肿瘤细胞治疗研究
英文原题：Immune Checkpoint Blockade via PD-L1 Potentiates More CD28-Based than 4-1BB-Based Anti-Carbonic Anhydrase IX Chimeric Antigen Receptor T Cells.
在临床前研究中，使用抗碳酸酐酶IX（CAIX）G36嵌合抗原受体（CAR）T细胞，在相当于10^8 CAR T细胞/kg的剂量下，实现了对透明细胞肾细胞癌（ccRCC）的完全消退，这重新激发了该靶点治疗ccRCC及其他缺氧肿瘤的潜力。
临床前研究显示，以相当于每千克 10⁸ 个 CAR T 细胞的剂量给予靶向碳酸酐酶 IX（CAIX）的 G36 嵌合抗原受体（CAR）T 细胞，可使透明细胞肾细胞癌（ccRCC）完全消退，这重新凸显了该靶点治疗 ccRCC 及其他缺氧肿瘤的潜力。免疫检查点阻断（ICB）已使晚期 ccRCC 和其他肿瘤患者获得持久临床缓解。本研究在体外及体内原位 NSG 小鼠模型中，比较基于 CD8/4-1BB 与 CD28 的抗 CAIX CAR 外周血单个核细胞（PBMC）；这些细胞可释放抗程序性细胞死亡配体 1（PD-L1）IgG4。按每千克 10⁷ 个 CAR PBMC 的剂量给药时，释放抗 PD-L1 IgG 的抗 CAIX CD28 CAR T 细胞显著降低体内肿瘤体积和重量，并避免转移发生。在 PD-L1 ICB 条件下，基于 CD28 的 CAR PBMC 优于 4-1BB。除 CD8 T 细胞外，外周 CD4 T 细胞的耗竭状态也对 CAR T 细胞疗效至关重要。给予每千克 10⁷ 个 CAR PMBC 后未见肝毒性或肾毒性，这为开展临床试验提供了依据；候选方案包括可释放抗 PD-L1 抗体的抗 CAIX CD28 CAR PBMC，以及抗 CAIX 4-1BB CAR T 细胞，为难治性 ccRCC 和缺氧肿瘤治疗带来新的前景。
The complete regression of clear cell renal cell carcinoma (ccRCC) obtained pre-clinically with anti-carbonic anhydrase IX (CAIX) G36 chimeric antigen receptor (CAR) T cells in doses equivalent to 10 8 CAR T cells/kg renewed the potential of this target to treat ccRCC and other tumors in hypoxia. The immune checkpoint blockade (ICB) brought durable clinical responses in advanced ccRCC and other tumors. Here, we tested CD8 /4-1BB compared to CD28-based anti-CAIX CAR peripheral blood mononuclear cells (PBMCs) releasing anti-programmed cell death ligand-1 (PD-L1) IgG4 for human ccRCC treatment in vitro and in an orthotopic NSG mice model in vivo. Using a 10 7 CAR PBMCs cells/kg dose, anti-CAIX CD28 CAR T cells releasing anti-PD-L1 IgG highly decrease both tumor volume and weight in vivo, avoiding the occurrence of metastasis. This antitumoral superiority of CD28-based CAR PBMCs cells compared to 4-1BB occurred under ICB via PD-L1. Furthermore, the T cell exhaustion status in peripheral CD4 T cells, additionally to CD8, was critical for CAR T cells efficiency. The lack of hepatotoxicity and nephrotoxicity upon the administration of a 10 7 CAR PMBCs cells/kg dose is the basis for carrying out clinical trials using anti-CAIX CD28 CAR PBMCs cells releasing anti-PD-L1 antibodies or anti-CAIX 4-1BB CAR T cells, offering exciting new prospects for the treatment of refractory ccRCC and hypoxic tumors.
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