PBT138-030-VeryHigh from Mathematical deconvolution of CAR T-cell proliferation and exhaustion from real-time killing assay data

Chimeric antigen receptor (CAR) T-cell therapy has shown promise in the treatment of haematological cancers and is currently being investigated for solid tumours, including high-grade glioma brain tumours. There is a desperate need to quantitatively study the factors that contribute to the efficacy of CAR T-cell therapy in solid tumours. In this work, we use a mathematical model of predator–prey dynamics to explore the kinetics of CAR T-cell killing in glioma: the chimeric antigen receptor T-cell treatment response in GliOma (CARRGO) model. The model includes rates of cancer cell proliferation, CAR T-cell killing, CAR T-cell proliferation and exhaustion, and CAR T-cell persistence. We use patient-derived and engineered cancer cell lines with an in vitro real-time cell analyser to parameterize the CARRGO model. We observe that CAR T-cell dose correlates inversely with the killing rate and correlates directly with the net rate of proliferation and exhaustion. This suggests that at a lower dose of CAR T-cells, individual T-cells kill more cancer cells but become more exhausted when compared with higher doses. Furthermore, the exhaustion rate was observed to increase significantly with tumour growth rate and was dependent on level of antigen expression. The CARRGO model highlights nonlinear dynamics involved in CAR T-cell therapy and provides novel insights into the kinetics of CAR T-cell killing. The model suggests that CAR T-cell treatment may be tailored to individual tumour characteristics including tumour growth rate and antigen level to maximize therapeutic benefit.

嵌合抗原受体（chimeric antigen receptor, CAR）T细胞疗法已在血液系统恶性肿瘤治疗中展现出应用前景，目前正针对实体瘤开展研究，其中包括高级别脑胶质瘤。当下亟需对影响实体瘤中CAR-T细胞疗法疗效的各类因素开展定量研究。本研究采用捕食者-猎物动态数学模型，探究胶质瘤中CAR-T细胞杀伤的动力学特征，并构建了胶质瘤嵌合抗原受体T细胞治疗应答（CARRGO）模型。该模型涵盖了癌细胞增殖速率、CAR-T细胞杀伤速率、CAR-T细胞增殖与耗竭速率以及CAR-T细胞存续速率等参数。本研究借助患者来源及工程化癌细胞系，结合体外实时细胞分析仪完成CARRGO模型的参数标定。研究发现，CAR-T细胞给药剂量与杀伤速率呈负相关，而与净增殖速率及耗竭速率呈正相关。这表明，与高剂量给药方案相比，低剂量CAR-T细胞组中单个T细胞可杀伤更多癌细胞，但同时会发生更为显著的耗竭。此外，研究观察到耗竭速率随肿瘤生长速率显著升高，且与抗原表达水平密切相关。CARRGO模型揭示了CAR-T细胞疗法所涉及的非线性动力学特征，为CAR-T细胞杀伤动力学机制提供了全新的研究视角。该模型提示，可根据患者肿瘤的生长速率、抗原表达水平等个体特征对CAR-T细胞治疗方案进行个性化定制，以最大化治疗获益。