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JAK and mTOR inhibitors prevent cytokine release while retaining T cell bispecific antibody in vivo efficacy

BACKGROUND: T cell engaging therapies, like chimeric antigen receptor T cells and T cell bispecific antibodies (TCBs), efficiently redirect T cells towards tumor cells, facilitating the formation of a cytotoxic synapse and resulting in subsequent tumor cell killing, a process that is accompanied by...

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Autores principales: Leclercq, Gabrielle, Haegel, Hélène, Toso, Alberto, Zimmermann, Tina, Green, Luke, Steinhoff, Nathalie, Sam, Johannes, Pulko, Vesna, Schneider, Anneliese, Giusti, Anna Maria, Challier, John, Freimoser-Grundschober, Anne, Larivière, Laurent, Odermatt, Alex, Stern, Martin, Umana, Pablo, Bacac, Marina, Klein, Christian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8785208/
https://www.ncbi.nlm.nih.gov/pubmed/35064010
http://dx.doi.org/10.1136/jitc-2021-003766
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author Leclercq, Gabrielle
Haegel, Hélène
Toso, Alberto
Zimmermann, Tina
Green, Luke
Steinhoff, Nathalie
Sam, Johannes
Pulko, Vesna
Schneider, Anneliese
Giusti, Anna Maria
Challier, John
Freimoser-Grundschober, Anne
Larivière, Laurent
Odermatt, Alex
Stern, Martin
Umana, Pablo
Bacac, Marina
Klein, Christian
author_facet Leclercq, Gabrielle
Haegel, Hélène
Toso, Alberto
Zimmermann, Tina
Green, Luke
Steinhoff, Nathalie
Sam, Johannes
Pulko, Vesna
Schneider, Anneliese
Giusti, Anna Maria
Challier, John
Freimoser-Grundschober, Anne
Larivière, Laurent
Odermatt, Alex
Stern, Martin
Umana, Pablo
Bacac, Marina
Klein, Christian
author_sort Leclercq, Gabrielle
collection PubMed
description BACKGROUND: T cell engaging therapies, like chimeric antigen receptor T cells and T cell bispecific antibodies (TCBs), efficiently redirect T cells towards tumor cells, facilitating the formation of a cytotoxic synapse and resulting in subsequent tumor cell killing, a process that is accompanied by the release of cytokines. Despite their promising efficacy in the clinic, treatment with TCBs is associated with a risk of cytokine release syndrome (CRS). The aim of this study was to identify small molecules able to mitigate cytokine release while retaining T cell-mediated tumor killing. METHODS: By screening a library of 52 Food and Drug Administration approved kinase inhibitors for their impact on T cell proliferation and cytokine release after CD3 stimulation, we identified mTOR, JAK and Src kinases inhibitors as potential candidates to modulate TCB-mediated cytokine release at pharmacologically active doses. Using an in vitro model of target cell killing by human peripheral blood mononuclear cells, we assessed the effects of mTOR, JAK and Src kinase inhibitors combined with 2+1 T cell bispecific antibodies (TCBs) including CEA-TCB and CD19-TCB on T cell activation, proliferation and target cell killing measured by flow cytometry and cytokine release measured by Luminex. The combination of mTOR, JAK and Src kinase inhibitors together with CD19-TCB was evaluated in vivo in non-tumor bearing stem cell humanized NSG mice in terms of B cell depletion and in a lymphoma patient-derived xenograft (PDX) model in humanized NSG mice in terms of antitumor efficacy. RESULTS: The effect of Src inhibitors differed from those of mTOR and JAK inhibitors with the suppression of CD19-TCB-induced tumor cell lysis in vitro, whereas mTOR and JAK inhibitors primarily affected TCB-mediated cytokine release. Importantly, we confirmed in vivo that Src, JAK and mTOR inhibitors strongly reduced CD19-TCB-induced cytokine release. In humanized NSG mice, continuous treatment with a Src inhibitor prevented CD19-TCB-mediated B cell depletion in contrast to mTOR and JAK inhibitors, which retained CD19-TCB efficacy. Ultimately, transient treatment with Src, mTOR and JAK inhibitors minimally interfered with antitumor efficacy in a lymphoma PDX model. CONCLUSIONS: Taken together, these data support further evaluation of the use of Src, JAK and mTOR inhibitors as prophylactic treatment to prevent occurrence of CRS.
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spelling pubmed-87852082022-02-04 JAK and mTOR inhibitors prevent cytokine release while retaining T cell bispecific antibody in vivo efficacy Leclercq, Gabrielle Haegel, Hélène Toso, Alberto Zimmermann, Tina Green, Luke Steinhoff, Nathalie Sam, Johannes Pulko, Vesna Schneider, Anneliese Giusti, Anna Maria Challier, John Freimoser-Grundschober, Anne Larivière, Laurent Odermatt, Alex Stern, Martin Umana, Pablo Bacac, Marina Klein, Christian J Immunother Cancer Clinical/Translational Cancer Immunotherapy BACKGROUND: T cell engaging therapies, like chimeric antigen receptor T cells and T cell bispecific antibodies (TCBs), efficiently redirect T cells towards tumor cells, facilitating the formation of a cytotoxic synapse and resulting in subsequent tumor cell killing, a process that is accompanied by the release of cytokines. Despite their promising efficacy in the clinic, treatment with TCBs is associated with a risk of cytokine release syndrome (CRS). The aim of this study was to identify small molecules able to mitigate cytokine release while retaining T cell-mediated tumor killing. METHODS: By screening a library of 52 Food and Drug Administration approved kinase inhibitors for their impact on T cell proliferation and cytokine release after CD3 stimulation, we identified mTOR, JAK and Src kinases inhibitors as potential candidates to modulate TCB-mediated cytokine release at pharmacologically active doses. Using an in vitro model of target cell killing by human peripheral blood mononuclear cells, we assessed the effects of mTOR, JAK and Src kinase inhibitors combined with 2+1 T cell bispecific antibodies (TCBs) including CEA-TCB and CD19-TCB on T cell activation, proliferation and target cell killing measured by flow cytometry and cytokine release measured by Luminex. The combination of mTOR, JAK and Src kinase inhibitors together with CD19-TCB was evaluated in vivo in non-tumor bearing stem cell humanized NSG mice in terms of B cell depletion and in a lymphoma patient-derived xenograft (PDX) model in humanized NSG mice in terms of antitumor efficacy. RESULTS: The effect of Src inhibitors differed from those of mTOR and JAK inhibitors with the suppression of CD19-TCB-induced tumor cell lysis in vitro, whereas mTOR and JAK inhibitors primarily affected TCB-mediated cytokine release. Importantly, we confirmed in vivo that Src, JAK and mTOR inhibitors strongly reduced CD19-TCB-induced cytokine release. In humanized NSG mice, continuous treatment with a Src inhibitor prevented CD19-TCB-mediated B cell depletion in contrast to mTOR and JAK inhibitors, which retained CD19-TCB efficacy. Ultimately, transient treatment with Src, mTOR and JAK inhibitors minimally interfered with antitumor efficacy in a lymphoma PDX model. CONCLUSIONS: Taken together, these data support further evaluation of the use of Src, JAK and mTOR inhibitors as prophylactic treatment to prevent occurrence of CRS. BMJ Publishing Group 2022-01-21 /pmc/articles/PMC8785208/ /pubmed/35064010 http://dx.doi.org/10.1136/jitc-2021-003766 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Clinical/Translational Cancer Immunotherapy
Leclercq, Gabrielle
Haegel, Hélène
Toso, Alberto
Zimmermann, Tina
Green, Luke
Steinhoff, Nathalie
Sam, Johannes
Pulko, Vesna
Schneider, Anneliese
Giusti, Anna Maria
Challier, John
Freimoser-Grundschober, Anne
Larivière, Laurent
Odermatt, Alex
Stern, Martin
Umana, Pablo
Bacac, Marina
Klein, Christian
JAK and mTOR inhibitors prevent cytokine release while retaining T cell bispecific antibody in vivo efficacy
title JAK and mTOR inhibitors prevent cytokine release while retaining T cell bispecific antibody in vivo efficacy
title_full JAK and mTOR inhibitors prevent cytokine release while retaining T cell bispecific antibody in vivo efficacy
title_fullStr JAK and mTOR inhibitors prevent cytokine release while retaining T cell bispecific antibody in vivo efficacy
title_full_unstemmed JAK and mTOR inhibitors prevent cytokine release while retaining T cell bispecific antibody in vivo efficacy
title_short JAK and mTOR inhibitors prevent cytokine release while retaining T cell bispecific antibody in vivo efficacy
title_sort jak and mtor inhibitors prevent cytokine release while retaining t cell bispecific antibody in vivo efficacy
topic Clinical/Translational Cancer Immunotherapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8785208/
https://www.ncbi.nlm.nih.gov/pubmed/35064010
http://dx.doi.org/10.1136/jitc-2021-003766
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