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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
Nature medicine, 04/2022, Letnik: 28, Številka: 4Journal Article
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.
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Dostop do baze podatkov JCR je dovoljen samo uporabnikom iz Slovenije. Vaš trenutni IP-naslov ni na seznamu dovoljenih za dostop, zato je potrebna avtentikacija z ustreznim računom AAI.
Leto | Faktor vpliva | Izdaja | Kategorija | Razvrstitev | ||||
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
Baze podatkov, v katerih je revija indeksirana
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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