Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Nat Med. 2022 Apr;28(4):724-734. doi: 10.1038/s41591-022-01726-1. Epub 2022 Mar 21.
Chimeric antigen receptor (CAR) T cells have demonstrated promising efficacy, particularly in hematologic malignancies. One challenge regarding CAR T cells in solid tumors is the immunosuppressive tumor microenvironment (TME), characterized by high levels of multiple inhibitory factors, including transforming growth factor (TGF)-β. We report results from an in-human phase 1 trial of castration-resistant, prostate cancer-directed CAR T cells armored with a dominant-negative TGF-β receptor (NCT03089203). Primary endpoints were safety and feasibility, while secondary objectives included assessment of CAR T cell distribution, bioactivity and disease response. All prespecified endpoints were met. Eighteen patients enrolled, and 13 subjects received therapy across four dose levels. Five of the 13 patients developed grade ≥2 cytokine release syndrome (CRS), including one patient who experienced a marked clonal CAR T cell expansion, >98% reduction in prostate-specific antigen (PSA) and death following grade 4 CRS with concurrent sepsis. Acute increases in inflammatory cytokines correlated with manageable high-grade CRS events. Three additional patients achieved a PSA reduction of ≥30%, with CAR T cell failure accompanied by upregulation of multiple TME-localized inhibitory molecules following adoptive cell transfer. CAR T cell kinetics revealed expansion in blood and tumor trafficking. Thus, clinical application of TGF-β-resistant CAR T cells is feasible and generally safe. Future studies should use superior multipronged approaches against the TME to improve outcomes.
嵌合抗原受体 (CAR) T 细胞已显示出良好的疗效，尤其在血液恶性肿瘤中。CAR T 细胞在实体瘤中面临的一个挑战是免疫抑制性肿瘤微环境 (TME)，其特征是存在高水平的多种抑制因子，包括转化生长因子 (TGF)-β。我们报告了一项针对去势抵抗性前列腺癌的 CAR T 细胞的 1 期人体临床试验结果，该 CAR T 细胞被武装了一种显性负 TGF-β受体 (NCT03089203)。主要终点是安全性和可行性，次要目标包括评估 CAR T 细胞的分布、生物活性和疾病反应。所有预设的终点都达到了。18 名患者入组，其中 13 名患者在 4 个剂量水平接受了治疗。13 名患者中有 5 名发生了 ≥2 级细胞因子释放综合征 (CRS)，其中 1 名患者发生了明显的克隆性 CAR T 细胞扩增，前列腺特异性抗原 (PSA) 下降超过 98%，并在伴有败血症的 4 级 CRS 后死亡。炎症细胞因子的急性增加与可管理的高级别 CRS 事件相关。另外 3 名患者 PSA 降低 ≥30%，在过继细胞转移后，CAR T 细胞衰竭伴随着多个 TME 定位抑制分子的上调。CAR T 细胞动力学显示在血液和肿瘤中的扩展。因此，TGF-β 抗性 CAR T 细胞的临床应用是可行的，通常是安全的。未来的研究应该使用针对 TME 的优越的多管齐下的方法来改善结果。
