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Foltz, Jennifer A; Hess, Brian T; Bachanova, Veronika; Bartlett, Nancy L; Berrien-Elliott, Melissa M; McClain, Ethan; Becker-Hapak, Michelle; Foster, Mark; Schappe, Timothy; Kahl, Brad; Mehta-Shah, Neha; Cashen, Amanda F; Marin, Nancy D; McDaniels, Kristen; Moreno, Chaz; Mosior, Matthew; Gao, Feng; Griffith, Obi L; Griffith, Malachi; Wagner, Julia A; Epperla, Narendranath; Rock, Amy D; Lee, John; Petti, Allegra A; Soon-Shiong, Patrick; Fehniger, Todd A
Clinical cancer research, 06/2021, Letnik: 27, Številka: 12Journal Article
N-803 is an IL15 receptor superagonist complex, designed to optimize persistence and trans-presentation, thereby activating and expanding natural killer (NK) cells and CD8 T cells. Monoclonal antibodies (mAbs) direct Fc receptor-bearing immune cells, including NK cells, to recognize and eliminate cancer targets. The ability of IL15R agonists to enhance tumor-targeting mAbs in patients has not been reported previously. Relapsed/refractory patients with indolent non-Hodgkin lymphoma were treated with rituximab and intravenous or subcutaneous N-803 on an open-label, dose-escalation phase I study using a 3+3 design (NCT02384954). Primary endpoint was maximum tolerated dose. Immune correlates were performed using multidimensional analysis via mass cytometry and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) which simultaneously measures protein and single-cell RNA expression. This immunotherapy combination was safe and well tolerated and resulted in durable clinical responses including in rituximab-refractory patients. Subcutaneous N-803 plus rituximab induced sustained proliferation, expansion, and activation of peripheral blood NK cells and CD8 T cells, with increased NK cell and T cells present 8 weeks following last N-803 treatment. CITE-seq revealed a therapy-altered NK cell molecular program, including enhancement of AP-1 transcription factor. Furthermore, the monocyte transcriptional program was remodeled with enhanced MHC expression and antigen-presentation genes. N-803 combines with mAbs to enhance tumor targeting in patients, and warrants further investigation in combination with immunotherapies.
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Leto | Faktor vpliva | Izdaja | Kategorija | Razvrstitev | ||||
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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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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