Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1β in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.

Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade

Iebba V.;
2021-01-01

Abstract

Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1β in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.
File in questo prodotto:
File Dimensione Formato  
Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade.pdf

Accesso chiuso

Tipologia: Documento in Versione Editoriale
Licenza: Copyright Editore
Dimensione 6.97 MB
Formato Adobe PDF
6.97 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
3007821_Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade-Post_print.pdf

Open Access dal 09/01/2022

Tipologia: Bozza finale post-referaggio (post-print)
Licenza: Digital Rights Management non definito
Dimensione 4.54 MB
Formato Adobe PDF
4.54 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11368/3007821
Citazioni
  • ???jsp.display-item.citation.pmc??? 166
  • Scopus 254
  • ???jsp.display-item.citation.isi??? 241
social impact