The majority of sarcomas are under the influence of a tumor microenvironment that dampens immune activity,resulting in resistance to monoclonal antibodies targeting immune checkpoints and reduced clinical effectivenes...The majority of sarcomas are under the influence of a tumor microenvironment that dampens immune activity,resulting in resistance to monoclonal antibodies targeting immune checkpoints and reduced clinical effectiveness.Preclinical studies indicate that targeting abnormal neoangiogenesis by inhibiting vascular endothelial growth factor receptor(VEGFR)can alter the TME,thereby promoting T cell infiltration and increasing tumor immunogenicity.The REGOMUNE study,a phase II clinical trial,assessed the therapeutic combination of regorafenib,a multityrosine kinase inhibitor that targets VEGFR2 and the PD-L1 blocker avelumab,in individuals with advanced“cold”STS characterized by a lack of mature tertiary lymphoid structures(mTLS).Forty-nine mTLSnegative STS patients were enrolled,including leiomyosarcoma(45%),synovial sarcoma(18%),and other subtypes.The objective response rate was 11.0%(95%CI:4.0%-22.0%),with median progression-free survival and overall survival of 1.8 months(95%CI,1.7-3.5 months)and 15.1 months,respectively.Frequent adverse events included grade 1 or 2 palmar-plantar erythrodysesthesia,fatigue,and diarrhea.On-treatment multiplex immunofluorescence analysis revealed significant increases in CD8+T cell and B cell infiltration and PD1 expression on immune cells.Plasma analysis indicated significant upregulation of soluble PD-L1(sPD-L1)levels and tryptophan consumption.Overall,these results indicate that anti-angiogenic therapy modulates the tumor microenvironment in patients with cold STS and highlight the need for complementary strategies to enhance the functional activity of immune cells in this particular setting.展开更多
基金Institut National du Cancer,from the Association pour la Recherche contre le Cancer and by the Agence Nationale de la Recherche(ANR 21 RHUS 0010).
文摘The majority of sarcomas are under the influence of a tumor microenvironment that dampens immune activity,resulting in resistance to monoclonal antibodies targeting immune checkpoints and reduced clinical effectiveness.Preclinical studies indicate that targeting abnormal neoangiogenesis by inhibiting vascular endothelial growth factor receptor(VEGFR)can alter the TME,thereby promoting T cell infiltration and increasing tumor immunogenicity.The REGOMUNE study,a phase II clinical trial,assessed the therapeutic combination of regorafenib,a multityrosine kinase inhibitor that targets VEGFR2 and the PD-L1 blocker avelumab,in individuals with advanced“cold”STS characterized by a lack of mature tertiary lymphoid structures(mTLS).Forty-nine mTLSnegative STS patients were enrolled,including leiomyosarcoma(45%),synovial sarcoma(18%),and other subtypes.The objective response rate was 11.0%(95%CI:4.0%-22.0%),with median progression-free survival and overall survival of 1.8 months(95%CI,1.7-3.5 months)and 15.1 months,respectively.Frequent adverse events included grade 1 or 2 palmar-plantar erythrodysesthesia,fatigue,and diarrhea.On-treatment multiplex immunofluorescence analysis revealed significant increases in CD8+T cell and B cell infiltration and PD1 expression on immune cells.Plasma analysis indicated significant upregulation of soluble PD-L1(sPD-L1)levels and tryptophan consumption.Overall,these results indicate that anti-angiogenic therapy modulates the tumor microenvironment in patients with cold STS and highlight the need for complementary strategies to enhance the functional activity of immune cells in this particular setting.
