Abstract LB346: Dynamic changes in the tumor microenvironment from initial diagnosis through sequential therapies in patients with large B cell lymphoma undergoing axicabtagene ciloleucel (axi-cel) treatment

Abstract Axicabtagene ciloleucel (axi-cel), marketed as YESCARTA®, is an approved autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory large B cell lymphoma patients following one prior therapeutic intervention. The pivotal ZUMA-1 trial (NCT02348216), a Phase 1/2 multicenter study, reported an impressive 83% objective response rate and a robust 58% complete response rate at 5 years (Locke et al. , Lancet Oncol. 2019). Subsequently, ZUMA-7 (NCT03391466), a Phase 3 multicenter trial focusing on patients with one prior systemic therapy, demonstrated comparable outcomes with an 83% objective response rate and a remarkable 65% complete response rate at 2 years (Locke et al. , Lancet Oncol. 2022). Previous studies have highlighted the crucial connection between the tumor microenvironment (TME) and CAR T-cell therapy outcomes. Notably, the pre-treatment tumor immune contexture has been proposed as a major determinant of clinical outcomes in ZUMA-1 and ZUMA-7 patients (Scholler et al. , Nature Medicine 2022; Locke et al. , Nature Medicine, in press; ASH2023 oral presentation #226). This study aims to provide novel insights into the dynamic changes in the TME from initial diagnosis through sequential therapeutic interventions in large B-cell lymphoma patients treated with axi-cel. Utilizing multiplex immunohistochemistry (Brightplex®), we analyzed 165 commercial tumor biopsies (at diagnosis), 100 ZUMA-7 samples (40 at diagnosis, 60 after 1 prior therapeutic line), and 35 ZUMA-1 samples (20 pre- and 15 post-CAR T infusion). Three Brightplex® assays were developed to assess T-cell (CD3 CD8 FOXP3 TIM3 PD1 LAG3 GZMB) and macrophages infiltration (CD68 CD64 CD163 CD204 CD206 PDL1), along with single staining for the NK cell marker, NKP46. Our findings revealed significant changes and evolution from diagnosis through post-axi-cel infusion: a significant decrease in lymphocyte levels (cytotoxic, helper, and regulatory, with p-values of 0. 042, 1. 3e-05, 0. 024, respectively), a notable decrease in M1 macrophages proportion (p-value=5. 8e-06), and a substantial increase in M2 macrophages proportion (p-value=4. 5e-10) across different lines of standard care therapy. Importantly, high baseline proportions of protumor M2 macrophages may serve as predictors of disease relapse post-axi-cel treatment, while low baseline M2 proportions could be associated with a complete response. This comprehensive characterization of the immune contexture provides crucial insights to better highlight TME modification depending on the line of therapy, and further correlative analysis of cell subsets will be presented, contributing to a deeper understanding of treatment impact on the TME in large B cell lymphoma. Citation Format: Michael Mattie, Regis Perbost, Aurelie Auguste, Sarah Turcan, Jenny J. Kim, Christina To, Jenny Nater, Simone Filosto, Rhine R. Shen, Jérôme Galon. Dynamic changes in the tumor microenvironment from initial diagnosis through sequential therapies in patients with large B cell lymphoma undergoing axicabtagene ciloleucel (axi-cel) treatment 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 (7Suppl): Abstract nr LB346.