Center for Natural and Human Sciences, Federal University of ABC, Santo Andre 09210-580, SP, Brazil.
A.C. Camargo Cancer Center, Centro Internacional de Pesquisa, Sao Paulo 01508-010, SP, Brazil.
Int J Mol Sci. 2022 May 13;23(10):5448. doi: 10.3390/ijms23105448.
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 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 CD8α/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 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 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.
用抗碳酸酐酶 IX（CAIX）G36 嵌合抗原受体（CAR）T 细胞进行临床前治疗，可使透明细胞肾细胞癌（ccRCC）完全消退，其剂量相当于 ≅10 CAR T 细胞/kg，这重新激发了该靶点治疗 ccRCC 和其他缺氧肿瘤的潜力。免疫检查点阻断（ICB）为晚期 ccRCC 和其他肿瘤带来了持久的临床反应。在这里，我们测试了 CD8α/4-1BB 与基于 CD28 的抗 CAIX CAR 外周血单核细胞（PBMC）相比，后者释放抗程序性细胞死亡配体-1（PD-L1）IgG4，用于体外人 ccRCC 治疗和体内 NSG 小鼠原位模型。使用 ≅10 CAR PBMC 细胞/kg 剂量，释放抗 PD-L1 IgG 的抗 CAIX CD28 CAR T 细胞可显著减少体内肿瘤体积和重量，避免转移的发生。与 4-1BB 相比，ICB 下基于 CD28 的 CAR PBMC 细胞具有抗肿瘤优势，通过 PD-L1 发挥作用。此外，外周 CD4 T 细胞中 T 细胞耗竭状态，除了 CD8，对 CAR T 细胞效率至关重要。在给予 10 CAR PMBC 细胞/kg 剂量时，缺乏肝毒性和肾毒性，为使用抗 CAIX CD28 CAR PBMC 细胞释放抗 PD-L1 抗体或抗 CAIX 4-1BB CAR T 细胞进行临床试验奠定了基础，为治疗难治性 ccRCC 和缺氧肿瘤提供了令人兴奋的新前景。
