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

Rosalie M. Sterner, Reona Sakemura, Michelle J. Cox, Nan Yang, Roman H. Khadka, Cynthia L. Forsman, Michael J. Hansen, Fang Jin, Katayoun Ayasoufi, Mehrdad Hefazi, Kendall J. Schick, Denise K. Walters, Omar Ahmed, Dale Chappell, Tarek Sahmoud, Cameron Durrant, Wendy K. Nevala, Mrinal M Patnaik, Larry R Pease, Karen Elaine Hedin & 3 others Neil Elliot Kay, Aaron J. Johnson, Saad Kenderian

Research output: Contribution to journalArticle

14 Citations (Scopus)

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-CSF k/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.

Original languageEnglish (US)
Pages (from-to)697-709
Number of pages13
JournalBlood
Volume133
Issue number7
DOIs
StatePublished - Feb 14 2019

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Granulocyte-Macrophage Colony-Stimulating Factor
T-Cell Antigen Receptor
Heterografts
Cytokines
Cell- and Tissue-Based Therapy
Antigen Receptors
Neurotoxicity Syndromes
Toxicity
Clustered Regularly Interspaced Short Palindromic Repeats
T-cells
Macrophages
Cell proliferation
Neurology
Myeloid Cells
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Infiltration
Monocytes
Therapeutics
Central Nervous System
Cell Proliferation

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. / 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 Elaine; Kay, Neil Elliot; Johnson, Aaron J.; Kenderian, Saad.

In: Blood, Vol. 133, No. 7, 14.02.2019, p. 697-709.

Research output: Contribution to journalArticle

Sterner, RM, Sakemura, R, Cox, MJ, Yang, N, Khadka, RH, Forsman, CL, Hansen, MJ, Jin, F, Ayasoufi, K, Hefazi, M, Schick, KJ, Walters, DK, Ahmed, O, Chappell, D, Sahmoud, T, Durrant, C, Nevala, WK, Patnaik, MM, Pease, LR, Hedin, KE, Kay, NE, Johnson, AJ & Kenderian, S 2019, 'GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts', Blood, vol. 133, no. 7, pp. 697-709. https://doi.org/10.1182/blood-2018-10-881722
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 Elaine ; Kay, Neil Elliot ; Johnson, Aaron J. ; Kenderian, Saad. / GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. In: Blood. 2019 ; Vol. 133, No. 7. pp. 697-709.
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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-CSF k/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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AU - Sterner, Rosalie M.

AU - Sakemura, Reona

AU - Cox, Michelle J.

AU - Yang, Nan

AU - Khadka, Roman H.

AU - Forsman, Cynthia L.

AU - Hansen, Michael J.

AU - Jin, Fang

AU - Ayasoufi, Katayoun

AU - Hefazi, Mehrdad

AU - Schick, Kendall J.

AU - Walters, Denise K.

AU - Ahmed, Omar

AU - Chappell, Dale

AU - Sahmoud, Tarek

AU - Durrant, Cameron

AU - Nevala, Wendy K.

AU - Patnaik, Mrinal M

AU - Pease, Larry R

AU - Hedin, Karen Elaine

AU - Kay, Neil Elliot

AU - Johnson, Aaron J.

AU - Kenderian, Saad

PY - 2019/2/14

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N2 - 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-CSF k/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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