Abstract LB092: Novel tumor gene expression signatures predictive of outcome in large B cell lymphoma treated with CAR T cell therapy (axicabtagene ciloleucel)
Authors: Tian Yuan , Budka Justin , Locke Frederick L. , Westin Jason R. , To Christina , Shahani Shilpa , Bedognetti Davide , Shen Rhine R. , Andrade Jorge , Filosto Simone 
Published: April 2024

Abstract
We leveraged ZUMA-7, the first and largest, phase III randomized CAR-T cell clinical study of relapsed/refractory large B cell lymphoma (LBCL) in the 2nd line setting, to discover tumor gene expression (GE) signatures associated with outcome to anti-CD19 CAR-T cell therapy, Axicabtagene Ciloleucel (axi-cel).
We performed GE profiling on pre-treatment LBCL tumor samples from 134 axi-cel-treated (safety dataset) patients using IO-360 Nanostring panel (769 genes). Multivariate analysis with penalized Cox models was conducted to identify genes whose expression (transcripts) associated with event-free survival (EFS), progression-free survival (PFS), and duration of response (DOR), leading to identification of two predictive GE signatures. For technical validation, the predictive value of these signatures was reproduced in a subset of ZUMA-7 samples profiled by RNA-seq (n=124).
High levels (&gt; median) of a favorable 6-transcript GE signature (6-GES) composed of CD19, CD45RA, CCL22, KLRK1, SOX11, and SIGLEC5 positively correlated with EFS (HR: 0.27, 95% CI: 0.16–0.44; P=1.82 × 10−8) and PFS (HR: 0.27, 95% CI: 0.16–0.46; P=1.35 × 10−7) in patients treated with axi-cel. The 6-GES may capture lymphomas with abundant adhesion molecules, a relatively low inflammation, and abundant expression of the targeted antigen (CD19). Conversely, high levels of an unfavorable 17-transcript GE signature (17-GES; CD45RO, BCL2, IL-18R1, TNFSF4 [OX40L], KLRB1 [CD161], KIR3DL2, ITGB8, DUSP5, GPC4, PSMB5, RPS6KB1, SERPINA9, NBN, GLUD1, ESR1, ARID1A, and SLC16A1) negatively correlated with Axi-cel EFS (HR: 6.19, 95% CI: 3.60–10.65; P=1.51 × 10−13) and PFS (HR: 7.58, 95% CI: 4.16–13.81; P=2.70 × 10−14). The 17-GES signature is consistent with a high level of immune infiltration and inflammation paralleled by the activation of immune-escape mechanisms, such as the upregulation of anti-apoptotic genes. Notably, the 17-GES was elevated at progression after axi-cel treatment (n=18). These signatures did not associate with outcome to 2nd-line SOC from ZUMA-7 (n = 122 for nanostring and n = 125 for ZUMA-7 RNAseq datasets, respectively), nor with outcome to 1st -line R-CHOP from two online datasets, indicating their predictive rather than prognostic value.
In conclusion, our transcriptomic analysis of ZUMA-7 dataset identified novel GE signatures predictive of outcome with axi-cel. These GE signatures could support risk-stratification of LBCL patients.
Citation Format: Yuan Tian, Justin Budka, Frederick L. Locke, Jason R. Westin, Christina To, Shilpa Shahani, Davide Bedognetti, Rhine R. Shen, Jorge Andrade, Simone Filosto. Novel tumor gene expression signatures predictive of outcome in large B cell lymphoma treated with CAR T cell therapy (axicabtagene ciloleucel) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB092.