Tumor mutational burden and survival on immune checkpoint inhibition in >8000 patients across 24 cancer types

Journal for ImmunoTherapy of Cancer, Год журнала: 2025, Номер 13(2), С. e010311 - e010311

Опубликована: Фев. 1, 2025

Background There is uncertainty around clinical applicability of tumor mutational burden (TMB) across cancer types, in part because inconsistency between TMB measurements from different platforms. The KEYNOTE 158 trial supported United States Food and Drug Administration (FDA) approval the Foundation Medicine test (FoundationOneCDx) at TMB≥10 mut/Mb as a companion diagnostic (CDx) for single-agent pembrolizumab second+line. Using large real-world dataset with validated survival endpoint data, we evaluated validity measurement by over 8000 patients 24 types who received immune checkpoint inhibitor (ICI). Methods Patients advanced-stage cancers treated anti-PD(L)1 therapy standard-of-care settings were included. Deidentified data electronic health records approximately 280 treatment facilities captured into clinico-genomic database. This study used algorithm FDA-approved supporting solid CDx composite mortality variable against national death index: overall (rwOS). Following prespecified analysis plan, rwOS level was assessed using Cox PH models adjusted Eastern Cooperative Oncology Group performance status, prior treatment, microsatellite instability, sex, age, opioid rx pretherapy, socioeconomic assessment. Results 8440 met inclusion criteria. Adjusting aforementioned factors, increasing significantly associated types; HRs (95% CIs) relative to TMB<5: 5 <10: 0.95 (0.89 1.02), 10 <20: 0.79 (0.73 0.85), TMB≥20: 0.52 (0.47 0.58). For individual statistical power, comparing vs TMB<10 favored 9 types. In stable subcohorts (except colorectal cancer), remained enriched ICI benefit. Exploratory assessments receiving ICI+chemotherapy (n=4369) observed more favorable only TMB≥20. Conclusions Across >8000 ICI, within sufficient elevated based on compared similar lower levels. biomarker deserves further investigation potentially guide use immunotherapy expanded contexts.

Язык: Английский

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Immunogenicity of cell death and cancer immunotherapy with immune checkpoint inhibitors

Cellular and Molecular Immunology, Год журнала: 2024, Номер unknown

Опубликована: Дек. 10, 2024

While immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized the clinical management of various malignancies, a large fraction patients are refractory to ICIs employed as standalone therapeutics, necessitating development combinatorial treatment strategies. Immunogenic cell death (ICD) inducers have attracted considerable interest partners for ICIs, at least in part owing their ability initiate tumor-targeting adaptive response. However, compared either approach alone, regimens involving ICD and not always shown superior activity. Here, we discuss accumulating evidence on therapeutic interactions between oncological settings, identify key factors that may explain discrepancies preclinical findings, propose strategies address existing challenges increase efficacy these combinations cancer.

Язык: Английский

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Oncogenic competence: balancing mutations, cellular state, and microenvironment

Trends in cancer, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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Peptide-Assisted CRISPR/Cas9 Delivery to Tumors

Methods in pharmacology and toxicology, Год журнала: 2025, Номер unknown, С. 155 - 175

Опубликована: Янв. 1, 2025

Язык: Английский

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Defeating lethal cancer: Interrupting the ecologic and evolutionary basis of death from malignancy

CA A Cancer Journal for Clinicians, Год журнала: 2025, Номер unknown

Опубликована: Март 9, 2025

Despite the advances in cancer prevention, early detection, and treatments, all of which have led to improved survival, globally, there is an increased incidence cancer-related deaths. Although each patient tumor wholly unique, tipping point incurable disease common across patients: dual capacity for cancers metastasize resist systemic treatment. The discovery genetic mutations epigenetic variation that emerges during progression highlights evolutionary ecology principles can be used understand how evolves a lethal phenotype. By applying such eco-evolutionary framework, authors reinterpret our understanding metastatic process as one ecologic invasion define paths evolving therapy resistance. With this understanding, draw from successful strategies optimized strategic interventions with goal altering trajectory cancer. Ultimately, studying, treating using provides opportunity improve lives patients

Язык: Английский

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Comment on ‘Tumor mutational burden and survival on immune checkpoint inhibition in >8000 patients across 24 cancer types’

Journal for ImmunoTherapy of Cancer, Год журнала: 2025, Номер 13(3), С. e011943 - e011943

Опубликована: Март 1, 2025

Язык: Английский

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Assessing the prognostic and therapeutic value of cuproptosis-related genes in colon adenocarcinoma patients

Frontiers in Cell and Developmental Biology, Год журнала: 2025, Номер 13

Опубликована: Апрель 10, 2025

Background Colon adenocarcinoma (COAD) remains a major global health challenge with poor prognosis despite advances in treatment, underscoring the need for new biomarkers. As novel mode of cell death, cuproptosis is thought to be potentially involved development cancer. However, particularly as role cuproptosis-related genes (CRGs) COAD and therapy unclear. Methods We analyzed RNA sequencing data from The Cancer Genome Atlas COAD, focusing on CRG expression patterns their clinicopathological correlations. Using Weighted Gene Co-expression Network Analysis (WGCNA) method, we identified gene module most strongly linked conducted functional enrichment analysis explore roles within this tumorigenesis. A prognostic risk model based four CRGs (ORC1, PTTG1, DLAT, PDHB) was developed stratify patients into high-risk low-risk groups, assessing overall survival, tumor microenvironment, mutational landscape differences. also evaluated therapeutic effects ferredoxin 1 (FDX1) elesclomol promoting HCT116 LoVo lines through various experiments, including proliferation, apoptosis assessment, mitochondrial membrane potential evaluation, DLAT lipoylation detection via Western blot. Results Certain showed different expressions versus normal tissues. WGCNA cuproptosis, crucial pathways like cycle regulation, citrate (TCA cycle), DNA replication. stratified high groups scores, revealing that had shorter survival distinct immune infiltration, while were more sensitive immunotherapy. Experimental results indicated FDX1 exerted an inhibitory effect its combination significantly reduced promoted apoptosis, increased lipoylation, lowered cells. Conclusion findings study provided perspective research biomarkers strategies value patients, laid theoretical foundation future clinical application CRGs.

Язык: Английский

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A Comprehensive Review About the Use of Monoclonal Antibodies in Cancer Therapy

Antibodies, Год журнала: 2025, Номер 14(2), С. 35 - 35

Опубликована: Апрель 11, 2025

Monoclonal antibodies (mAbs) targeting various pathways in cancer therapy play crucial roles enhancing the immune system’s ability to recognise and eliminate tumour cells. These therapies are designed either block inhibitory checkpoint or target specific cell markers for direct destruction. Additionally, mAbs can modulate microenvironment, enhance antibody-dependent cellular cytotoxicity, inhibit angiogenesis, further amplifying their therapeutic impact. Below is a summary of monoclonal key pathways, along with indications mechanisms action, which reviewed based on mechanisms.

Язык: Английский

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Tumour Mutational Burden and Immune Checkpoint Inhibitor Response in Non-small Cell Lung Cancer: A Continuous Modelling Approach

Targeted Oncology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 7, 2025

Tumour mutational burden (TMB) is an established biomarker for patients treated with immune checkpoint inhibitors (ICIs). The optimal TMB cut-off uncertain. It also uncertain whether there a sharp threshold or more graduated change in clinical outcomes as increases. We aimed to determine the relationship between and ICI treatment using alternative statistical approaches non-small cell lung cancer. was evaluated prognostic predictive advanced cancer utilising data from two real-world cohorts of use (n = 968) three randomised controlled trials evaluating ICIs 1588). non-linear continuous response/survival/efficacy methods that do not require specifying cut-off. Median all seven mutations/megabase, excluding MYSTIC, where median 13 mutations/megabase. Progressively higher significantly associated progressively objective response rate progression-free survival ICI-treated Memorial Sloan Kettering-Integrated Mutation Profiling Actionable Cancer Targets [MSK-IMPACT] (objective rate: p < 0.001, survival: 0.001), Strata Clinical Molecular Database [SCMD] (progression-free 0.023) OAK/POPLAR 0.017, 0.001) This apparent chemotherapy. There no obvious response. overall complex heterogeneous. Using single analyse may hide important information. Methods provide nuance underlying enable readers judge themselves value limitations cut-offs proposed practice.

Язык: Английский

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TMBocelot: an omnibus statistical control model optimizing the TMB thresholds with systematic measurement errors

Frontiers in Immunology, Год журнала: 2025, Номер 15

Опубликована: Янв. 20, 2025

Tumor mutation burden (TMB), defined as the number of somatic mutations tumor DNA, is a well-recognized immunotherapy biomarker endorsed by regulatory agencies and pivotal in stratifying patients for clinical decision-making. However, measurement errors can compromise accuracy TMB assessments reliability outcomes, introducing bias into statistical inferences adversely affecting thresholds through cumulative magnified effects. Given unavoidable with current technologies, it essential to adopt modeling methods determine optimal TMB-positive threshold. Therefore, we proposed universal framework, TMBocelot, which accounts pairwise data stabilize determination hierarchical thresholds. TMBocelot utilizes Bayesian approach based on stationarity principle Markov chains implement an enhanced error control mechanism, utilizing moderately informative priors. Simulations retrospective from 438 reveal that outperforms conventional terms accuracy, consistency parameter estimations, threshold determination. enables precise reliable delineation thresholds, facilitating implementation immunotherapy. The source code publicly available at https://github.com/YixuanWang1120/TMBocelot .

Язык: Английский

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