Gabriela E. Wachholz, Parvin Akbari, Elisabeth J.M. Huijbers, Prachi Jalan, Judy R. van Beijnum, Arjan W. Griffioen
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引用次数: 0
摘要
嵌合抗原受体(CAR)T细胞疗法效果显著,尤其是在治疗血液系统恶性肿瘤方面。然而,要在实体瘤治疗中取得类似的成功,还需要克服一些限制和挑战。这些挑战涉及靶点的选择、肿瘤微环境的渗透和功能的维持。肿瘤血管是白细胞进入肿瘤实质的主要屏障。在肿瘤进展过程中,由于血管暴露于血管生成生长因子,内皮细胞对炎症细胞因子过敏,导致白细胞粘附分子表达减少。由于这种粘附分子是白细胞外渗的先决条件,内皮细胞过敏使肿瘤得以逃避内源性免疫以及 CAR T 细胞等细胞免疫疗法。因此,通过使用血管生成抑制剂等方法克服内皮细胞凋亡,被认为可以恢复抗肿瘤免疫力。同时,内源性免疫细胞和细胞疗法(如 CAR T 细胞)都可以渗透到肿瘤实质中。在此,我们将讨论如何通过事先或同时使用抗血管生成药物来改善 CAR T 细胞疗法,使其成为治疗实体瘤的一种有吸引力的策略。
Targeting endothelial cell anergy to improve CAR T cell therapy for solid tumors
Chimeric antigen receptor (CAR) T cell therapy presents significant results, especially for the treatment of hematologic malignancies. However, there are limitations and challenges to be overcome to achieve similar success for the treatment of solid tumors. These challenges involve selection of the target, infiltration into the tumor microenvironment and maintenance of functionality. The tumor vasculature is a major barrier for leukocytes to enter the tumor parenchyma. Due to the exposure of the vasculature to angiogenic growth factors during tumor progression, the endothelial cells become anergic to inflammatory cytokines, resulting in reduced leukocyte adhesion molecule expression. As such adhesion molecules are a prerequisite for leukocyte extravasation, endothelial cell anergy allows tumors to escape from endogenous immunity, as well as from cellular immunotherapies such as CAR T cells. Hence, overcoming endothelial cell anergy, e.g. through the administration of angiogenesis inhibitors, is believed to restore anti-tumor immunity. Concomitantly, both endogenous immune cells as well as cellular therapeutics such as CAR T cells can permeate into the tumor parenchyma. Here, we discuss how prior or concomitant treatment with an antiangiogenic drug can improve CAR T cell therapy, to become an attractive strategy for the treatment of solid tumors.
期刊介绍:
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer encompasses the entirety of cancer biology and biochemistry, emphasizing oncogenes and tumor suppressor genes, growth-related cell cycle control signaling, carcinogenesis mechanisms, cell transformation, immunologic control mechanisms, genetics of human (mammalian) cancer, control of cell proliferation, genetic and molecular control of organismic development, rational anti-tumor drug design. It publishes mini-reviews and full reviews.