Locke and Filosto et al. analyzed pretreatment samples from the phase 3 ZUMA-7 trial in patients with large B cell lymphoma to discover tumor-specific features predictive of CAR T cell therapy (axi-cel) or SOC (salvage chemotherapy/HDT-ASCT) efficacy. A B cell gene expression signature and CD19 expression were associated with improved event-free survival for axi-cel, but not SOC, whereas the stromal and immunosuppressive index (SII) was negatively associated with axi-cel. TME immune features, such as antigen presentation and dendritic cells, were positively associated with outcomes after SOC. In patients with high tumor burden or elevated LDH, Axi-cel showed superior efficacy compared to SOC.
Contributed by Shishir Pant
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.
Author Info: (1) Moffitt Cancer Center, Tampa, FL, USA. frederick.locke@moffitt.org. (2) Kite, a Gilead Company, Santa Monica, CA, USA. (3) Kite, a Gilead Company, Santa Monica, CA, USA. (4) Ki
Author Info: (1) Moffitt Cancer Center, Tampa, FL, USA. frederick.locke@moffitt.org. (2) Kite, a Gilead Company, Santa Monica, CA, USA. (3) Kite, a Gilead Company, Santa Monica, CA, USA. (4) Kite, a Gilead Company, Santa Monica, CA, USA. (5) Veracyte, Marseille, France. (6) Heidelberg University Hospital, Heidelberg, Germany. (7) Cleveland Clinic Foundation, Cleveland, OH, USA. (8) Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. (9) IRCCS Azienda Ospedaliero-Universitaria di Bologna Istituto di Ematologia Sergnol and Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale Universit di Bologna, Bologna, Italy. (10) University Medical Center Hamburg, Hamburg, Germany. (11) Department of Hematology, Hospital Clinic, Barcelona, Spain. (12) Division of Hematology Medical University Graz, Graz, Austria. (13) Kite, a Gilead Company, Santa Monica, CA, USA. (14) Kite, a Gilead Company, Santa Monica, CA, USA. (15) Kite, a Gilead Company, Santa Monica, CA, USA. (16) Kite, a Gilead Company, Santa Monica, CA, USA. (17) Kite, a Gilead Company, Santa Monica, CA, USA. (18) Kite, a Gilead Company, Santa Monica, CA, USA. (19) Kite, a Gilead Company, Santa Monica, CA, USA. (20) Kite, a Gilead Company, Santa Monica, CA, USA. (21) Kite, a Gilead Company, Santa Monica, CA, USA. (22) Kite, a Gilead Company, Santa Monica, CA, USA. (23) Kite, a Gilead Company, Santa Monica, CA, USA. (24) Kite, a Gilead Company, Santa Monica, CA, USA. (25) Veracyte, Marseille, France. INSERM, Sorbonne Universit, Universit Paris Cit, Centre de Recherche des Cordeliers, Equipe Labellise Ligue Contre le Cancer, Laboratory of Integrative Cancer Immunology F-75006, Paris, France.
