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.

尽管来自小鼠模型的数据令人鼓舞，但 CAR（嵌合抗原受体）T 细胞已在治疗多种淋巴瘤和白血病方面取得了临床成功，但对各种实体瘤却未能取得成功。与人类血液恶性肿瘤和小鼠实体瘤相比，CAR T 细胞向人类实体瘤的有效递送率较低，这可能部分解释了这些不同的结果。我们使用人类和啮齿动物循环系统的解剖和生理数据来计算健康和肿瘤组织的典型灌注，并估计不同器官、肿瘤类型和物种的免疫细胞递送率的上限。据估计，小鼠体内的最大递送率比人类高出 10000 倍，但据报道，小鼠体内的 CAR T 细胞剂量通常仅低 10-100 倍，这表明临床试验中 CAR T 细胞向肿瘤的有效递送率远低于相应的小鼠模型。估计的输送率被发现与已发表的正电子发射断层扫描数据一致。结果表明，可能需要更高的有效人体剂量才能达到与小鼠实体瘤模型相当的疗效，并且应该在小鼠中测试较低的剂量。我们认为，工程化 T 细胞的物种定量和器官特异性递送和归巢将是释放其实体瘤潜力的关键。