Effector T cells form immunological synapses (IS) with recognized target cells to elicit cytolytic effects. Facilitating IS formation is the principal pharmacological action of most T cell-based cancer immunotherapies. However, the dynamics of IS formation at the cell population level, the primary driver of the pharmacodynamics of many cancer immunotherapies, remains poorly defined. With classic immunotherapy CD3/CD19 bispecific T cell engager (BiTE) as a model system, we integrate experimental and theoretical approaches to investigate the population dynamics of IS formation and their relevance to clinical pharmacodynamics and treatment resistance. Our models produce experimentally consistent predictions when defining IS formation as a series of spatiotemporally coordinated events driven by molecular and cellular interactions. The models predict tumor-killing pharmacodynamics in patients and reveal trajectories of tumor evolution across anatomical sites under BiTE immunotherapy. Our model highlight the bone marrow may serve as a sanctuary site permitting tumor evolution and antigen escape. The models also suggest the optimal dosing regimens as a function of tumor growth and patient T cell abundance that confer adequate tumor control with minimal disease evolution. This work has implications for developing more effective T cell-based cancer immunotherapies.

中文翻译：

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双特异性 T 细胞接合剂诱导的免疫突触形成的种群动态预测临床药效学和治疗耐药性

效应 T 细胞与已识别的靶细胞形成免疫突触 (IS)，以引发细胞溶解作用。促进 IS 形成是大多数基于 T 细胞的癌症免疫疗法的主要药理作用。然而，细胞群水平的 IS 形成动力学（许多癌症免疫疗法的药效学的主要驱动因素）仍然不明确。以经典的免疫疗法 CD3/CD19 双特异性 T 细胞接合剂 (BiTE) 作为模型系统，我们整合实验和理论方法来研究 IS 形成的群体动态及其与临床药效学和治疗耐药性的相关性。当将 IS 形成定义为由分子和细胞相互作用驱动的一系列时空协调事件时，我们的模型产生了实验上一致的预测。该模型预测了患者的肿瘤杀伤药效学，并揭示了 BiTE 免疫疗法下肿瘤在解剖部位的进化轨迹。我们的模型强调骨髓可以作为允许肿瘤进化和抗原逃逸的避难所。这些模型还提出了最佳给药方案，作为肿瘤生长和患者 T 细胞丰度的函数，这赋予了足够的肿瘤控制和最小的疾病进展。这项工作对开发更有效的基于 T 细胞的癌症免疫疗法具有重要意义。这些模型还提出了最佳给药方案，作为肿瘤生长和患者 T 细胞丰度的函数，这赋予了足够的肿瘤控制和最小的疾病进展。这项工作对开发更有效的基于 T 细胞的癌症免疫疗法具有重要意义。这些模型还提出了最佳给药方案，作为肿瘤生长和患者 T 细胞丰度的函数，这赋予了足够的肿瘤控制和最小的疾病进展。这项工作对开发更有效的基于 T 细胞的癌症免疫疗法具有重要意义。