In a groundbreaking study led by Prof. Antoine Italiano from the Bergonié & Gustave Roussy Comprehensive Cancer Centers, 42 patients with advanced gastroenteropancreatic neuroendocrine neoplasms were treated with a combination of anti-PD-1/PD-L1 immunotherapy and the angiogenesis inhibitor regorafenib. The combination therapy resulted in increased response rates and improved survival outcomes compared to PD-1/PD-L1 immunotherapy alone. However, a significant portion of patients did not respond to this therapeutic regimen.
To uncover the mechanisms of resistance and identify potential predictive biomarkers, Explicyte developed a custom immunohistofluorescence (IHF) panel. Digital pathology revealed an overall increase in CD8+ T cell infiltration. In tumors from non-responding patients, we observed a higher proportion of PD1+ / IDO1+ neoplastic cells, suggesting the presence of an immunosuppressive environment mediated by tryptophan metabolism along the kynurenine pathway. This hypothesis was further supported by quantifying the Kynurenine/Tryptophan ratio, which was associated with IDO1 expression in tumor tissues and correlated with poorer clinical outcomes. Additionally, using Olink’s immuno-oncology and inflammation panels, we identified an enrichment of immune related proteins in the plasma of patients with high IDO1 activity. Soluble PD-L1, TNF receptor family members (OX40, CD40, 4-1BB), and the immunosuppressive cytokine interleukin-10 were associated with unfavorable outcomes.
Altogether, this translational study suggests shows that the combination of regorafenib plus avelumab is interesting for patients with highly pre-treated GEP NETs, and suggests that adding IDO1 inhibitors to the combination of anti-PD1/PDL1 therapy and anti-angiogenic agents could be a promising strategy to enhance patient responses.
To uncover the mechanisms of resistance and identify potential predictive biomarkers, Explicyte developed a custom immunohistofluorescence (IHF) panel. Digital pathology revealed an overall increase in CD8+ T cell infiltration. In tumors from non-responding patients, we observed a higher proportion of PD1+ / IDO1+ neoplastic cells, suggesting the presence of an immunosuppressive environment mediated by tryptophan metabolism along the kynurenine pathway. This hypothesis was further supported by quantifying the Kynurenine/Tryptophan ratio, which was associated with IDO1 expression in tumor tissues and correlated with poorer clinical outcomes. Additionally, using Olink’s immuno-oncology and inflammation panels, we identified an enrichment of immune related proteins in the plasma of patients with high IDO1 activity. Soluble PD-L1, TNF receptor family members (OX40, CD40, 4-1BB), and the immunosuppressive cytokine interleukin-10 were associated with unfavorable outcomes.
Altogether, this translational study suggests shows that the combination of regorafenib plus avelumab is interesting for patients with highly pre-treated GEP NETs, and suggests that adding IDO1 inhibitors to the combination of anti-PD1/PDL1 therapy and anti-angiogenic agents could be a promising strategy to enhance patient responses.
