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Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2022

Open Access 01-12-2022 | Systemic Lupus Erythematosus | Research

Identification of genomic determinants contributing to cytokine release in immunotherapies and human diseases

Authors: Lipei Shao, Alejandra Pelayo, Rongye Shi, Jinxia Ma, Hui Liu, Yihua Cai, Michaela Prochazkova, Robert P. Somerville, Sandhya R. Panch, Nirali N. Shah, David F. Stroncek, Ping Jin

Published in: Journal of Translational Medicine | Issue 1/2022

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Abstract

Background

Cytokine release syndrome (CRS) is a strong immune system response that can occur as a result of the reaction of a cellular immunotherapy with malignant cells. While the frequency and management of CRS in CAR T-cell therapy has been well documented, there is emerging interest in pre-emptive treatment to reduce CRS severity and improve overall outcomes. Accordingly, identification of genomic determinants that contribute to cytokine release may lead to the development of targeted therapies to prevent or abrogate the severity of CRS.

Methods

Forty three clinical CD22 CAR T-cell products were collected for RNA extraction. 100 ng of mRNA was used for Nanostring assay analysis which is based on the nCounter platform. Several public datasets were used for validation purposes.

Results

We found the expression of the PFKFB4 gene and glycolytic pathway activity were upregulated in CD22 CAR T-cells given to patients who developed CRS compared to those who did not experience CRS. Moreover, these results were further validated in cohorts with COVID-19, influenza infections and autoimmune diseases, and in tumor tissues. The findings were similar, except that glycolytic pathway activity was not increased in patients with influenza infections and systemic lupus erythematosus (SLE).

Conclusion

Our data strongly suggests that PFKFB4 acts as a driving factor in mediating cytokine release in vivo by regulating glycolytic activity. Our results suggest that it would beneficial to develop drugs targeting PFKFB4 and the glycolytic pathway for the treatment of CRS.
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Metadata
Title
Identification of genomic determinants contributing to cytokine release in immunotherapies and human diseases
Authors
Lipei Shao
Alejandra Pelayo
Rongye Shi
Jinxia Ma
Hui Liu
Yihua Cai
Michaela Prochazkova
Robert P. Somerville
Sandhya R. Panch
Nirali N. Shah
David F. Stroncek
Ping Jin
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2022
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-022-03531-3

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