PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial.
PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial.
复制标题
DOI：
10.1038/s41591-022-01726-1
复制
发表时间：
2022-04
期刊：
影响因子：
82.9
通讯作者：
Haas, Naomi B.
中科院分区：
文献类型：
--
作者：
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.
嵌合抗原受体（CAR）T细胞已经显示出有希望的功效，特别是在血液恶性肿瘤中。实体瘤中CAR T细胞面临的一个挑战是免疫抑制性肿瘤微环境（TME），其特征在于高水平的多种抑制因子，包括TGFβ。我们报告了来自去势抵抗性前列腺癌定向CAR T细胞的首次人体I期试验的结果，该T细胞装备有显性阴性TGFβ受体（NCT 03089203）。主要终点是安全性和可行性;次要目标包括评估CAR T细胞分布、生物活性和疾病反应。符合所有预先规定的终点。18例患者入组，13例受试者接受4个剂量水平的治疗。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名患者发生了显著的克隆CAR T细胞扩增，PSA降低>98%，并在4级CRS伴并发脓毒症后死亡。炎性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名患者的PSA下降≥ 30%，CAR T细胞衰竭伴随过继细胞转移后多种TME定位的抑制分子上调。CAR T细胞动力学揭示了血液和肿瘤运输中的扩增。因此，TGFβ抗性CAR T细胞的临床应用是可行的并且通常是安全的。未来的研究应使用针对TME的上级多管齐下的方法来改善结局。
Chimeric antigen receptor (CAR) T-cells have demonstrated promising efficacy, particularly in hematologic malignancies. A challenge for CAR T-cells in solid tumors is the immunosuppressive tumor microenvironment (TME), characterized by high levels of multiple inhibitory factors, including TGFβ. We report results from a first-in-human phase 1 trial of castration-resistant prostate cancer-directed CAR T-cells armored with a dominant-negative TGFβ receptor (NCT03089203). Primary endpoints were safety and feasibility; secondary objectives included assessing CAR T-cell distribution, bioactivity, and disease response. All pre-specified endpoints were met. Eighteen patients enrolled and thirteen subjects received therapy across four dose levels. Five of 13 patients developed grade ≥2 cytokine release syndrome (CRS), including one patient who experienced a marked clonal CAR T-cell expansion, >98% reduction in 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 PSA declines 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 the blood and tumor trafficking. Thus, clinical application of TGFβ-resistant CAR T-cells is feasible and generally safe. Future studies should use superior multi-pronged approaches against the TME to improve outcomes.
登录
查看更多内容
影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
DOI：
10.1038/nrc3322
发表时间：
2012-10
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Gattinoni L;Klebanoff CA;Restifo NP
通讯作者：
Restifo NP
影响因子：
4.6
作者：
Gevaert T;Van Eycke YR;Vanden Broeck T;Van Poppel H;Salmon I;Rorive S;Claessens F;De Ridder D;Decaestecker C;Joniau S
通讯作者：
Joniau S
影响因子：
8.8
作者：
Matthews E;Yang T;Janulis L;Goodwin S;Kundu SD;Karpus WJ;Lee C
通讯作者：
Lee C