotoxicity and durable surveillance, and identifies initial tumour burden as a key modifiable factor for reducing antigen-negative relapse. Together, these results offer a framework for designing more durable, individually tailored CAR T-cell therapies.
