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。

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