HT1080 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 <i>in vitro</i> 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细胞疗法在血液系统恶性肿瘤治疗中已展现出应用前景，目前正针对包括高级别胶质瘤在内的实体瘤开展相关研究。目前亟需定量研究影响实体瘤中CAR-T细胞疗法疗效的各类因素。本研究采用捕食者-猎物动力学数学模型，探索胶质瘤中CAR-T细胞杀伤的动力学过程——即胶质瘤嵌合抗原受体T细胞治疗应答（chimeric antigen receptor T-cell treatment response in GliOma, 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。研究团队使用患者来源及工程化癌细胞系，结合体外（in vitro）实时细胞分析仪对CARRGO模型进行参数化标定。研究观察到，CAR-T细胞剂量与杀伤速率呈负相关，与净增殖速率及耗竭速率呈正相关。这表明，相较于高剂量CAR-T细胞，低剂量下的单个T细胞可杀伤更多癌细胞，但同时更易发生耗竭。此外，研究还发现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细胞疗法中存在的非线性动力学过程，为CAR-T细胞杀伤动力学提供了全新见解。该模型提示，可根据肿瘤生长速率、抗原表达水平等个体肿瘤特征定制CAR-T细胞治疗方案，以最大化治疗获益。