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科学家完成新型CAR T细胞在去势抵抗型前列腺癌中的1期临床试验
作者：小柯机器人 发布时间：2022/3/27 14:34:45

美国宾夕法尼亚大学Naomi B. Haas等研究人员合作完成新型CAR T细胞在去势抵抗型前列腺癌中的1期临床试验。该项研究成果于2022年3月21日在线发表在《自然—医学》杂志上。

研究人员表示，嵌合抗原受体（CAR）T细胞已显示出良好的疗效，特别是在血液学恶性肿瘤中。CAR T细胞在实体瘤中的一个挑战是免疫抑制性肿瘤微环境（TME），其特点是高水平的多种抑制因子，包括转化生长因子（TGF）-β。
 
研究人员报告了耐去势型前列腺癌导向的CAR T细胞带有显性负抑制TGF-β受体（NCT03089203）的人体1期试验结果。主要终点是安全性和可行性，而次要目标包括评估CAR T细胞分布、生物活性和疾病反应。所有预设的终点都达到了。18名患者参加了治疗，13名受试者接受了四个剂量级别的治疗。13名患者中有5人出现了≥2级的细胞因子释放综合征（CRS），其中一名患者出现了明显的克隆性CAR T细胞扩增，前列腺特异性抗原（PSA）减少>98%，并在4级CRS后死亡，同时伴有败血症。炎症细胞因子的急性增加与可控的高级别CRS事件相关。
 
另有三名患者的PSA下降≥30%，CAR T细胞失败伴随着采用细胞转移后多种TME定位的抑制性分子上调。CAR T细胞动力学显示在血液和肿瘤运输中的扩张。因此，抗TGF-β的CAR T细胞的临床应用是可行的，而且普遍安全。未来的研究应该使用多管齐下的方法来对抗TME，从而改善治疗结果。
 
附：英文原文

Title: PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial

Author: Narayan, Vivek, Barber-Rotenberg, Julie S., Jung, In-Young, Lacey, Simon F., Rech, Andrew J., Davis, Megan M., Hwang, Wei-Ting, Lal, Priti, Carpenter, Erica L., Maude, Shannon L., Plesa, Gabriela, Vapiwala, Neha, Chew, Anne, Moniak, Michael, Sebro, Ronnie A., Farwell, Michael D., Marshall, Amy, Gilmore, Joan, Lledo, Lester, Dengel, Karen, Church, Sarah E., Hether, Tyler D., Xu, Jun, Gohil, Mercy, Buckingham, Thomas H., Yee, Stephanie S., Gonzalez, Vanessa E., Kulikovskaya, Irina, Chen, Fang, Tian, Lifeng, Tien, Kyle, Gladney, Whitney, Nobles, Christopher L., Raymond, Hayley E., Hexner, Elizabeth O., Siegel, Donald L., Bushman, Frederic D., June, Carl H., Fraietta, Joseph A., Haas, Naomi B.

Issue&Volume: 2022-03-21

Abstract: Chimeric antigen receptor (CAR) Tcells have demonstrated promising efficacy, particularly in hematologic malignancies. One challenge regarding CAR Tcells 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 phase1 trial of castration-resistant, prostate cancer-directed CAR Tcells armored with a dominant-negative TGF-β receptor (NCT03089203). Primary endpoints were safety and feasibility, while secondary objectives included assessment of CAR Tcell distribution, bioactivity and disease response. All prespecified endpoints were met. Eighteen patients enrolled, and 13subjects received therapy across four dose levels. Five of the 13patients developed grade≥2 cytokine release syndrome (CRS), including one patient who experienced a marked clonal CAR Tcell expansion, >98% reduction in prostate-specific antigen (PSA) and death following grade4 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 Tcell failure accompanied by upregulation of multiple TME-localized inhibitory molecules following adoptive cell transfer. CAR Tcell kinetics revealed expansion in blood and tumor trafficking. Thus, clinical application of TGF-β-resistant CAR Tcells is feasible and generally safe. Future studies should use superior multipronged approaches against the TME to improve outcomes.

DOI: 10.1038/s41591-022-01726-1

Source: https://www.nature.com/articles/s41591-022-01726-1

期刊信息

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：30.641
官方网址：https://www.nature.com/nm/
投稿链接：https://mts-nmed.nature.com/cgi-bin/main.plex