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Cited by 621

The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.

GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts

Open access
Sterner, Rosalie M., Sakemura, Reona, Cox, Michelle J., Yang, Nan, Khadka, Roman H., Forsman, Cynthia L., Hansen, Michael J., Jin, Fang, Ayasoufi, Katayoun, Hefazi, Mehrdad, Schick, Kendall J., Walters, Denise K., Ahmed, Omar, Chappell, Dale, Sahmoud, Tarek, Durrant, Cameron, Nevala, Wendy K., Patnaik, Mrinal M., Pease, Larry R., Hedin, Karen E., Kay, Neil E., Johnson, Aaron J., Kenderian, Saad S.·2019·Blood
DOI 10.1182/blood-2018-10-881722
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Abstract

Chimeric antigen receptor T (CAR-T) cell therapy is a new pillar in cancer therapeutics; however, its application is limited by the associated toxicities. These include cytokine release syndrome (CRS) and neurotoxicity. Although the IL-6R antagonist tocilizumab is approved for treatment of CRS, there is no approved treatment of neurotoxicity associated with CD19-targeted CAR-T (CART19) cell therapy. Recent data suggest that monocytes and macrophages contribute to the development of CRS and neurotoxicity after CAR-T cell therapy. Therefore, we investigated neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) as a potential strategy to manage CART19 cell–associated toxicities. In this study, we show that GM-CSF neutralization with lenzilumab does not inhibit CART19 cell function in vitro or in vivo. Moreover, CART19 cell proliferation was enhanced and durable control of leukemic disease was maintained better in patient-derived xenografts after GM-CSF neutralization with lenzilumab. In a patient acute lymphoblastic leukemia xenograft model of CRS and neuroinflammation (NI), GM-CSF neutralization resulted in a reduction of myeloid and T cell infiltration in the central nervous system and a significant reduction in NI and prevention of CRS. Finally, we generated GM-CSF–deficient CART19 cells through CRISPR/Cas9 disruption of GM-CSF during CAR-T cell manufacturing. These GM-CSFk/o CAR-T cells maintained normal functions and had enhanced antitumor activity in vivo, as well as improved overall survival, compared with CART19 cells. Together, these studies illuminate a novel approach to abrogate NI and CRS through GM-CSF neutralization, which may potentially enhance CAR-T cell function. Phase 2 studies with lenzilumab in combination with CART19 cell therapy are planned.

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Metadata

Authors
Sterner, R. M., Sakemura, R., Cox, M. J., Yang, N., Khadka, R. H., Forsman, C. L., Hansen, M. J., Jin, F., Ayasoufi, K., Hefazi, M., Schick, K. J., Walters, D. K., Ahmed, O., Chappell, D., Sahmoud, T., Durrant, C., Nevala, W. K., Patnaik, M. M., Pease, L. R., Hedin, K. E., Kay, N. E., Johnson, A. J., & Kenderian, S. S.
Venue
Blood
Publisher
American Society of Hematology
Published
2019-02-14
Volume
133
Issue
7
Pages
697-709
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood-2018-10-881722
OpenAlex
W2901478468
Cited by
621
References
30
FWCI
20.90
Type
journal article
Language
en
Open access
bronze

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CoChat. (2026). Citation check: GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. https://app.cochat.ai/papers/10.1182/blood-2018-10-881722
The paper
Sterner, R. M., Sakemura, R., Cox, M. J., Yang, N., Khadka, R. H., Forsman, C. L., Hansen, M. J., Jin, F., Ayasoufi, K., Hefazi, M., Schick, K. J., Walters, D. K., Ahmed, O., Chappell, D., Sahmoud, T., Durrant, C., Nevala, W. K., Patnaik, M. M., Pease, L. R., . . . Kenderian, S. S. (2019). GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. Blood. https://doi.org/10.1182/blood-2018-10-881722

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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.