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

Abstract

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

Revisiting Secondary Information Related to Pharmacogenetic Testing

“…Medication response is a complex phenotype impacted by both host genetics, environmental factors and the gut microbiome. A growing body of literature highlights the important role of the gut microbiome on drug response (Zhang et al, 2018;Clarke et al, 2019) as well as disease risk (Andrews et al, 2021;Zhang et al, 2021). Thus, we should not confine the definition of secondary findings to host genetic variants.…”

Current Progress and Future Perspectives of Immune Checkpoint in Cancer and Infectious Diseases

“…4) The composition and percentage of the commensal microbiome may influence the curative effect for patients treated with ICI ( Figure 2 ). The conclusion discovered from several kinds of research said that various irAEs were associated with the different superior microbiome, application of antibiotics was linked to poor prognosis, and fecal microbiota transplantation (FMT) could reduce immune colitis ( Pierrard and Seront, 2019 ; Hommes et al, 2020 ; Andrews et al, 2021 ; Seton-Rogers, 2021 ). 5) Genetic susceptibility includes HLA haplotypes ( Stamatouli et al, 2018 ).…”

Microbiota and Colorectal Cancer: From Gut to Bedside

“…As a final proof, the authors performed FMT from healthy human donors harbouring high levels of endogenous Bacteroides intestinalis into tumour-bearing mice . This led to induction of Il1b expression in the intestine following CICB treatment of a melanoma mouse model ( Andrews et al, 2021 ).…”

“…Nonetheless, a significant proportion of subjects experience immune-related adverse events as a consequence of this treatment (Sznol et al, 2017). A recent study suggests that CICB toxicity may be mediated bacteria that lead to increased production of IL-1β in this cancer model (Andrews et al, 2021). IL-1β is produced by monocytes in response to commensal microbiota and induces inflammation in the intestine (Seo et al, 2015).…”