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| Open AccessMultimodal analysis of cfDNA methylomes for early detecting esophageal squamous cell carcinoma and precancerous lesions
Please let us know if there are any inaccuracies: ‘Esophageal squamous cell carcinoma is most commonly detected at a late stage, which limits survival and treatment options. Here, the authors utilise whole genome bisulfite sequencing to create a cfDNA framework to detect cfDNA methylation, copy number variants and fragmentation.
- Jiaqi Liu
- , Lijun Dai
- & Zhihua Liu
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Article
| Open AccessFn-OMV potentiates ZBP1-mediated PANoptosis triggered by oncolytic HSV-1 to fuel antitumor immunity
The potential of oncolytic virus (OV) for cancer therapy is limited by the efficiency of immune response induced. Here the authors show that HSV-1-based OV is capable of triggering ZBP1-mediated PANoptosis resulting in effective tumor growth inhibition.
- Shuo Wang
- , An Song
- & Zhi-Jun Sun
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Article
| Open AccessPrimary prophylaxis with mTOR inhibitor enhances T cell effector function and prevents heart transplant rejection during talimogene laherparepvec therapy of squamous cell carcinoma
Cutaneous squamous cell carcinoma is more frequent and more aggressive in the organ transplanted and represent a therapeutic challenge due to the ongoing transplantrelated immune suppression. Here, the authors present a case report of a patient whose T cell responses were successfully strengthened via primary prophylactic therapy with mammalian target of rapamycin inhibition and intra-lesion injection of the oncolytic herpesvirus T-VEC.
- Victor Joo
- , Karim Abdelhamid
- & Michel Obeid
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Article
| Open AccessMacrophage-fibroblast JAK/STAT dependent crosstalk promotes liver metastatic outgrowth in pancreatic cancer
An inflammatory-fibrotic tumor microenvironment supports metastatic disease progression in pancreatic ductal adenocarcinoma (PDAC). Here the authors show that metastasis-infiltrating macrophages influence metastasis-associated fibroblast (MAF) heterogeneity in liver metastatic PDAC, by promoting JAK/STAT signalling pathway activation in MAFs.
- Meirion Raymant
- , Yuliana Astuti
- & Michael C. Schmid
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Article
| Open AccessAn individualized protein-based prognostic model to stratify pediatric patients with papillary thyroid carcinoma
Papillary thyroid carcinoma has a heterogenous outcome, particularly in paediatric patients. Here, the authors utilise machine learning to create a protein-based prognostic model to predict recurrence risk.
- Zhihong Wang
- , He Wang
- & Yaoting Sun
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Article
| Open AccessCAR affinity modulates the sensitivity of CAR-T cells to PD-1/PD-L1-mediated inhibition
It has been suggested that targeting the PD-1/PD-L1 axis can increase the anti-tumor properties of chimeric antigen receptor (CAR)-T cells. Here the authors report that CAR affinity modulates the sensitivity of CAR-T cells to PD-1/PD-L1-mediated inhibition.
- Irene Andreu-Saumell
- , Alba Rodriguez-Garcia
- & Sonia Guedan
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Article
| Open AccessLineage specific transcription factor waves reprogram neuroblastoma from self-renewal to differentiation
This study identifies temporal and coordinately regulated cell-state-specific super-enhancers driving the expression of transcription factors that control circuits needed to switch neuroblastoma tumor cells from self-renewal to differentiation.
- Deblina Banerjee
- , Sukriti Bagchi
- & Carol J. Thiele
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Article
| Open AccessThe gut microbiome-prostate cancer crosstalk is modulated by dietary polyunsaturated long-chain fatty acids
Here, using murine models of prostate cancer, the authors show that reduced fecal microbiota alpha-diversity correlates with increased prostate tumor burden, and that Omega-3 prebiotic supplementation reduces prostate cancer up-grading associated with a reduction of gut Ruminococcaceae and fecal butyrate levels.
- Gabriel Lachance
- , Karine Robitaille
- & Vincent Fradet
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Article
| Open AccessBispecific CAR T cell therapy targeting BCMA and CD19 in relapsed/refractory multiple myeloma: a phase I/II trial
CAR-T cell therapies targeting BCMA have shown promising responses in patients with multiple myeloma (MM), however primary resistance and relapse are frequently observed. Here the authors report the results of a phase I//II study of bispecific CAR T-cells targeting BCMA and CD19 in relapsed/refractory MM.
- Ming Shi
- , Jiaojiao Wang
- & Jiang Cao
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Article
| Open AccessNeoadjuvant tislelizumab plus stereotactic body radiotherapy and adjuvant tislelizumab in early-stage resectable hepatocellular carcinoma: the Notable-HCC phase 1b trial
The feasibility and efficacy of neoadjuvant immunotherapy for resectable hepatocellular carcinoma (HCC) have been previously suggested. Here the authors report the results of a phase 1b trial of neoadjuvant tislelizumab plus stereotactic body radiotherapy and adjuvant tislelizumab in early-stage resectable HCC.
- Zhongchao Li
- , Jing Liu
- & Lei Zhao
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Article
| Open AccessUveal melanoma immunogenomics predict immunotherapy resistance and susceptibility
Metastatic uveal melanoma is poorly responsive to immune checkpoint inhibition. Here, the authors analyse 100 uveal melanoma metastases using bulk and single cell RNA-seq, TCR analysis, and immune reactivity to show potent, yet, quiescent tumour infiltrating lymphocytes that can be harnessed by adoptive transfer to confer tumour immunity.
- Shravan Leonard-Murali
- , Chetana Bhaskarla
- & Udai S. Kammula
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| Open AccessThe physiological interactome of TCR-like antibody therapeutics in human tissues
The use of bispecific antibodies to target tumour-specific epitopes presented by MHC molecules in tumour tissue is a promising avenue for cancer immunotherapy. Here the authors use a mass-spectrometry guided analysis to identify off-target MHC-peptide complexes that bind to TCR-like antibodies next to the target peptide, enabling a novel approach to monitoring of antibody specificity during clinical maturation and development.
- Estelle Marrer-Berger
- , Annalisa Nicastri
- & Nicola Ternette
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Article
| Open AccessIntegrated proteogenomic and metabolomic characterization of papillary thyroid cancer with different recurrence risks
Papillary thyroid cancers (PTC) generally have good prognosis, but their recurrence rate remains high. Here, the authors use proteogenomics and metabolomics to identify molecular features in PTC tumours and determine PTC subtypes that are associated with prognosis and potential targeted therapies.
- Ning Qu
- , Di Chen
- & Rongliang Shi
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Article
| Open AccessEnhancing NSCLC recurrence prediction with PET/CT habitat imaging, ctDNA, and integrative radiogenomics-blood insights
Predicting recurrence risk in non small cell lung cancer can help to guide treatment decisions. Here, the authors use CT and PET imaging to develop predictive imaging subtypes, which can be integrated with existing ctDNA methods to predict recurrence.
- Sheeba J. Sujit
- , Muhammad Aminu
- & Jia Wu
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| Open AccessReporting outcome comparisons by sex in oncology clinical trials
Many aspects of human health and disease are influenced by sex as a biological variable and gender as a social construct. A recent study from Nature Communications reported the landscape of outcome comparisions by sex in oncology clinical trials, highlighting the need for a more thorough reporting of sex differences.
- Guo Zhao
- , Yuning Wang
- & Ning Li
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Article
| Open AccessMolecular patterns of resistance to immune checkpoint blockade in melanoma
A large fraction of patients with melanoma still does not benefit from immune checkpoint blockade, associated with both primary and acquired resistance. Here the authors report genetic and immunological patterns of resistance in patients with melanoma after progression on anti-CTLA4 or anti-PD1 monotherapy.
- Martin Lauss
- , Bengt Phung
- & Göran Jönsson
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Article
| Open AccessAccelerated DNA replication fork speed due to loss of R-loops in myelodysplastic syndromes with SF3B1 mutation
Here the authors find that erythroblasts of myelodysplastic syndromes with SF3B1 mutation leading to inefficient erythropoiesis show DNA replication stress with accelerated forks and reduced R-loops. Restoring R-loops by a histone deacetylase inhibitor rescues erythroid differentiation.
- David Rombaut
- , Carine Lefèvre
- & Michaela Fontenay
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Article
| Open AccessGadd45g insufficiency drives the pathogenesis of myeloproliferative neoplasms
Different gene mutations have been reported as drivers for myeloproliferative neoplasms (MPN). Here, the authors show that Gadd45g insufficiency induces MPN in mouse models and associates with MPN in patients.
- Peiwen Zhang
- , Na You
- & Xiaotong Ma
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Article
| Open AccessConcomitant medication, comorbidity and survival in patients with breast cancer
Preliminary epidemiological evidence suggests that some non-cancer medications may affect breast cancer risk, recurrence, and survival. In this study, the authors utilized a nationwide database of breast cancer patients to estimate the association between frequently used drugs taken prior to diagnosis and breast cancer prognosis. And they identified 16 drugs associated with breast cancer outcomes.
- Elise Dumas
- , Beatriz Grandal Rejo
- & Anne-Sophie Hamy
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Article
| Open AccessA population-based cohort study of longitudinal change of high-density lipoprotein cholesterol impact on gastrointestinal cancer risk
High-density Lipoprotein Cholesterol (HDL-C) levels have been associated with cancer. Here, the authors show the association between longitudinal changes of HDL-C and risk of gastrointestinal cancer in a patients.
- Su Youn Nam
- , Junwoo Jo
- & Chang-Min Cho
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Article
| Open AccessVISTA checkpoint inhibition by pH-selective antibody SNS-101 with optimized safety and pharmacokinetic profiles enhances PD-1 response
VISTA is a pH-dependent inhibitory checkpoint for T-cells that is abundant on myeloid lineage cells and antagonists of VISTA may successfully reinvigorate anti-tumour immunity. Here, the authors show that the antibody SNS-101, which is currently being investigated in humans in a clinical trial, is characterized by pH-sensitivity that endows it with favorable pharmacokinetic and safety profiles, and enhanced therapeutic effect when combined with PD-1 checkpoint inhibitors.
- Thomas Thisted
- , F. Donelson Smith
- & Edward H. van der Horst
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Article
| Open AccessMesenchymal glioma stem cells trigger vasectasia—distinct neovascularization process stimulated by extracellular vesicles carrying EGFR
Vasectasia is a newly described, non-angiogenic form of blood vessel formation induced by mesenchymal glioblastoma cells, and driven by endothelial cell responses to extracellular vesicles containing oncogenic EGFR.
- Cristiana Spinelli
- , Lata Adnani
- & Janusz Rak
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Article
| Open AccessTargeting branched N-glycans and fucosylation sensitizes ovarian tumors to immune checkpoint blockade
Cancer cells can employ aberrant glycosylation patterns to evade the host immune response. Here the authors report that inhibition of branched N-glycans sensitizes homologous recombination (HR)-proficient, but not HR-deficient, epithelial ovarian cancer to immune checkpoint inhibitors.
- Hao Nie
- , Pratima Saini
- & Rugang Zhang
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Article
| Open AccessSystematic analysis of RNA-binding proteins identifies targetable therapeutic vulnerabilities in osteosarcoma
Proteomic, transcriptomic, and genomic analysis has shown osteosarcoma (OS) to be a complex and heterogenous disease but revealed little about its carcinogenesis or potential therapeutic targets. Here, the authors profile the RNA interactome, transcriptome and proteome of cells derived from OS patients, identifying a targetable vulnerability to translation inhibition.
- Yang Zhou
- , Partho Sarothi Ray
- & Andreas E. Kulozik
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Article
| Open AccessDeciphering the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer
The heterogeneity of cancer associated fibroblasts (CAFs) in breast cancer has been previously described. Here the authors provide further insights into the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer.
- Hugo Croizer
- , Rana Mhaidly
- & Fatima Mechta-Grigoriou
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Article
| Open AccessThe CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial
ATR/CHK1 pathway inhibitors represent a therapeutic option for platinum-resistant high-grade serous ovarian carcinoma (HGSOC). Here the authors report the results of a phase 2 clinical study of the CHK1 inhibitor prexasertib in patients with BRCA wild-type platinum-resistant HGSOC with or without biopsiable disease.
- Elena Giudice
- , Tzu-Ting Huang
- & Jung-Min Lee
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Article
| Open AccessCombination of acalabrutinib with lenalidomide and rituximab in relapsed/refractory aggressive B-cell non-Hodgkin lymphoma: a single-arm phase II trial
Potential synergism between BTK inhibitor and lenalidomide in treating aggressive B-cell lymphoma has been suggested. Here, the authors report a single-arm phase II clinical trial of combination of acalabrutinib, lenalidomide and rituximab in patients with aggressive Relapsed/Refractory aggressive B-cell non-Hodgkin lymphoma.
- Changhee Park
- , Ho Sup Lee
- & Youngil Koh
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Article
| Open AccessComprehensive mutational scanning of EGFR reveals TKI sensitivities of extracellular domain mutants
EGFR mutations are frequent in glioblastoma and lung cancer. Here, the authors perform deep mutational scanning of EGFR, followed by a high-throughput functional screen and analysis of patient data, to identify variants with differing sensitivities to a range of EGFR tyrosine kinase inhibitors.
- Tikvah K. Hayes
- , Elisa Aquilanti
- & Matthew Meyerson
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Article
| Open AccessAdjuvant nivolumab, capecitabine or the combination in patients with residual triple-negative breast cancer: the OXEL randomized phase II study
Post-neoadjuvant treatment options for patients with triple-negative breast cancer (TNBC) include the chemo-drug capecitabine but also immune checkpoint inhibitors. Here the authors report the results of a phase II study of adjuvant nivolumab, capecitabine or the combination in patients with residual TNBC.
- Filipa Lynce
- , Candace Mainor
- & Claudine Isaacs
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Article
| Open AccessDevelopment and validation of an interpretable model integrating multimodal information for improving ovarian cancer diagnosis
Ovarian cancer diagnosis can be complex and can be improved through integration of multimodal data. Here, the authors develop OvcaFinder which can significantly outperform clinical models using ultrasound images and known clinical characteristics.
- Huiling Xiang
- , Yongjie Xiao
- & Hao Chen
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Article
| Open AccessPhenome-wide Mendelian randomisation analysis of 378,142 cases reveals risk factors for eight common cancers
Mendelian randomisation can identify potential risk factors from large populations. Here, the authors analyse 3000 traits across multiple cancer types to search for potential risk factors and molecular biomarkers.
- Molly Went
- , Amit Sud
- & Richard Houlston
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Article
| Open AccessOutcome differences by sex in oncology clinical trials
The role of sex differences in response to cancer therapy remains unclear but this could be improved by reporting sex comparisons of outcomes in clinical trials. Here, the authors characterise the sex outcome comparisons in 89,221 interventional trials, finding that while comparisons were rare, important insights could be obtained.
- Ashwin V. Kammula
- , Alejandro A. Schäffer
- & Eytan Ruppin
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Article
| Open AccessCancer cell genetics shaping of the tumor microenvironment reveals myeloid cell-centric exploitable vulnerabilities in hepatocellular carcinoma
Distinct genetic mutations can shape the tumor immune microenvironment. Here the authors generate preclinical mouse models of hepatocellular carcinoma bearing clinically-relevant oncogenic driver combinations, identifying myeloid cell-centric exploitable therapeutic vulnerabilities.
- Christel F. A. Ramirez
- , Daniel Taranto
- & Leila Akkari
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Article
| Open AccessMultipeptide vaccines for melanoma in the adjuvant setting: long-term survival outcomes and post-hoc analysis of a randomized phase II trial
Peptide-based cancer vaccines require epitopes for both CD8+ and CD4+ T cells. Here the authors report the long-term outcomes of a randomized phase II trial (NCT00118274) in patients with melanoma designed to evaluate a class I MHC-restricted peptide vaccine plus one of two “helper” peptide preparations to stimulate CD4+ T cells, either non-specific help or melanoma-specific help.
- Emily K. Ninmer
- , Hong Zhu
- & Craig L. Slingluff Jr
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Article
| Open AccessSingle cell deciphering of progression trajectories of the tumor ecosystem in head and neck cancer
Head and neck squamous cell carcinoma (HNSCC) is characterised with high heterogeneity and unfavourable prognosis. Here, the authors perform single cell transcriptomics to investigate the tumour microenvironment features of HNSCC initiation, progression, lymph node metastasis and recurrence.
- Z. L. Liu
- , X. Y. Meng
- & Y. He
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Article
| Open AccessSpatial relationships in the urothelial and head and neck tumor microenvironment predict response to combination immune checkpoint inhibitors
Spatial positioning of cells within the tumour microenvironment may have a function in the success of immune checkpoint immunotherapy (ICI). Here the authors analyse spatial relationships from immunohistochemistry samples prior to ICI therapy and show that CD8 T cell or macrophage proximity to cancer cells is associated with better responses.
- Alberto Gil-Jimenez
- , Nick van Dijk
- & Lodewyk F. A. Wessels
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Article
| Open AccessArtificial intelligence-enabled prediction of chemotherapy-induced cardiotoxicity from baseline electrocardiograms
Anthracyclines can induce cancer therapy-related cardiac dysfunction (CTRCD), of which occurrence remains unpredictable. Here, the authors develop an artificial intelligence model to robustly predict CTRCD from a single recording of 12-lead electrocardiogram taken before the initiation of chemotherapy in cancer patients treated with anthracyclines.
- Ryuichiro Yagi
- , Shinichi Goto
- & Rahul C. Deo
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Article
| Open AccessReciprocal inhibition between TP63 and STAT1 regulates anti-tumor immune response through interferon-γ signaling in squamous cancer
TP63 is a master regulator transcription factor in squamous cell carcinomas (SCCs). Here the authors report that TP63 suppresses IFNγ signaling in SCC tumors and that its inhibition is associated with enhanced anti-tumor immunity and response to anti-PD1.
- Yuan Jiang
- , Yueyuan Zheng
- & Yan-Yi Jiang
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Article
| Open AccessMetabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas
Cancer associated fibroblasts can shape the tumor microenvironment (TME) and modulate immune infiltration. Here the authors characterize the TME in preclinical models of softtissue sarcomas, identifying a subset of “glycolytic” cancer-associated fibroblasts that inhibit cytotoxic T cell infiltration into the tumor parenchyma.
- Marina T. Broz
- , Emily Y. Ko
- & Jlenia Guarnerio
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Article
| Open AccessExemestane plus everolimus and palbociclib in metastatic breast cancer: clinical response and genomic/transcriptomic determinants of resistance in a phase I/II trial
Intrinsic and acquired resistances to CDK4/6 inhibitors have been described in patients with breast cancer. Here the authors report the results from a phase I/II clinical trial of the aromatase inhibitor exemestane plus everolimus (mTOR inhibitor) and palbociclib (CDK4/6i) in patients with metastatic breast cancer, assessing safety, clinical efficacy, as well as genomic and transcriptomic determinants of resistance.
- Jorge Gómez Tejeda Zañudo
- , Romualdo Barroso-Sousa
- & Nikhil Wagle
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Article
| Open AccessThe bone ecosystem facilitates multiple myeloma relapse and the evolution of heterogeneous drug resistant disease
Here, the authors develop a hybrid agent-based model to quantify the contributions of intrinsic cellular mechanisms and bone ecosystem factors to therapy resistance in multiple myeloma. They show that intrinsic mechanisms are essential for resistance, and that the bone microenvironment provides a protective niche that increases the likelihood.
- Ryan T. Bishop
- , Anna K. Miller
- & David Basanta
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Article
| Open AccessHematopoietic stem cells with granulo-monocytic differentiation state overcome venetoclax sensitivity in patients with myelodysplastic syndromes
Secondary resistance to venetoclax in patients with myelodysplastic syndromes (MDS) is not completely elucidated. Here, the authors show that haematopoietic stem cells with a granulo-monocytic differentiation transcriptional state drive secondary resistance to venetoclax in MDS patients who previously failed hypomethylating agent therapy.
- Juan Jose Rodriguez-Sevilla
- , Irene Ganan-Gomez
- & Simona Colla
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Article
| Open AccessTranslation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis
Here the authors uncovered CNOT3, a subunit of the CCR4-NOT complex, as an essential modulator of translation in leukemia. The work pointed to the potential of targeting the posttranscriptional circuitry via CNOT3 as a therapeutic vulnerability in acute myeloid leukemia.
- Maryam Ghashghaei
- , Yilin Liu
- & Ly P. Vu
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Article
| Open AccessDendritic cell-targeted therapy expands CD8 T cell responses to bona-fide neoantigens in lung tumors
Response to immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC) remains suboptimal, even for tumors with elevated tumor mutational burden. Here the authors generate a model of NSCLC with enhanced mutational load, showing that, while still resistant to ICIs, hypermutated tumors become sensitive to dendritic cell-targeted therapy.
- Lucía López
- , Luciano Gastón Morosi
- & Federica Benvenuti
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Article
| Open AccessNeoadjuvant chemo-immunotherapy with camrelizumab plus nab-paclitaxel and cisplatin in resectable locally advanced squamous cell carcinoma of the head and neck: a pilot phase II trial
Neoadjuvant chemo-immunotherapy represents a therapeutic option for resectable head and neck squamous cell carcinoma (HNSCC). Here the authors report the results of a phase II trial of neoadjuvant camrelizumab plus nab-paclitaxel and cisplatin in resectable locally advanced HNSCC.
- Di Wu
- , Yong Li
- & Xuekui Liu
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Article
| Open AccessThe phosphatidylserine targeting antibody bavituximab plus pembrolizumab in unresectable hepatocellular carcinoma: a phase 2 trial
Bavituximab is a genetically engineered IgG1 chimeric antibody that targets phosphatidylserine. Here the authors report the results of a single-arm phase 2 trial of bavituximab in combination with pembrolizumab (anti-PD1) for patients with unresectable hepatocellular carcinoma.
- David Hsiehchen
- , Muhammad S. Beg
- & Adam C. Yopp
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Article
| Open AccessDelivery of a BET protein degrader via a CEACAM6-targeted antibody–drug conjugate inhibits tumour growth in pancreatic cancer models
Therapeutic options for pancreatic ductal adenocarcinoma (PDAC) are limited. Here the authors report the characterization of a CEACAM6-targeting antibody drug conjugate loaded with a BET protein degrader, showing antitumour activity in PDAC preclinical models.
- Youya Nakazawa
- , Masayuki Miyano
- & Akihito Machinaga
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Article
| Open AccessNeoadjuvant–adjuvant pertuzumab in HER2-positive early breast cancer: final analysis of the randomized phase III PEONY trial
Previously, the authors reported the primary analysis of a phase III randomized control trial investigating dual HER2 blockade in HER2-positive early/locally advanced breast cancer. Here, the authors report the long-term efficacy and safety analysis of this trial.
- Liang Huang
- , Da Pang
- & Zhimin Shao
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Article
| Open AccessMi-2β promotes immune evasion in melanoma by activating EZH2 methylation
Mi-2β is an enzyme of the chromodomain helicase DNA family with roles in chromatin assembly, genomic stability and gene repression. Here the authors report that Mi-2β promotes immune evasion by activating EZH2 methylation and that loss of Mi-2β or its inhibition promote anti-tumor immune responses in preclinical melanoma models.
- Cang Li
- , Zhengyu Wang
- & Rutao Cui