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SHR Neuro Cancer Cardio Lipid Metab Microb

Locke, FL; Filosto, S; Chou, J; Vardhanabhuti, S; Perbost, R; Dreger, P; Hill, BT; Lee, C; Zinzani, PL; Kröger, N; López-Guillermo, A; Greinix, H; Zhang, W; Tiwari, G; Budka, J; Marincola, FM; To, C; Mattie, M; Schupp, M; Cheng, P; Bot, A; Shen, R; Bedognetti, D; Miao, H; Galon, J.
Impact of tumor microenvironment on efficacy of anti-CD19 CAR T cell therapy or chemotherapy and transplant in large B cell lymphoma.
Nat Med. 2024; Doi: 10.1038/s41591-023-02754-1 [OPEN ACCESS]
Web of Science PubMed FullText FullText_MUG

Co-authors Med Uni Graz: Greinix Hildegard
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Abstract:: 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.