CAR-T cell therapy-related cytokine release syndrome and therapeutic response is modulated by the gut microbiome in hematologic malignancies

Yongxian Hu, Jingjing Li, Fang Ni, Zhongli Yang, Xiaohua Gui, Zhiwei Bao, Houli Zhao, Guoqing Wei, Yiyun Wang, Mingming Zhang, Ruimin Hong, Linqin Wang, Wenjun Wu, Mohamad Mohty, Arnon Nagler, Alex H. Chang (), Marcel R. M. Brink (), Ming D. Li () and He Huang ()
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Yongxian Hu: Zhejiang University
Jingjing Li: The First Affiliated Hospital, Zhejiang University School of Medicine
Fang Ni: Zhejiang University
Zhongli Yang: The First Affiliated Hospital, Zhejiang University School of Medicine
Xiaohua Gui: The First Affiliated Hospital, Zhejiang University School of Medicine
Zhiwei Bao: The First Affiliated Hospital, Zhejiang University School of Medicine
Houli Zhao: Zhejiang University
Guoqing Wei: Zhejiang University
Yiyun Wang: Zhejiang University
Mingming Zhang: Zhejiang University
Ruimin Hong: Zhejiang University
Linqin Wang: Zhejiang University
Wenjun Wu: Zhejiang University
Mohamad Mohty: Hospital Saint Antoine
Arnon Nagler: Chaim Sheba Medical Center
Alex H. Chang: Tongji University School of Medicine
Marcel R. M. Brink: Memorial Sloan Kettering Cancer Center
Ming D. Li: The First Affiliated Hospital, Zhejiang University School of Medicine
He Huang: Zhejiang University

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Immunotherapy utilizing chimeric antigen receptor T cell (CAR-T) therapy holds promise for hematologic malignancies, however, response rates and associated immune-related adverse effects widely vary among patients. Here we show, by comparing diversity and composition of the gut microbiome during different CAR-T therapeutic phases in the clinical trial ChiCTR1800017404, that the gut flora characteristically differs among patients and according to treatment stages, and might also reflect patient response to therapy in relapsed/refractory multiple myeloma (MM; n = 43), acute lympholastic leukemia (ALL; n = 23) and non-Hodgkin lymphoma (NHL; n = 12). We observe significant temporal differences in diversity and abundance of Bifidobacterium, Prevotella, Sutterella, and Collinsella between MM patients in complete remission (n = 24) and those in partial remission (n = 11). Furthermore, we find that patients with severe cytokine release syndrome present with higher abundance of Bifidobacterium, Leuconostoc, Stenotrophomonas, and Staphylococcus, which is reproducible in an independent cohort of 38 MM patients. This study has important implications for understanding the biological role of the microbiome in CAR-T treatment responsiveness of hematologic malignancy patients, and may guide therapeutic intervention to increase efficacy. The success rate of CAR-T cell therapy is high in blood cancers, yet individual patient characteristics might reduce therapeutic benefit. Here we show that therapeutic response in MM, ALL and NHL, and occurrence of severe cytokine release syndrome in multiple myeloma are associated with specific gut microbiome alterations.

Date: 2022
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DOI: 10.1038/s41467-022-32960-3

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