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The PI3Kδ-selective inhibitor idelalisib minimally interferes with immune effector function mediated by rituximab or obinutuzumab and significantly augments B cell depletion In vivo

The PI3Kδ-selective inhibitor idelalisib minimally interferes with immune effector function mediated by rituximab or obinutuzumab and significantly augments B cell depletion In vivo
The PI3Kδ-selective inhibitor idelalisib minimally interferes with immune effector function mediated by rituximab or obinutuzumab and significantly augments B cell depletion In vivo
Idelalisib is a highly selective oral inhibitor of PI3Kδ indicated for the treatment of patients with relapsed chronic lymphocytic leukemia in combination with rituximab. Despite additive clinical effects, previous studies have paradoxically demonstrated that targeted therapies potentially negatively affect anti-CD20 mAb effector mechanisms. To address these potential effects, we investigated the impact of PI3Kδ inhibition by idelalisib on the effector mechanisms of rituximab and obinutuzumab. At clinically relevant concentrations, idelalisib minimally influenced rituximab- and obinutuzumab-mediated Ab-dependent cellular cytotoxicity and phagocytosis on human lymphoma cell lines, while maintaining the superiority of obinutuzumab-mediated Ab-dependent cellular cytotoxicity. Consistent with this, idelalisib did not influence obinutuzumab-mediated B cell depletion in whole-blood B cell–depletion assays. Further, idelalisib significantly enhanced obinutuzumab-mediated direct cell death of chronic lymphocytic leukemia cells. In murine systems, in vivo inhibition of PI3Kδ minimally interfered with maximal rituximab- or obinutuzumab-mediated depletion of leukemic targets. In addition, the duration of rituximab- and obinutuzumab-mediated depletion of leukemia cells was extended by combination with PI3Kδ inhibition. Collectively, these data demonstrate that PI3Kδ inhibition does not significantly affect the effector mechanisms induced by rituximab or obinutuzumab and provides an effective in vivo therapeutic combination. Therefore, combinations of obinutuzumab and idelalisib are currently being assessed in clinical studies.
0022-1767
1-10
Palazzo, Adam
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Herter, Sylvia
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Grosmaire, Laura
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Jones, Randy
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Frey, Christian
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Bacac, Marina
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Umana, Pablo
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Oldham, Robert James
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Marshall, Michael
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Cox, Kerry
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Turaj, Anna
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Cragg, Mark
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Klein, Christian
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Carter, Matthew
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Tannheimer, Stacey
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Palazzo, Adam
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Herter, Sylvia
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Grosmaire, Laura
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Jones, Randy
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Frey, Christian
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Bacac, Marina
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Umana, Pablo
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Oldham, Robert James
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Marshall, Michael
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Cox, Kerry
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Turaj, Anna
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Cragg, Mark
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Klein, Christian
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Carter, Matthew
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Tannheimer, Stacey
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Palazzo, Adam, Herter, Sylvia, Grosmaire, Laura, Jones, Randy, Frey, Christian, Bacac, Marina, Umana, Pablo, Oldham, Robert James, Marshall, Michael, Cox, Kerry, Turaj, Anna, Cragg, Mark, Klein, Christian, Carter, Matthew and Tannheimer, Stacey (2018) The PI3Kδ-selective inhibitor idelalisib minimally interferes with immune effector function mediated by rituximab or obinutuzumab and significantly augments B cell depletion In vivo. The Journal of Immunology, 1-10. (doi:10.4049/jimmunol.1700323).

Record type: Article

Abstract

Idelalisib is a highly selective oral inhibitor of PI3Kδ indicated for the treatment of patients with relapsed chronic lymphocytic leukemia in combination with rituximab. Despite additive clinical effects, previous studies have paradoxically demonstrated that targeted therapies potentially negatively affect anti-CD20 mAb effector mechanisms. To address these potential effects, we investigated the impact of PI3Kδ inhibition by idelalisib on the effector mechanisms of rituximab and obinutuzumab. At clinically relevant concentrations, idelalisib minimally influenced rituximab- and obinutuzumab-mediated Ab-dependent cellular cytotoxicity and phagocytosis on human lymphoma cell lines, while maintaining the superiority of obinutuzumab-mediated Ab-dependent cellular cytotoxicity. Consistent with this, idelalisib did not influence obinutuzumab-mediated B cell depletion in whole-blood B cell–depletion assays. Further, idelalisib significantly enhanced obinutuzumab-mediated direct cell death of chronic lymphocytic leukemia cells. In murine systems, in vivo inhibition of PI3Kδ minimally interfered with maximal rituximab- or obinutuzumab-mediated depletion of leukemic targets. In addition, the duration of rituximab- and obinutuzumab-mediated depletion of leukemia cells was extended by combination with PI3Kδ inhibition. Collectively, these data demonstrate that PI3Kδ inhibition does not significantly affect the effector mechanisms induced by rituximab or obinutuzumab and provides an effective in vivo therapeutic combination. Therefore, combinations of obinutuzumab and idelalisib are currently being assessed in clinical studies.

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The PI3Kδ-Selective Inhibitor Idelalisib Minimally Interferes With Immune Effector Function Mediated by Rituximab or Obinutuzumab and Significantly Augments B Cell Deple - Accepted Manuscript
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Accepted/In Press date: 22 January 2018
e-pub ahead of print date: 16 February 2018

Identifiers

Local EPrints ID: 418400
URI: https://eprints.soton.ac.uk/id/eprint/418400
ISSN: 0022-1767
PURE UUID: 9b06ecb1-a1ea-4be8-82fb-9f221976aece
ORCID for Robert James Oldham: ORCID iD orcid.org/0000-0002-8007-1145
ORCID for Mark Cragg: ORCID iD orcid.org/0000-0003-2077-089X

Catalogue record

Date deposited: 06 Mar 2018 17:30
Last modified: 14 Mar 2019 01:49

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Contributors

Author: Adam Palazzo
Author: Sylvia Herter
Author: Laura Grosmaire
Author: Randy Jones
Author: Christian Frey
Author: Marina Bacac
Author: Pablo Umana
Author: Robert James Oldham ORCID iD
Author: Michael Marshall
Author: Kerry Cox
Author: Anna Turaj
Author: Mark Cragg ORCID iD
Author: Christian Klein
Author: Matthew Carter
Author: Stacey Tannheimer

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