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Profiling of donor-specific immune effector signatures in response to rituximab in a human whole blood loop assay using blood from CLL patients

Profiling of donor-specific immune effector signatures in response to rituximab in a human whole blood loop assay using blood from CLL patients
Profiling of donor-specific immune effector signatures in response to rituximab in a human whole blood loop assay using blood from CLL patients
Rituximab is widely used in the treatment of haematological malignancies, including chronic lymphocytic leukaemia (CLL), the most common leukaemia in adults. However, some patients, especially those with high tumour burden, develop cytokine release syndrome (CRS). It is likely that more patients will develop therapy-linked CRS in the future due to the implementation of other immunotherapies, such as CAR T-cell, for many malignancies. Current methods for CRS risk assessment are limited, hence there is a need to develop new methods. To better recapitulate an in vivo setting, we implemented a unique human whole blood “loop” system to study patient-specific immune responses to rituximab in blood derived from CLL patients. Upon rituximab infusion, both complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) profiles were evident in CLL patient blood, coincident with CLL cell depletion. Whereas B cell depletion is induced in healthy persons in the blood loop, only patients display B cell depletion coupled with CRS. With the exception of one donor who lacked NK cells, all other five patients displayed variable B cell depletion along with CRS profile. Additionally, inhibition of CDC or ADCC via either inhibitors or antibody Fc modification resulted in skewing of the immune killing mechanism consistent with published literature. Herein we have shown that the human whole blood loop model can be applied using blood from a specific indication to build a disease-specific CRS and immune activation profiling ex vivo system. Other therapeutic antibodies used for other indications may benefit from antibody characterization in a similar setting.
Anti-CD20 antibodies, Antibody immunotherapy, CLL patients, CRS, Cytokine release syndrome, Rituximab, Whole blood loop assay
1567-5769
Eltahir, M.
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Fletcher, E.
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Dynesius, L.
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Jarblad, J.L.
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Lord, M.
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Laurén, I.
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Zekarias, M.
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Yu, X.
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Cragg, M.S.
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Hammarström, C.
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Levedahl, K.H.
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Höglund, M.
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Ullenhag, G.
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Mattsson, M.
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Mangsbo, S.M.
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Eltahir, M.
aa1b1487-6c37-402b-989f-dbc35cbcf18d
Fletcher, E.
1b65251e-aae4-44af-be27-5c75b1617183
Dynesius, L.
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Jarblad, J.L.
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Lord, M.
3b8b59f2-76dd-4e58-a9f8-f3200dac41b9
Laurén, I.
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Zekarias, M.
ee500993-4e6b-4b34-8615-9bcc521a58ab
Yu, X.
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Cragg, M.S.
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Hammarström, C.
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Levedahl, K.H.
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Höglund, M.
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Ullenhag, G.
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Mattsson, M.
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Mangsbo, S.M.
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Eltahir, M., Fletcher, E., Dynesius, L., Jarblad, J.L., Lord, M., Laurén, I., Zekarias, M., Yu, X., Cragg, M.S., Hammarström, C., Levedahl, K.H., Höglund, M., Ullenhag, G., Mattsson, M. and Mangsbo, S.M. (2021) Profiling of donor-specific immune effector signatures in response to rituximab in a human whole blood loop assay using blood from CLL patients. International Immunopharmacology, 90, [107226]. (doi:10.1016/j.intimp.2020.107226).

Record type: Article

Abstract

Rituximab is widely used in the treatment of haematological malignancies, including chronic lymphocytic leukaemia (CLL), the most common leukaemia in adults. However, some patients, especially those with high tumour burden, develop cytokine release syndrome (CRS). It is likely that more patients will develop therapy-linked CRS in the future due to the implementation of other immunotherapies, such as CAR T-cell, for many malignancies. Current methods for CRS risk assessment are limited, hence there is a need to develop new methods. To better recapitulate an in vivo setting, we implemented a unique human whole blood “loop” system to study patient-specific immune responses to rituximab in blood derived from CLL patients. Upon rituximab infusion, both complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) profiles were evident in CLL patient blood, coincident with CLL cell depletion. Whereas B cell depletion is induced in healthy persons in the blood loop, only patients display B cell depletion coupled with CRS. With the exception of one donor who lacked NK cells, all other five patients displayed variable B cell depletion along with CRS profile. Additionally, inhibition of CDC or ADCC via either inhibitors or antibody Fc modification resulted in skewing of the immune killing mechanism consistent with published literature. Herein we have shown that the human whole blood loop model can be applied using blood from a specific indication to build a disease-specific CRS and immune activation profiling ex vivo system. Other therapeutic antibodies used for other indications may benefit from antibody characterization in a similar setting.

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More information

Accepted/In Press date: 18 November 2020
e-pub ahead of print date: 11 December 2020
Published date: January 2021
Keywords: Anti-CD20 antibodies, Antibody immunotherapy, CLL patients, CRS, Cytokine release syndrome, Rituximab, Whole blood loop assay

Identifiers

Local EPrints ID: 447228
URI: http://eprints.soton.ac.uk/id/eprint/447228
ISSN: 1567-5769
PURE UUID: 95bb37e3-c74f-4c52-b7d6-ab13596f91a0
ORCID for M.S. Cragg: ORCID iD orcid.org/0000-0003-2077-089X

Catalogue record

Date deposited: 05 Mar 2021 17:30
Last modified: 06 Mar 2021 02:35

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Contributors

Author: M. Eltahir
Author: E. Fletcher
Author: L. Dynesius
Author: J.L. Jarblad
Author: M. Lord
Author: I. Laurén
Author: M. Zekarias
Author: X. Yu
Author: M.S. Cragg ORCID iD
Author: C. Hammarström
Author: K.H. Levedahl
Author: M. Höglund
Author: G. Ullenhag
Author: M. Mattsson
Author: S.M. Mangsbo

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