Desensitizing the autonomic nervous system to mitigate anti-GD2 monoclonal antibody side effects

Background Anti-GD2 monoclonal antibodies (mAbs) have shown to improve the overall survival of patients with high-risk neuroblastoma (HR-NB). Serious adverse events (AEs), including pain, within hours of antibody infusion, have limited the development of these therapies. In this study, we provide ev...

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Autores: Mora J, Climent A, Roldán M, Flores MC, Varo A, Perez-Jaume S, Jou C, Celma MS, Lazaro JJ, Cheung I, Castañeda A, Gorostegui M, Rodriguez E, Chamorro S, Muñoz JP, Cheung NK
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Fundació Sant Joan de Déu
Repositorio:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
OAI Identifier:oai:fsjd.fundanetsuite.com:p26332
Acceso en línea:https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=26332
Access Level:acceso abierto
Palabra clave:anti-GD2 immunotherapy
autonomic nervous system
visceral pain
neuroblastoma
infusion protocol
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spelling Desensitizing the autonomic nervous system to mitigate anti-GD2 monoclonal antibody side effectsMora JCliment ARoldán MFlores MCVaro APerez-Jaume SJou CCelma MSLazaro JJCheung ICastañeda AGorostegui MRodriguez EChamorro SMuñoz JPCheung NKanti-GD2 immunotherapyautonomic nervous systemvisceral painneuroblastomainfusion protocolBackground Anti-GD2 monoclonal antibodies (mAbs) have shown to improve the overall survival of patients with high-risk neuroblastoma (HR-NB). Serious adverse events (AEs), including pain, within hours of antibody infusion, have limited the development of these therapies. In this study, we provide evidence of Autonomic Nervous System (ANS) activation as the mechanism to explain the main side effects of anti-GD2 mAbs.Methods Through confocal microscopy and computational super-resolution microscopy experiments we explored GD2 expression in postnatal nerves of infants. In patients we assessed the ANS using the Sympathetic Skin Response (SSR) test. To exploit tachyphylaxis, a novel infusion protocol (the Step-Up) was mathematically modelled and tested.Results Through confocal microscopy, GD2 expression is clearly visible in the perineurium surrounding the nuclei of nerve cells. By computational super-resolution microscopy experiments we showed the selective expression of GD2 on the cell membranes of human Schwann cells in peripheral nerves (PNs) significantly lower than on NB. In patients, changes in the SSR were observed 4 minutes into the anti-GD2 mAb naxitamab infusion. SSR latency quickly shortened followed by gradual decrease in the amplitude before disappearance. SSR response did not recover for 24 hours consistent with tachyphylaxis and absence of side effects in the clinic. The Step-Up protocol dissociated on-target off-tumor side effects while maintaining serum drug exposure.Conclusion We provide first evidence of the ANS as the principal non-tumor target of anti-GD2 mAbs in humans. We describe the development and modeling of the Step-Up protocol exploiting the tachyphylaxis phenomenon we demonstrate in patients using the SSR test.FRONTIERS MEDIA SA2024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=26332Frontiers in OncologyISSN: 2234943Xreponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déuinstname:Fundació Sant Joan de DéuInglésinfo:eu-repo/semantics/openAccessoai:fsjd.fundanetsuite.com:p263322026-05-27T12:37:41Z
dc.title.none.fl_str_mv Desensitizing the autonomic nervous system to mitigate anti-GD2 monoclonal antibody side effects
title Desensitizing the autonomic nervous system to mitigate anti-GD2 monoclonal antibody side effects
spellingShingle Desensitizing the autonomic nervous system to mitigate anti-GD2 monoclonal antibody side effects
Mora J
anti-GD2 immunotherapy
autonomic nervous system
visceral pain
neuroblastoma
infusion protocol
title_short Desensitizing the autonomic nervous system to mitigate anti-GD2 monoclonal antibody side effects
title_full Desensitizing the autonomic nervous system to mitigate anti-GD2 monoclonal antibody side effects
title_fullStr Desensitizing the autonomic nervous system to mitigate anti-GD2 monoclonal antibody side effects
title_full_unstemmed Desensitizing the autonomic nervous system to mitigate anti-GD2 monoclonal antibody side effects
title_sort Desensitizing the autonomic nervous system to mitigate anti-GD2 monoclonal antibody side effects
dc.creator.none.fl_str_mv Mora J
Climent A
Roldán M
Flores MC
Varo A
Perez-Jaume S
Jou C
Celma MS
Lazaro JJ
Cheung I
Castañeda A
Gorostegui M
Rodriguez E
Chamorro S
Muñoz JP
Cheung NK
author Mora J
author_facet Mora J
Climent A
Roldán M
Flores MC
Varo A
Perez-Jaume S
Jou C
Celma MS
Lazaro JJ
Cheung I
Castañeda A
Gorostegui M
Rodriguez E
Chamorro S
Muñoz JP
Cheung NK
author_role author
author2 Climent A
Roldán M
Flores MC
Varo A
Perez-Jaume S
Jou C
Celma MS
Lazaro JJ
Cheung I
Castañeda A
Gorostegui M
Rodriguez E
Chamorro S
Muñoz JP
Cheung NK
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv anti-GD2 immunotherapy
autonomic nervous system
visceral pain
neuroblastoma
infusion protocol
topic anti-GD2 immunotherapy
autonomic nervous system
visceral pain
neuroblastoma
infusion protocol
description Background Anti-GD2 monoclonal antibodies (mAbs) have shown to improve the overall survival of patients with high-risk neuroblastoma (HR-NB). Serious adverse events (AEs), including pain, within hours of antibody infusion, have limited the development of these therapies. In this study, we provide evidence of Autonomic Nervous System (ANS) activation as the mechanism to explain the main side effects of anti-GD2 mAbs.Methods Through confocal microscopy and computational super-resolution microscopy experiments we explored GD2 expression in postnatal nerves of infants. In patients we assessed the ANS using the Sympathetic Skin Response (SSR) test. To exploit tachyphylaxis, a novel infusion protocol (the Step-Up) was mathematically modelled and tested.Results Through confocal microscopy, GD2 expression is clearly visible in the perineurium surrounding the nuclei of nerve cells. By computational super-resolution microscopy experiments we showed the selective expression of GD2 on the cell membranes of human Schwann cells in peripheral nerves (PNs) significantly lower than on NB. In patients, changes in the SSR were observed 4 minutes into the anti-GD2 mAb naxitamab infusion. SSR latency quickly shortened followed by gradual decrease in the amplitude before disappearance. SSR response did not recover for 24 hours consistent with tachyphylaxis and absence of side effects in the clinic. The Step-Up protocol dissociated on-target off-tumor side effects while maintaining serum drug exposure.Conclusion We provide first evidence of the ANS as the principal non-tumor target of anti-GD2 mAbs in humans. We describe the development and modeling of the Step-Up protocol exploiting the tachyphylaxis phenomenon we demonstrate in patients using the SSR test.
publishDate 2024
dc.date.none.fl_str_mv 2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=26332
url https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=26332
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv FRONTIERS MEDIA SA
publisher.none.fl_str_mv FRONTIERS MEDIA SA
dc.source.none.fl_str_mv Frontiers in Oncology
ISSN: 2234943X
reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
instname:Fundació Sant Joan de Déu
instname_str Fundació Sant Joan de Déu
reponame_str r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
collection r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
repository.name.fl_str_mv
repository.mail.fl_str_mv
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