Synergistic efficacy of simultaneous anti-TGF-β/VEGF bispecific antibody and PD-1 blockade in cancer therapy

Journal of Hematology & Oncology, Journal Year: 2023, Volume and Issue: 16(1)

Published: Aug. 12, 2023

Recently, therapeutic antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1) have exerted potent anticancer effect in a variety of tumors. However, blocking the PD-1/PD-L1 axis alone is not sufficient to restore normal immune response. Other negative regulators antitumor immunity, like TGF-β VEGFA, are also involved escape tumor cells induce immunotherapy resistance.We developed novel anti-TGF-β/VEGF bispecific antibody Y332D based on Nano-YBODY™ technology platform. The CCK-8, flow cytometry, SBE4 luciferase reporter assay, western blotting transwell assays were used measure biological activities anti-TGF-β moiety. NFAT luminescent viability assay tube formation anti-VEGF vivo efficacy or combination with PD-1 blockade was evaluated H22, EMT-6, 4T1, AKT/Ras-driven murine hepatocellular carcinoma models. Immunofluorescent staining, RNA-seq quantitative RT-PCR adopted analyze alterations microenvironment.Y332D could maintain specific binding affinities for VEGFA. almost entirely counteracted vitro functions including immunosuppression, activated signaling, epithelial-mesenchymal transition (EMT), VEGF/VEGFR HUVEC proliferation formation. experiment data demonstrated that more effective inhibiting growth metastasis than monotherapies. In therapies, plus exhibited most durable effect. Mechanistically, upregulated density function tumor-infiltrating lymphocytes reinvigorated immunity.Y332D simultaneously block VEGF signalings. comparison monotherapies, combined exerts superior through improving microenvironment.

Language: Английский

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Advances and prospects of biomarkers for immune checkpoint inhibitors

Cell Reports Medicine, Journal Year: 2024, Volume and Issue: 5(7), P. 101621 - 101621

Published: June 20, 2024

Immune checkpoint inhibitors (ICIs) activate anti-cancer immunity by blocking T cell molecules such as programmed death 1 (PD-1) and cytotoxic lymphocyte-associated protein 4 (CTLA-4). Although ICIs induce some durable responses in various cancer patients, they also have disadvantages, including low response rates, the potential for severe side effects, high treatment costs. Therefore, selection of patients who can benefit from ICI is critical, identification biomarkers essential to improve efficiency ICIs. In this review, we provide updated information on established predictive (tumor death-ligand [PD-L1] expression, DNA mismatch repair deficiency, microsatellite instability high, tumor mutational burden) currently under investigation tumor-infiltrated peripheral lymphocytes, gut microbiome, signaling pathways related damage antigen presentation. particular, review aims summarize current knowledge biomarkers, discuss issues, further explore future biomarkers.

Language: Английский

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CD8+ T cell exhaustion in the tumor microenvironment of breast cancer

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Dec. 9, 2024

CD8+ T cells are crucial cytotoxic components of the tumor immune system. In chronic inflammation, they become low-responsive, a state known as cell exhaustion (TEX). The aim checkpoint blockade is to counteract TEX, yet its dynamics in breast cancer remain poorly understood. This review defines TEX and outlines features underlying mechanisms. It also discusses primary mechanisms cancer, covering inhibitory receptors, immunosuppressive cells, cytokines, transcriptomic epigenetic alterations, metabolic reprogramming, exosome pathways, offering insights into potential immunotherapy strategies for cancer.

Language: Английский

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Soluble immune checkpoint factors reflect exhaustion of antitumor immunity and response to PD-1 blockade

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(7)

Published: March 31, 2024

BACKGROUNDPrecise stratification of patients with non-small cell lung cancer (NSCLC) is needed for appropriate application PD-1/PD-L1 blockade therapy.METHODSWe measured soluble forms the immune-checkpoint molecules PD-L1, PD-1, and CTLA-4 in plasma advanced NSCLC before blockade. A prospective biomarker-finding trial (cohort A) included 50 previously treated who received nivolumab. retrospective observational study was performed any therapy (cohorts B C), cytotoxic chemotherapy D), or targeted E). Plasma samples from all were assayed a highly sensitive chemiluminescence-based assay.RESULTSNonresponsiveness to associated higher concentrations these immune factors among immune-reactive (hot) tumors. Such an association not apparent therapy. Integrative analysis tumor size, PD-L1 expression tissue (tPD-L1), gene peripheral CD8+ T cells revealed that high 3 hyper terminal exhaustion antitumor immunity. The combination (sPD-L1) sCTLA-4 efficiently discriminated responsiveness tumors.CONCLUSIONCombinations might be able identify unlikely respond as result Our data suggest such better predicts, along tPD-L1, response NSCLC.TRIAL REGISTRATIONUMIN000019674.FUNDINGThis funded by Ono Pharmaceutical Co. Ltd. Sysmex Corporation.

Language: Английский

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TGF-β: A novel predictor and target for anti-PD-1/PD-L1 therapy

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Dec. 19, 2022

Transforming growth factor-β (TGF-β) signaling regulates multiple physiological processes, such as cell proliferation, differentiation, immune homeostasis, and wound healing. Besides, TGF-β plays a vital role in diseases, including cancer. Accumulating evidence indicates that controls the composition behavior of components tumor microenvironment (TME). Advanced cancers leverage to reshape TME escape surveillance. TGF-β-mediated evasion is an unfavorable factor for cancer immunotherapy, especially checkpoint inhibitors (ICI). Numerous preclinical clinical studies have demonstrated hyperactive closely associated with ICI resistance. It has been validated blockade synergizes overcomes treatment TGF-β-targeted therapies, trap bispecific antibodies, shown immense potential immunotherapy. In this review, we summarized predictive value prospects therapies

Language: Английский

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The therapeutic potential of PD-1/PD-L1 pathway on immune-related diseases: Based on the innate and adaptive immune components

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 167, P. 115569 - 115569

Published: Sept. 26, 2023

Currently, immunotherapy targeting programmed cell death 1 (PD-1) or ligand (PD-L1) has revolutionized the treatment strategy of human cancer patients. Meanwhile, PD-1/PD-L1 pathway also been implicated in pathogenesis many immune-related diseases, such as autoimmune chronic infection diseases and adverse pregnancy outcomes, by regulating components innate adaptive immune systems. Given power new therapy, a better understanding regulatory effects on responses will facilitate discovery novel biomarkers therapeutic drug targets. Targeting this may successfully halt potentially even reverse these pathological processes. In review, we discuss recent major advances axis diseases. We reveal that impact system is complex manifold multi-strategies targeted are taken Consequently, pathway, alone combination with other treatments, represent for future intervention

Language: Английский

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NSCLC: from tumorigenesis, immune checkpoint misuse to current and future targeted therapy

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 7, 2024

Non-small cell lung cancer (NSCLC) is largely promoted by a multistep tumorigenesis process involving various genetic and epigenetic alterations, which essentially contribute to the high incidence of mortality among patients with NSCLC. Clinical observations revealed that NSCLC also co-opts multifaceted immune checkpoint dysregulation as an important driving factor in progression development. For example, deregulated PI3K/AKT/mTOR pathway has been noticed 50-70% cases, primarily modulated mutations key oncogenes such ALK, EGFR, KRAS, others. Additionally, association studies containing patient-specific factors local reimbursement criteria expose/reveal EGFR/ALK/ROS/BRAF/KRAS/PD-L1 proteins determine suitability available immunotherapy or tyrosine kinase inhibitor therapy. Thus, expression checkpoints on tumors cells pivotal understanding therapeutic efficacy extensively studied for treatments. Therefore, this review summarizes current knowledge tumorigenesis, focusing its intricacies, dysregulation, evolving landscape targeted therapies. In context future therapies, we emphasize significance antibodies targeting PD-1/PD-L1 CTLA-4 interactions primary strategy system reactivation Other approaches promising potential nanobodies, probodies, affibodies, DARPINs are described; these under active research clinical trials mediate regulation reduce progression. This comprehensive underscores nature, state directions treatment.

Language: Английский

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Developing a risk score using liquid biopsy biomarkers for selecting Immunotherapy responders and stratifying disease progression risk in metastatic melanoma patients

Journal of Experimental & Clinical Cancer Research, Journal Year: 2025, Volume and Issue: 44(1)

Published: Feb. 5, 2025

Abstract Background Despite the high response rate to PD-1 blockade therapy in metastatic melanoma (MM) patients, a significant proportion of patients do not respond. Identifying biomarkers predict patient is crucial, ideally through non-invasive methods such as liquid biopsy. Methods Soluble forms PD1, PD-L1, LAG-3, CTLA-4, CD4, CD73, and CD74 were quantified using ELISA assay plasma cohort 110 MM at baseline, investigate possible correlations with clinical outcomes. A risk prediction model was applied validated pilot studies. Results No biomarker showed statistically differences between responders non-responders. However, number observed among certain Through univariate multivariate Cox analyses, we identified sPD-L1, sCTLA-4, sCD73, sCD74 independent predicting progression-free survival overall survival. According ROC analysis discovered that, except for values lower than cut-off predicted disease progression reduced mortality. comprehensive score developed by incorporating ​​of two factors, sCTLA-4 sCD74, which significantly improved accuracy outcome prediction. Pilot validations highlighted potential use treatment-naive individuals long responders. Conclusion In summary, based on circulating reflects immune checkpoint inhibitor (ICI) patients. If confirmed, further validation, these findings could assist recommending likely experience long-lasting response.

Language: Английский

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Assessing the Clinical Relevance of Soluble PD-1 and PD-L1: A Multi-Cohort Study Across Diverse Tumor Types and Prognostic Implications

Biomedicines, Journal Year: 2025, Volume and Issue: 13(2), P. 500 - 500

Published: Feb. 17, 2025

Background/Objectives: Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have revolutionized cancer immunotherapy, however clinical relevance of their soluble forms (sPD-1 and sPD-L1) remains less studied. Soluble PD-1 PD-L1 been implicated in tumor progression, prognosis, treatment response across various malignancies. This study aims to provide a comprehensive analysis sPD-1 sPD-L1 levels serum diverse types, including rare malignancies, evaluate associations with clinicopathological characteristics prognostic significance. Methods: In this we analyzed samples from 675 patients representing range ovarian cancer, breast gastric colorectal renal cell carcinoma, bone tumors. concentrations were measured using ELISA. Statistical analyses performed between marker factors, stage, size, histological subtype, survival outcomes. Results: Elevated observed several where they associated features advanced disease, such as metastases. contrast, showed limited associations, significant findings solely tumors, correlated subtype differentiation. Prognostic identified poor outcomes while displayed no consistent Conclusions: identifies potential biomarker for progression prognosis multiple relevance, suggesting importance further investigation. These contribute our understanding immune proteins integration into personalized oncology strategies.

Language: Английский

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Impact of cannabinoids on cancer outcomes in patients receiving immune checkpoint inhibitor immunotherapy

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: March 5, 2025

Cannabinoids relieve pain, nausea, anorexia and anxiety, improve quality of life in several cancer patients. The immunotherapy with checkpoint inhibitors (ICIs), although very successful a subset patients, is accompanied by moderate to severe immune-related adverse events (ir-AE) that often necessitate its discontinuation. Because their role symptomatic relief, cannabinoids have been used combination immune inhibitor (ICI) immunotherapy. A few studies strongly suggest the use medicinal cannabis patients attenuates many ir-AE associated ICI increase tolerability. However, no significant beneficial effects on overall survival, progression free survival or relapses were observed; rather, some noted concurrent administration clinical benefits latter. cannabinoids' well documented immunosuppressive mediated through cannabinoid recptor-2 (CB2), we propose considering this receptor as an inhibitory per se. simultaneous neutralization CB2, treatment, may lead better outcomes receiving In regard, such cannabidiol (CBD) cannabigerol (CBG), little agonism for be therapeutic choices. Additional strategies e.g., monoacylglycerol lipase (MAGL) degrade endocannabinoids lipogenesis formation lipid bilayers cells also explored. Future should take into consideration gut microbiota, CYP450 polymorphism haplotypes, cannabinoid-drug interactions genetic somatic variations occurring receptors signaling pathways personalized cannabis-based therapies ICIs. This rational knowledge-based regimens tailored individual

Language: Английский

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