Immune checkpoint therapy for solid tumours: clinical dilemmas and future trends

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Aug. 28, 2023

Abstract Immune-checkpoint inhibitors (ICBs), in addition to targeting CTLA-4, PD-1, and PD-L1, novel LAG-3 drugs have also been approved clinical application. With the widespread use of drug, we must deeply analyze dilemma agents seek a breakthrough treatment prospect. Over past decades, these demonstrated dramatic efficacy, especially patients with melanoma non-small cell lung cancer (NSCLC). Nonetheless, field broad concept solid tumours, non-specific indications, inseparable immune response side effects, unconfirmed progressive disease, complex regulatory networks resistance are four barriers that limit its Fortunately, successful trials ICB combination therapies, advent era oncolytic virus gene editing, technical mRNA vaccines nano-delivery systems made remarkable breakthroughs currently. In this review, enumerate mechanisms each checkpoint targets, associations between tumour mutation burden, key or signalling pathways, specific evidence efficacy classical targets new among different types put forward dialectical thoughts on drug safety. Finally, discuss importance accurate triage based recent advances predictive biomarkers diagnostic testing techniques.

Language: Английский

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Evaluation of Clinical and Safety Outcomes of Neoadjuvant Immunotherapy Combined With Chemotherapy for Patients With Resectable Esophageal Cancer

JAMA Network Open, Journal Year: 2022, Volume and Issue: 5(11), P. e2239778 - e2239778

Published: Nov. 2, 2022

Importance A considerable number of clinical trials neoadjuvant immunotherapy for patients with resectable esophageal cancer are emerging. However, systematic evaluations these studies lacking. Objective To provide state-of-the-art evidence and normative theoretical support locally advanced cancer. Data Sources PubMed, Embase, Cochrane Library, ClinicalTrials.gov databases were searched relevant original articles conference proceedings that published in English through April 1, 2022. Study Selection Published phase 2 or 3 included stage I to IV who received immune checkpoint inhibitors (ICIs) before surgery as monotherapy combination other therapies. Extraction Synthesis The Preferred Reporting Items Systematic Reviews Meta-analyses the Meta-analysis Observational Studies Epidemiology guidelines meta-analysis followed extract data. random-effects model was adopted if heterogeneity significant ( statistic >50%); otherwise, common-effects used. analyses conducted from 8, Main Outcomes Measures Pathological complete response (pCR) rate major pathological (MPR) considered be primary outcomes calculated immunotherapy. Incidence treatment-related severe adverse events set measure safety outcome. R0 surgical resection summarized. Subgroup according histologic subtype ICI types. Results total 27 815 included. Pooled rates 31.4% (95% CI, 27.6%-35.3%) pCR 48.9% 42.0-55.9%) MCR In terms safety, pooled incidence 26.9% 16.7%-38.3%). Most achieved (98.6%; 95% 97.1%-99.6%). Regarding subtypes, 32.4% 28.2%-36.8%) squamous cell carcinoma 25.2% 16.3%-35.1%) adenocarcinoma. MPR 49.4% 42.1%-56.7%) carcinoma. Conclusions Relevance This study found chemotherapy had promising Randomized long-term follow-up warranted validate findings benefits ICIs.

Language: Английский

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Atezolizumab for Advanced Alveolar Soft Part Sarcoma

New England Journal of Medicine, Journal Year: 2023, Volume and Issue: 389(10), P. 911 - 921

Published: Sept. 6, 2023

Alveolar soft part sarcoma (ASPS) is a rare soft-tissue with poor prognosis and no established therapy. Recently, encouraging responses to immune checkpoint inhibitors have been reported.

Language: Английский

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Pan-cancer and experimental analyses reveal the immunotherapeutic significance of CST2 and its association with stomach adenocarcinoma proliferation and metastasis

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 24, 2025

Purpose Cystatin 2 (CST2) is a cysteine protease inhibitor, and recent research suggests its potential involvement in cancer development. However, role the occurrence, progression, prognosis of pan-cancer has not been systematically investigated. Materials methods This study comprehensively analyzes differential expression CST2 pan-cancer. The distribution patterns were examined using single-cell datasets. Furthermore, we conducted comprehensive evaluation correlation between various factors. These factors include prognosis, immune cell infiltration, immune-related genes, mutations, methylation, tumor mutation burden (TMB), microsatellite instability (MSI). In addition, analyzed sensitivity drugs dependent on expression. We utilized gene set enrichment analysis (GSEA) to explore biological functions across different types. Finally, gastric lines, will investigate impact knockout levels, clonal proliferation, apoptosis, migration. Results exhibits abnormal overexpression multiple tumors. Single-cell reveals high fibroblasts. closely associated with TMB, MSI. Enrichment demonstrated significant pathways. stomach adenocarcinoma (STAD), CST2-related risk models are demonstrate strong predictive capabilities, while also being linked microenvironment. Drug indicates 21 chemotherapy drugs. experimental validation revealed significantly elevated STAD, indicating as driver regulating malignant proliferation Conclusion serves biomarker, playing critical facilitating migration processes STAD.

Language: Английский

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Pretrained transformers applied to clinical studies improve predictions of treatment efficacy and associated biomarkers

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 1, 2025

Abstract Cancer treatment has made significant advancements in recent decades, however many patients still experience failure or resistance. Attempts to identify determinants of response have been hampered by a lack tools that simultaneously accommodate smaller datasets, sparse missing measurements, multimodal clinicogenomic data, and can be interpreted extract biological clinical insights. We introduce the Clinical Transformer, an explainable transformer-based deep-learning framework addresses these challenges. Our maximizes data via self-supervised, gradual, transfer learning, yields survival predictions surpassing performance state-of-the-art methods across diverse, independent datasets. The framework’s generative capability enables silico perturbation experiments test counterfactual hypotheses. By perturbing immune-associated features immunotherapy-naive patients, we patient subset may benefit from immunotherapy, validate this finding three immunotherapy-treated cohorts. anticipate our work will empower scientific community further harness for patients.

Language: Английский

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Identification of cuproptosis-related subtypes, construction of a prognosis model, and tumor microenvironment landscape in gastric cancer

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

Published: Nov. 21, 2022

Introduction Cuproptosis is a novel identified regulated cell death (RCD), which correlated with the development, treatment response and prognosis of cancer. However, potential role cuproptosis-related genes (CRGs) in tumor microenvironment (TME) gastric cancer (GC) remains unknown. Methods Transcriptome profiling, somatic mutation, copy number alteration clinical data GC samples were downloaded from Cancer Genome Atlas (TCGA) Gene Expression Omnibus (GEO) database to describe alterations CRGs genetic transcriptional fields. Differential, survival univariate cox regression analyses carried out investigate GC. molecular subtypes by using consensus unsupervised clustering analysis based on expression profiles CRGs, further analyzed GO KEGG gene set variation (GSVA). Genes distinct also enrichment (GSEA). Differentially expressed (DEGs) screened analysis. Consensus prognostic DEGs was performed identify genomic subtypes. Next, patients randomly categorized into training testing group at ratio 1:1. CRG Risk scoring system constructed through logistic least absolute shrinkage selection operator (LASSO) analysis, multivariate validated combined groups. Real-time quantitative polymerase chain reaction (RT-qPCR) used evaluate key genes. Sensitivity specificity examined receiver operating characteristic (ROC) curves. pRRophetic package R therapeutic effects drugs high- low- risk score group. Finally, nomogram developed predict patients’ incorporating clinicopathological features score. Results Most up-regulated tissues showed relatively high mutation frequency. Survival revealed that LIAS FDX1 significantly associated survival. After classified two cuproptosis subtypes, (gender, age, grade TNM stage), prognosis, metabolic related pathways immune infiltration TME 84 DEGs, obtained primarily enriched regulation metabolism intracellular/extracellular structure Univariate 32 DEGs. According re-classified grade, T N stage, patients. Nest, moderate sensitivity specificity. A score, characterized decreased microsatellite instability-high (MSI-H), burden (TMB) stem (CSC) index, stromal TME, indicated poor Four five dysregulated compared normal samples. Moreover, greatly multiple drugs. we established highly accurate for promoting applicability system. Discussion Our comprehensive demonstrated their roles features, prognosis. These findings may improve our understanding provide new perceptions doctors develop more effective personalized therapy strategies.

Language: Английский

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A tumor microenvironment-based prognostic index for osteosarcoma

Journal of Biomedical Science, Journal Year: 2023, Volume and Issue: 30(1)

Published: April 13, 2023

The tumor microenvironment (TME) has a central role in the oncogenesis of osteosarcomas. composition TME is essential for interaction between and immune cells. aim this study was to establish prognostic index (TMEindex) osteosarcoma based on TME, from which estimates about patient survival individual response checkpoint inhibitor (ICI) therapy can be deduced.

Language: Английский

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Based on disulfidptosis, revealing the prognostic and immunological characteristics of renal cell carcinoma with tumor thrombus of vena cava and identifying potential therapeutic target AJAP1

Journal of Cancer Research and Clinical Oncology, Journal Year: 2023, Volume and Issue: 149(12), P. 9787 - 9804

Published: May 29, 2023

Language: Английский

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Neoadjuvant immunochemotherapy for locally advanced resectable oral squamous cell carcinoma: a prospective single-arm trial (Illuminate Trial)

International Journal of Surgery, Journal Year: 2023, Volume and Issue: unknown

Published: June 6, 2023

Locally advanced oral squamous cell carcinoma (LAOSCC) is associated with a high rate of recurrence and poor survival. Given the recent successes neoadjuvant immunochemotherapy (NAICT) in solid tumors, it promising to use this treatment modality achieve better pathological response improve survival LAOSCC, clinical evidence needed assess its safety efficacy.A prospective trial NAICT toripalimab (PD-1 inhibitor) albumin paclitaxel/cisplatin (TTP) was conducted patients stage III IVA OSCC. Intravenous paclitaxel (260 mg/m 2 ), cisplatin (75 (240 mg) were given sequence on day 1 each 21 cycle for two cycles, followed by radical surgery risk-adapted adjuvant (chemo)radiotherapy. The primary endpoints major (MPR). Targeted next generation sequencing multiplex immunofluorescence performed molecular characteristics tumor immune microenvironment pre-NAICT post-NAICT samples.Twenty enrolled. well-tolerated low incidence grades 3-4 adverse events three patients. completion rates subsequent R0 resection 100%. MPR 60%, including 30% complete response. achieved all four combined positive score PD-L1>10. density tertiary lymphatic structure samples predicted NAICT. During median 23-month follow-up, disease-free 90%, overall 95%.NAICT TTP protocol LAOSCC feasible well tolerated, no obstruction surgery. This supportive further randomized trials using LAOSCC.

Language: Английский

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Durable responders in advanced NSCLC with elevated TMB and treated with 1L immune checkpoint inhibitor: a real-world outcomes analysis

Journal for ImmunoTherapy of Cancer, Journal Year: 2023, Volume and Issue: 11(1), P. e005801 - e005801

Published: Jan. 1, 2023

For patients with advanced non-small cell lung carcinoma (NSCLC), immune checkpoint inhibitor (ICPI) and chemotherapy (chemo) ICPI represent two distinct first-line standard-of-care regimens without clear established biomarkers to inform the optimal choice for individual patients. Here, we examined complementary roles of tumor mutational burden (TMB) programmed death ligand-1 (PD-L1) immunohistochemistry (IHC) therapy using a large real-world (rw) data set.

Language: Английский

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