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Impact of tumor microenvironment on efficacy of anti-CD19 CAR T cell therapy or chemotherapy and transplant in large B cell lymphoma

The phase 3 ZUMA-7 trial in second-line large B cell lymphoma demonstrated superiority of anti-CD19 CAR T cell therapy (axicabtagene ciloleucel (axi-cel)) over standard of care (SOC; salvage chemotherapy followed by hematopoietic transplantation) (NCT03391466). Here, we present a prespecified explor...

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Main Authors: Locke, Frederick (Author) , Filosto, Simone (Author) , Chou, Justin (Author) , Vardhanabhuti, Saran (Author) , Perbost, Regis (Author) , Dreger, Peter (Author) , Hill, Brian T. (Author) , Lee, Catherine (Author) , Zinzani, Pier L. (Author) , Kröger, Nicolaus (Author) , López-Guillermo, Armando (Author) , Greinix, Hildegard (Author) , Zhang, Wangshu (Author) , Tiwari, Gayatri (Author) , Budka, Justin (Author) , Marincola, Francesco M. (Author) , To, Christina (Author) , Mattie, Mike (Author) , Schupp, Marco (Author) , Cheng, Paul (Author) , Bot, Adrian (Author) , Shen, Rhine (Author) , Bedognetti, Davide (Author) , Miao, Harry (Author) , Galon, Jérôme (Author)
Format: Article (Journal)
Language:English
Published: February 2024
In: Nature medicine
Year: 2024, Volume: 30, Issue: 2, Pages: 507-518
ISSN:1546-170X
DOI:10.1038/s41591-023-02754-1
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41591-023-02754-1
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41591-023-02754-1
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Author Notes:Frederick L. Locke, Simone Filosto, Justin Chou, Saran Vardhanabhuti, Regis Perbost, Peter Dreger, Brian T. Hill, Catherine Lee, Pier L. Zinzani, Nicolaus Kröger, Armando López-Guillermo, Hildegard Greinix, Wangshu Zhang, Gayatri Tiwari, Justin Budka, Francesco M. Marincola, Christina To, Mike Mattie, Marco Schupp, Paul Cheng, Adrian Bot, Rhine Shen, Davide Bedognetti, Harry Miao & Jérôme Galon
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Summary:The phase 3 ZUMA-7 trial in second-line large B cell lymphoma demonstrated superiority of anti-CD19 CAR T cell therapy (axicabtagene ciloleucel (axi-cel)) over standard of care (SOC; salvage chemotherapy followed by hematopoietic transplantation) (NCT03391466). Here, we present a prespecified exploratory analysis examining the association between pretreatment tumor characteristics and the efficacy of axi-cel versus SOC. B cell gene expression signature (GES) and CD19 expression associated significantly with improved event-free survival for axi-cel (P = 0.0002 for B cell GES; P = 0.0165 for CD19 expression) but not SOC (P = 0.9374 for B cell GES; P = 0.5526 for CD19 expression). Axi-cel showed superior event-free survival over SOC irrespective of B cell GES and CD19 expression (P = 8.56 × 10-9 for B cell GES high; P = 0.0019 for B cell GES low; P = 3.85 × 10-9 for CD19 gene high; P = 0.0017 for CD19 gene low). Low CD19 expression in malignant cells correlated with a tumor GES consisting of immune-suppressive stromal and myeloid genes, highlighting the inter-relation between malignant cell features and immune contexture substantially impacting axi-cel outcomes. Tumor burden, lactate dehydrogenase and cell-of-origin impacted SOC more than axi-cel outcomes. T cell activation and B cell GES, which are associated with improved axi-cel outcome, decreased with increasing lines of therapy. These data highlight differences in resistance mechanisms to axi-cel and SOC and support earlier intervention with axi-cel.
Item Description:Online veröffentlicht: 17. Januar 2024
Gesehen am 10.05.2024
Physical Description:Online Resource
ISSN:1546-170X
DOI:10.1038/s41591-023-02754-1

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