GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts
| Autor: | Rosalie M. Sterner, Fang Jin, Omar H. Ahmed, Karen E. Hedin, Katayoun Ayasoufi, Denise K. Walters, Nan Yang, Cynthia L. Forsman, Tarek Sahmoud, Michelle J. Cox, Michael J. Hansen, Reona Sakemura, Dale Chappell, Aaron J. Johnson, Larry R. Pease, Wendy K. Nevala, Neil E. Kay, Mehrdad Hefazi, Mrinal M. Patnaik, Saad S. Kenderian, Kendall J. Schick, Roman H. Khadka, Cameron Durrant |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Immunobiology and Immunotherapy Immunology Cell Transplantation Heterologous Receptors Antigen T-Cell Biochemistry Cell therapy 03 medical and health sciences Mice 0302 clinical medicine medicine Tumor Cells Cultured Animals Humans Neuroinflammation Cell Proliferation Inflammation Receptors Chimeric Antigen business.industry Cell growth Macrophages Neurotoxicity Granulocyte-Macrophage Colony-Stimulating Factor Cell Biology Hematology Syndrome Precursor Cell Lymphoblastic Leukemia-Lymphoma medicine.disease Antibodies Neutralizing Xenograft Model Antitumor Assays Chimeric antigen receptor Cytokine release syndrome 030104 developmental biology medicine.anatomical_structure Granulocyte macrophage colony-stimulating factor Immune System Diseases 030220 oncology & carcinogenesis Cancer research Cytokines business medicine.drug |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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