Exploratory Study Of β-Glucan Combined With PD-1/PD-L1 Checkpoint Blockade In Patients With Advanced Tumors

Background:Programmed death receptor-1(PD-1)/ programmed death receptor-ligand 1(PD-L1)checkpoint blocking antibody has been proven to be a powerful immune checkpoint blockade agent(ICB)for patients with advanced tumors,but patients often develop resistance to it,and the efficacy is subject to the immune negative microenvironment.In this study,we conducted the study of Whole Glucan Particle(WGP)β-glucan,an immune adjuvant that stimulates innate and adaptive immune responses,in combination with PD-1 / PD-L1 blocking antibodies for immunotherapy of malignant tumors,and evaluated the efficacy of β-glucan in reversing resistance to immune checkpoint blockers.Objective:To explore the efficacy and safety of WGP β-glucan combined with PD-1 / PD-L1 blocking antibody.Methods:AC57BL / 6 mouse Lewis lung cancer(LLC)subcutaneous tumor model was constructed,and LLC cells(3×05)were suspended in 100 μ L of phosphate buffer solution(PBS;Thermo Fisher Scientifific)and injected subcutaneously into the flanks of C57 BL / 6 mice.Tumor-bearing mice were randomly divided into four groups: control group(PBS),WGP β-glucan group,PD-1inhibitor group,and WGP β-glucan + PD-1 inhibitor group.Treatment was initiated when the tumor mass was palpable(approximately 6-7 days after injection): Mice from the WGP β-glucan and WGP β-glucan + PD-1 inhibitor groups were given 1mg of WGP β-glucan dissolved in 100 μL PBS orally daily;Mice in the PD-1 inhibitor group and WGP β-glucan + PD-1 inhibitor group were injected with 20 μ g of 100 μL PBS PD-1 inhibitor(clone 29 F.1A12,Biolegend)once every 3 days;control mice were given 100 u L PBS.Tumors were measured with a radiometer every other day,and when the tumor length reached 15 mm(about 20 days after injection),the tumor-bearing mice were euthanized to assess their tumor growth curve,survival,and immune microenvironment characteristics.An investigator-initiated clinical trial was conducted for patients with β-glucan 500 mg orally twice daily with a PD-1 / PD-L1 inhibitor for a biweekly course until intolerable toxicity,disease progression or death.Follow-up treatment efficacy and survival,detect serum cytokine changes at each treatment node,and explore the reversal effect and action mechanism of β-glucan in patients with advanced tumors resistant to immune checkpoint inhibitors.Results:Experimental results from a tumor mouse model suggest that,The use of WGP β-glucan in combination with PD-1 / PD-L1 blocking antibody resulted in increased recruitment of immune-related cells,improved regulation of the balance between T cells activation and immune tolerance,and inhibition of tumor growth in tumor-bearing mice;A total of 13 patients with a previous regimen containing PD-1 /PD-L1 inhibitor were enrolled in this clinical study,With β-glucan on the basis of the original protocol,Nine patients(69.2%)had stable disease at disease assessment(Stable Disease,SD),4(30.8%)of disease progression(Progressive Disease,PD).The median progression-free survival(m PFS)was 3.67 months,the median overall survival(m OS)was 8.0 months,and the disease control rate(DCR)was 69.2%,effectively overcoming immunoresistance in patients with advanced tumors.In addition,there were also IL-significant differences in the concentrations of IL-1 β,IL-6 and IL-8 cytokines in serum samples before and after treatment.Conclusion:This study shows that β-glucan can be used as an immune adjuvant,which can inhibit tumor growth and reverse immune resistance by regulating the immune system.