Exploration Of The Predictive Biomarkers And Corresponding Strategies For Immune Monotherapy Response In Advanced Lung Cancer Patients

[Background]Cytokines have been reported to impact on immunological response and the concentrations of cytokines were associated with response to cancer.Hence,this study aimed to identify the circulating cytokine as biomarker to predict the response to immune monotherapy in advanced lung cancer patients.Besides,we further explore its potential value in combination therapy with immunotherapy.[Patients and Methods]This study enrolled advanced lung patients received anti-programmed death protein 1(anti-PD-1)antibody from January 2018 to December 2019.The responders(R)were defined as patients with complete response,partial response,or stable disease.Besides,the non-responders(NR)cohorts included ones with progressive disease.The different concentration of baseline circulating cytokines was examined by multi-analyte flow assay kit and validated by ELISA method between the responders and non-responders.And we established a mouse model with immune system to explore the anticancer efficacy of antibody to target cytokine and the mutual effect between antibody and anti-PD-L 1 antibodies.[Results]A total of 48 patients were included in this study.There were twenty-nine responders and nineteen non-responders.Plasma interleukin-6(IL-6)levels at baseline was significant higher in NR than R cohort.Patient with a higher level of plasma IL-6 had a significant inferior progression-free survival(PFS)(p=0.0088).Furthermore,circulating IL-6 was a negative predictor of PFS both in lung squamous cancer(p=0.0161)and lung adenocarcinoma patients(p=0.143).In addition,the IL-6 expression level on tissue was also negative and significantly related with PFS(p=0.003).Then,the vivo studies suggested that IL-6 and PD-L1 antibody blockade combination therapy reduced tumor progression in murine models of lung adenocarcinoma and squamous cancer.Further analysis revealed that targeting IL-6 may enhance the efficacy of ICIs by upregulating infiltration of CD8+T cells and reducing PD-L1 expression of tumor cells.[Discussion]This study elucidated that baseline level of IL-6 may emerge as a powerful predictive tool for immune monotherapy in advanced lung cancer patients.Considering to the availability of specimen,plasma IL-6 is more recommended.Meanwhile,the synergistic anti-tumor effect of anti-IL-6 antibody and anti-PD-L 1 drugs was found in the preclinical models,which paves the way for the progress of IL-6 as a therapeutic target for cancer treatment.[Background and Objective]Previous studies have demonstrated the relationship between gut microbiome and efficacy of immunotherapy.Few studies focused on the Asian patients while the majority of research was put on the Caucasians.This study mainly tried to investigate the correlation between gut microbiota and immune monotherapy in advanced thoracic carcinoma of Asian populations.[Methods]This study enrolled patients diagnosed with advanced thoracic cancer and received anti-programmed death protein 1(anti-PD-1)therapy from January 2018 to July 2019.The baseline characteristics including personal information,clinical data and laboratory data were collected.Baseline and time-serial stool specimens were collected and longitudinal analyzed with 16S ribosomal RNA gene sequencing.[Results]A total of 42 patients were included in this study.Twenty-three patients were responders to anti-PD-1 antibody,and 19 patients were non-responders.The relative abundance of the Akkermansiaceae,Enterococcaceae,Enterobacteriaceae,Carnobacteriaceae and Clostridiales Family XI bacterial families were dramatically higher in the responders.All these five bacterial families were defined as "commensal microbiome".The relative abundance of commensal microbiome was positively and significantly related with the efficacy of immune monotherapy(p=0.014).And patients with a higher abundance of commensal microbes had significant prolonged progression-free survival(p=0.00016).According to the multi-variable analysis,the abundance of the commensal microbes was an independent factor to predict the response to immune monotherapy(HR:0.17,95%CI:0.05-0.55,p=0.003).[Conclusions]Baseline gut microbiota may have a critical impact on immune monotherapy.And whether the commensal microbiota have the potential value to be a sensitive biomarker of immune monotherapy needs to be further validated in the future.[Background]While prospective clinical studies on immunotherapy in epidermal growth factor receptor(EGFR)mutant non-small-cell lung cancer(NSCLC)with acquired resistance to EGFR tyrosine kinase inhibitors(TKIs)are ongoing,this study aimed to investigate the outcomes of immunotherapy combinations in such a population in a real-world setting.[Methods]The clinical data of pretreated EGFR-mutated NSCLC patients who acquired EGFR-TKI resistance and received immunotherapy from September 2018 to June 2020 were retrospectively analyzed in this study.Progression-free survival(PFS)was assessed using the Kaplan-Meier method.Univariate analysis was performed with log-rank test,and multivariate analysis were using Cox regression test.[Results]A total of 31 patients were analyzed in this study.The median PFS was 3.25 months(95%CI 1.65-4.86).Sixteen patients(51.6%)were with EGFR 19del mutation,and 12 patients(38.7%)with EGFR 21L858R mutation.All patients received anti-programmed death protein 1(PD-1)drugs.A total of 25(80.6%)patients received combination immunotherapy.In the univariate analysis,patients who received combination immunotherapy acquired longer PFS than those who received monotherapy,although no significant difference was found(3.42 months vs.1.61 months;p=0.078;hazard ratio(HR)0.43,95%CI:0.16-1.13).Patients who received antiangiogenic drugs prior to immunotherapy acquired dramatically better PFS(3.42 months vs.1.58 months;p=0.027;HR 0.37,95%CI:0.15-0.93),while patients with liver metastasis had significantly inferior PFS(2.04 months vs.3.42 months;p=0.031;HR 2.83,95%CI:1.05-7.60).Furthermore,multivariate analysis confirmed that the above three factors had independent prognostic values.Four patients in this study experience grade 1 to 2 adverse events,including rash and hypothyroidism.[Conclusions]Immunotherapy combinations are considerable choices in pre-treated NSCLC patients with acquired EGFR-TKIs resistance.In future,more robust and prospective clinical trial results are expected to guide clinical practice.