PDF(Pubmed)
Abstract：
The modeling of chimeric antigen receptor (CAR) T cell therapies has been mostly focused on immunodeficient models. However, there are many advantages in studying CAR-T cell biology in an immunocompetent setting. We generated a fully murine CAR targeting CD105 (endoglin), a component of the TGFβ receptor expressed on the surface of certain solid tumors and acute leukemias. CD105-targeted CAR-T cells can be grown from various murine backgrounds, tracked in vivo by congenic marks, and be activated by CD105 in isolation or expressed by tumor cells. CD105-targeted CAR-T cells were toxic at higher doses but proved safe in lower doses and modestly effective in treating wild-type B16 melanoma-bearing mice. CAR-T cells infiltrating the tumor expressed high levels of exhaustion markers and exhibited metabolic insufficiencies. We also generated a human CD105 CAR, which was efficacious in treating human melanoma and acute myeloid leukemia in vivo. Our work details a new murine model of CAR-T cell therapy that can be used from immunologists to further our understanding of CAR-T cell biology. We also set the foundation for further exploration of CD105 as a possible human CAR-T cell target.
摘要：
嵌合抗原受体(CAR)T细胞疗法的建模主要集中在免疫缺陷模型上。然而,在有免疫能力的环境中研究CAR-T细胞生物学有许多优势.我们产生了一个完全的鼠CAR靶向CD105（endoglin），在某些实体瘤和急性白血病表面表达的TGFβ受体成分。CD105靶向的CAR-T细胞可以从各种鼠背景中生长，通过同基因标记在体内追踪，并被分离的CD105激活或由肿瘤细胞表达。CD105靶向的CAR-T细胞在较高剂量下是有毒的，但在较低剂量下被证明是安全的，并且在治疗携带野生型B16黑色素瘤的小鼠中效果适中。浸润肿瘤的CAR-T细胞表达高水平的耗竭标志物，并表现出代谢不足。我们还产生了人类CD105CAR，在体内治疗人类黑色素瘤和急性髓细胞性白血病是有效的。我们的工作详细介绍了一种新的CAR-T细胞疗法的小鼠模型，该模型可用于免疫学家进一步了解CAR-T细胞生物学。我们还为进一步探索CD105作为可能的人类CAR-T细胞靶标奠定了基础。
