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1595 Gut Microbiome Composition As a Prognostic Marker in CD19-Targeting CAR T-Cell Therapy for Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Program: Oral and Poster Abstracts
Session: 621. Lymphomas: Translational – Molecular and Genetic: Poster I
Hematology Disease Topics & Pathways:
Research, Translational Research
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Seok Jin Kim, MD, PhD1, SangEun Yoon, MD, PhD2*, Woorim Kang3*, Mauricio Chalita4*, Hong Hoe Koo, MD., PhD5*, Dong-Wook Hyun4*, Hyun Kim4*, Junhun Cho, MD., PhD6* and Won Seog Kim, MD7*

1Samsung Med. Ctr., Seoul, Korea, Republic of (South)
2Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, Republic of (South)
3CJ Bioscience Inc, Seoul, Korea, Republic of (South)
4CJ Bioscience Inc, Seoul, KOR
5Sungkyunkwan Univ., School of Med. Samsung Medical Ctr., Seoul, KOR
6Department of Pathology and Translational Genomics, Samsung Medical Center, SEOUL, KOR
7Samsung Medical Center, Division of Hematology-Oncology, Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea, Republic of (South)

Introduction

CD19-targeting chimeric Antigen Receptor (CAR) T-cell therapy represents a groundbreaking treatment for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). However, some patients experience disease progression despite this therapy, often due to CAR T-cell dysfunction or a hostile tumor microenvironment. This study aims to investigate resistance mechanisms to CAR T-cell therapies by analyzing the gut microbiome and exploring synergistic strategies to modulate the microbiome and overcome these resistance mechanisms.

Methods

We analyzed 47 patients with R/R DLBCL who were schedule to undergo anti-CD19 CAR T-cell therapy, including 29 patients receiving tisagenlecleucel (tisa-cel) and 18 receiving anbalcatagene autoleucel (anbal-cel). With patient consent, fecal and serum samples were collected at baseline before apheresis and one month after CAR T-cell infusion. Shotgun metagenomic sequencing was performed using the Ez-Mx platform. Treatment responses were assessed at one- and three-months post-infusion, with ongoing follow-up for progression-free survival (PFS).

Results

All patients had R/R DLBCL, with a median of two prior treatments (range: 1-4). Following CAR T-cell therapy, the complete response (CR) rate was 61%. The gut microbiome of these R/R DLBCL patients was compared with data from 150 treatment-naïve DLBCL patients and 47 age- and sex-matched healthy controls. R/R DLBCL patients exhibited a significantly different gut microbiome composition, characterized by a higher abundance of Enterobacteriaceae compared to both treatment-naïve DLBCL patients and healthy controls (P < 0.001). At baseline, significant differences in microbiome composition were observed between responders and non-responders (p=0.007, PERMANOVA), though no significant differences were noted post-treatment (p=0.4332, PERMANOVA). Taxonomic biomarker analysis using ANCOM-BC identified Bacteroides fragilis and Negativibacillus MSSCI00191739 as markers for responders, while Faecalibacterium prausnitzii, Faecalibacterium MSSCM00806154, and Faecalibacterium PRLE were identified as markers for non-responders. Bacteroides fragilis was significantly elevated in patients who achieved CR compared to those who did not (p=0.007, Mann-Whitney U test), whereas Faecalibacterium prausnitzii was more abundant in non-responders (p=0.03, Mann-Whitney U test). The presence of Bacteroides fragilis prior to CAR T-cell therapy was associated with significantly longer PFS (P = 0.022), while the absence of Faecalibacterium prausnitzii also correlated with extended PFS (p=0.008).

Conclusions

Our study suggests that the gut microbiome may serve as a prognostic marker for resistance to CAR T-cell therapy in R/R DLBCL patients. Pre-treatment samples revealed gut microbial dysbiosis in R/R DLBCL patients, characterized by high levels of Enterobacteriaceae compared to treatment-naïve DLBCL or healthy controls. Non-responders exhibited distinct pre-treatment microbiome compositions, with lower Bacteroides fragilis and higher Faecalibacterium prausnitzii associated with shorter PFS. These findings underscore the potential for microbiome modulation as a strategy to overcome CAR T-cell therapy resistance and improve patient outcomes. We are currently conducting functional studies to explore the interplay between the tumor microenvironment and microbiome.

Disclosures: Kim: Kyowa-Kirin: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Sanofi: Research Funding; BeiGene: Research Funding; Boryong: Research Funding; Donga: Research Funding.

*signifies non-member of ASH