Impact of tumor microenvironment on efficacy of anti-CD19 CAR T cell therapy or chemotherapy and transplant in large B cell lymphoma
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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. / Locke, Frederick L; Filosto, Simone; Chou, Justin; Vardhanabhuti, Saran; Perbost, Regis; Dreger, Peter; Hill, Brian T; Lee, Catherine; Zinzani, Pier L; Kröger, Nicolaus; López-Guillermo, Armando; Greinix, Hildegard; Zhang, Wangshu; Tiwari, Gayatri; Budka, Justin; Marincola, Francesco M; To, Christina; Mattie, Mike; Schupp, Marco; Cheng, Paul; Bot, Adrian; Shen, Rhine; Bedognetti, Davide; Miao, Harry; Galon, Jérôme.
In: NAT MED, Vol. 30, No. 2, 02.2024, p. 507-518.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Impact of tumor microenvironment on efficacy of anti-CD19 CAR T cell therapy or chemotherapy and transplant in large B cell lymphoma
AU - Locke, Frederick L
AU - Filosto, Simone
AU - Chou, Justin
AU - Vardhanabhuti, Saran
AU - Perbost, Regis
AU - Dreger, Peter
AU - Hill, Brian T
AU - Lee, Catherine
AU - Zinzani, Pier L
AU - Kröger, Nicolaus
AU - López-Guillermo, Armando
AU - Greinix, Hildegard
AU - Zhang, Wangshu
AU - Tiwari, Gayatri
AU - Budka, Justin
AU - Marincola, Francesco M
AU - To, Christina
AU - Mattie, Mike
AU - Schupp, Marco
AU - Cheng, Paul
AU - Bot, Adrian
AU - Shen, Rhine
AU - Bedognetti, Davide
AU - Miao, Harry
AU - Galon, Jérôme
N1 - © 2024. The Author(s).
PY - 2024/2
Y1 - 2024/2
N2 - 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.
AB - 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.
U2 - 10.1038/s41591-023-02754-1
DO - 10.1038/s41591-023-02754-1
M3 - SCORING: Journal article
C2 - 38233586
VL - 30
SP - 507
EP - 518
JO - NAT MED
JF - NAT MED
SN - 1078-8956
IS - 2
ER -