Wolfson Centre For Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, UK.
Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
J R Soc Interface. 2021 Mar;18(176):20201013. doi: 10.1098/rsif.2020.1013. Epub 2021 Mar 3.
CAR (Chimeric Antigen Receptor) T cells have demonstrated clinical success for the treatment of multiple lymphomas and leukaemias, but not for various solid tumours, despite promising data from murine models. Lower effective CAR T-cell delivery rates to human solid tumours compared to haematological malignancies in humans and solid tumours in mice might partially explain these divergent outcomes. We used anatomical and physiological data for human and rodent circulatory systems to calculate the typical perfusion of healthy and tumour tissues, and estimated the upper limits of immune cell delivery rates across different organs, tumour types and species. Estimated maximum delivery rates were up to 10 000-fold greater in mice than humans yet reported CAR T-cell doses are typically only 10-100-fold lower in mice, suggesting that the effective delivery rates of CAR T cells into tumours in clinical trials are far lower than in corresponding mouse models. Estimated delivery rates were found to be consistent with published positron emission tomography data. Results suggest that higher effective human doses may be needed to drive efficacy comparable to mouse solid tumour models, and that lower doses should be tested in mice. We posit that quantitation of species and organ-specific delivery and homing of engineered T cells will be key to unlocking their potential for solid tumours.
嵌合抗原受体 (CAR) T 细胞在治疗多种淋巴瘤和白血病方面已经取得了临床成功，但在各种实体瘤方面却没有，尽管在鼠模型中得到了有希望的数据。与血液系统恶性肿瘤相比，CAR T 细胞向人类实体瘤的有效传递率较低，而在鼠模型中向实体瘤的传递率也较低，这可能部分解释了这些不同的结果。我们使用了人类和啮齿动物循环系统的解剖学和生理学数据来计算健康组织和肿瘤组织的典型灌注情况，并估计了不同器官、肿瘤类型和物种中免疫细胞传递率的上限。估计的最大传递率在鼠中比人类高 10000 倍，但报告的 CAR T 细胞剂量通常在鼠中低 10-100 倍，这表明临床试验中 CAR T 细胞进入肿瘤的有效传递率远低于相应的鼠模型。估计的传递率与已发表的正电子发射断层扫描数据一致。结果表明，为了达到与鼠实体瘤模型相当的疗效，可能需要更高的有效人类剂量，并且应该在鼠中测试较低的剂量。我们假设定量研究工程化 T 细胞在物种和器官特异性传递和归巢方面的情况将是释放其在实体瘤方面潜力的关键。
