Desensitizing the autonomic nervous system to mitigate anti-GD2 monoclonal antibody side effects
Por:
Mora J, Climent A, Roldan-Molina M, Flores MC, Varo A, Pérez-Jaume S, Jou-Munoz C, Celma MS, Lazaro JJ, Cheung I, Castañeda-Heredia A, Gorostegui M, Rodriguez E, Chamorro S, Muñoz JP and Cheung NK
Publicada:
15 may 2024
Ahead of Print:
15 may 2024
Resumen:
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.
Filiaciones:
Mora J:
Pediatric Cancer Center Barcelona (PCCB), Hospital Sant Joan de Deu, Barcelona, Spain
Climent A:
Department of Neurophysiology, Hospital Sant Joan de Déu, Barcelona, Spain
Roldan-Molina M:
Department of Genetics, Hospital Sant Joan de Deu, Barcelona, Spain
Flores MC:
Department of Neurophysiology, Hospital Sant Joan de Déu, Barcelona, Spain
Varo A:
Pediatric Cancer Center Barcelona (PCCB), Hospital Sant Joan de Deu, Barcelona, Spain
Pérez-Jaume S:
Pediatric Cancer Center Barcelona (PCCB), Hospital Sant Joan de Deu, Barcelona, Spain
Jou-Munoz C:
Department of Pathology, Hospital Sant Joan de Déu, Barcelona, Spain
Celma MS:
Department of Pharmacy, Hospital Sant Joan de Déu, Barcelona, Spain
Lazaro JJ:
Department of Anesthesiology, Hospital Sant Joan De Déu, Barcelona, Spain
Cheung I:
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center (MSK), New York, NY, United States
Castañeda-Heredia A:
Pediatric Cancer Center Barcelona (PCCB), Hospital Sant Joan de Deu, Barcelona, Spain
Gorostegui M:
Pediatric Cancer Center Barcelona (PCCB), Hospital Sant Joan de Deu, Barcelona, Spain
Rodriguez E:
Department of Pathology, Hospital Sant Joan de Déu, Barcelona, Spain
Chamorro S:
Pediatric Cancer Center Barcelona (PCCB), Hospital Sant Joan de Deu, Barcelona, Spain
:
Pediatric Cancer Center Barcelona (PCCB), Hospital Sant Joan de Deu, Barcelona, Spain
Cheung NK:
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center (MSK), New York, NY, United States
Green Submitted, gold
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