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
Immunoradiotherapy holds promise for improving outcomes in patients with advanced solid tumors,including in soft-tissue sarcoma(STS).However,the ideal combination of treatment modalities remains to be determined,and r...Immunoradiotherapy holds promise for improving outcomes in patients with advanced solid tumors,including in soft-tissue sarcoma(STS).However,the ideal combination of treatment modalities remains to be determined,and reliable biomarkers to predict which patients will benefit are lacking.Here,we report the results of the STS cohort of the SABR-PDL1 phase Il trial that evaluated the anti-PDL1 atezolizumab combined with stereotactic body radiation therapy(SBRT)delivered concurrently with the 2nd cycle to at least one tumor site,Eligible patients received atezolizumab until progression or unmanageable toxicity,with SBRT at 45 Gy in 3 fractions).The primary endpoint was one-year progression-free survival(PFS)rate with success defined as 13 patients achieving 1-year PFS.Sixty-one heavily pretreated patients with STS(median 5 prior lines;52%men;median age 54 years;28%leiomyosarcoma)were enrolled across two centers(France,Spain).SBRT was delivered to 55 patients(90%),with the lung being the most commonly irradiated site(50%).After a median follow-up of 45 months,the one-year PFS rate was 8.3%[95%Cl:3.6-18.1].Median PFS and overall survival were 2.5 and 8.6 months,respectively.Best responses included partial responses(5%)and stable disease(60%).Immune profiling revealed increased immunosuppressive tumor-associated macrophages(e.g,IL4l1,HES1)and monocyte-recruiting chemokines in non-responders.Higher monocyte/lymphocyte ratios(MonoLR)in tumor and blood correlated with progression.PD-L1 status,lymphoid infiltration,and tertiary-lymphoid structures were not predictive.Although the primary endpoint was not met,this study highlights MonoLR imbalance as a potential biomarker to identify STS patients likely to benefit from immunoradiotherapy.EudraCT No.2015-005464-42;Clinicaltrial.gov number:NCT02992912.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.
基金supported by the French National Research Agency under the FRANCE2030 investment plan(grant application No.ANR-21-RHUS-0005)by the imCORE research network(No.SG40863)+1 种基金The authors would like to thank the collaborators from the histopathology department of Gustave Roussythe Experimental and Translational Pathology(PETRA,AMMICA,INSERM US23/CNRS)。
文摘Immunoradiotherapy holds promise for improving outcomes in patients with advanced solid tumors,including in soft-tissue sarcoma(STS).However,the ideal combination of treatment modalities remains to be determined,and reliable biomarkers to predict which patients will benefit are lacking.Here,we report the results of the STS cohort of the SABR-PDL1 phase Il trial that evaluated the anti-PDL1 atezolizumab combined with stereotactic body radiation therapy(SBRT)delivered concurrently with the 2nd cycle to at least one tumor site,Eligible patients received atezolizumab until progression or unmanageable toxicity,with SBRT at 45 Gy in 3 fractions).The primary endpoint was one-year progression-free survival(PFS)rate with success defined as 13 patients achieving 1-year PFS.Sixty-one heavily pretreated patients with STS(median 5 prior lines;52%men;median age 54 years;28%leiomyosarcoma)were enrolled across two centers(France,Spain).SBRT was delivered to 55 patients(90%),with the lung being the most commonly irradiated site(50%).After a median follow-up of 45 months,the one-year PFS rate was 8.3%[95%Cl:3.6-18.1].Median PFS and overall survival were 2.5 and 8.6 months,respectively.Best responses included partial responses(5%)and stable disease(60%).Immune profiling revealed increased immunosuppressive tumor-associated macrophages(e.g,IL4l1,HES1)and monocyte-recruiting chemokines in non-responders.Higher monocyte/lymphocyte ratios(MonoLR)in tumor and blood correlated with progression.PD-L1 status,lymphoid infiltration,and tertiary-lymphoid structures were not predictive.Although the primary endpoint was not met,this study highlights MonoLR imbalance as a potential biomarker to identify STS patients likely to benefit from immunoradiotherapy.EudraCT No.2015-005464-42;Clinicaltrial.gov number:NCT02992912.
