2024 AACR Meeting: Dynamic Changes in the Tumor Microenvironment from Initial Diagnosis to Sequential Treatment in Patients with Large B-Cell Lymphoma Receiving Axi-cel (Axicabtagene Ciloleucel)
2024 AACR Meeting: Dynamic Changes in the Tumor Microenvironment from Initial Diagnosis to Sequential Treatment in Patients with Large B-Cell Lymphoma Receiving Axi-cel (Axicabtagene Ciloleucel)
2024 AACR
The American Association for Cancer Research (AACR) Annual Meeting is the most influential oncology scientific event globally. From population science and prevention, to cancer biology, translational medicine, and clinical research, to survivorship and advocacy, the AACR Annual Meeting showcases the outstanding achievements of cancer research institutions worldwide.
Held in San Diego, USA, from April 5th to April 10th, 2024, the abstracts for the 2024 AACR Annual Meeting have been released. [Htology Hematology Frontier] has compiled cutting-edge basic and clinical research in the field of hematological malignancies to present to readers.
LB346/20
Dynamic changes in the tumor microenvironment from initial diagnosis to sequential treatment in patients with large B-cell lymphoma receiving axi-cel
Background
Axicabtagene ciloleucel (axi-cel) is an approved autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for the treatment of patients with relapsed/refractory large B-cell lymphoma after one prior therapy. The pivotal ZUMA-1 trial (NCT02348216) was a multicenter phase 1/2 study that reported an 83% objective response rate and a 58% 5-year complete response rate (Locke et al., Lancet Oncol. 2019). Subsequently, ZUMA-7 (NCT03391466) was a phase 3 multicenter trial primarily in patients with one prior line of systemic therapy, with comparable results, an 83% objective response rate, and a 65% 2-year complete response rate (Locke et al., Lancet Oncol. 2022).
Methods
Prior studies have emphasized the important link between the tumor microenvironment (TME) and CAR-T cell therapy outcomes. Notably, the baseline tumor immune environment has been identified as a key determinant of clinical efficacy in ZUMA-1 and ZUMA-7 patients (Scholler et al., Nature Medicine 2022; Locke et al., Nature Medicine, in press; ASH2023 oral presentation #226). The current study aimed to provide novel insights into the dynamic changes in the TME from initial diagnosis to sequential treatment in patients with large B-cell lymphoma treated with axi-cel.
Results
Using multiplexed immunohistochemistry (Brightplex®), the investigators analyzed 165 commercial tumor biopsy samples (at diagnosis), 100 ZUMA-7 samples (40 at diagnosis, 60 after one line of therapy), and 35 ZUMA-1 samples (20 pre-CAR-T and 15 post-CAR-T infusion).
Three Brightplex® assays were developed to evaluate T-cell (CD3 CD8 FOXP3 TIM3 PD1 LAG3 GZMB) and macrophage infiltration (CD68 CD64 CD163 CD204 CD206 PDL1), as well as single staining for the NK cell marker NKP46.
Results demonstrated a significant decrease in lymphocyte levels (cytotoxic, helper, and regulatory, p-values of 0.042, 1.3e-05, and 0.024, respectively) from diagnosis to post axi-cel infusion, a marked reduction in the proportion of M1 macrophages (p-value=5.8e-06), and a substantial increase in the proportion of M2 macrophages across different standard-of-care regimens (p-value=4.5e-10). Importantly, a high baseline tumor M2 macrophage proportion may be predictive of disease progression after axi-cel treatment, while a low baseline M2 macrophage proportion may be associated with complete response.
Conclusions
This study provides critical insights into a comprehensive characterization of the immune landscape, shedding light on the TME changes across different treatment regimens, while further relevant subset analyses will be introduced to gain deeper understanding of the impact of treatment on the large B-cell lymphoma TME.
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