Short-course neoadjuvant radiotherapy combined with chemotherapy and toripalimab for locally advanced esophageal squamous cell carcinoma (SCALE-1): a single-arm phase Ib clinical trial DOI Creative Commons
Ning Jiang, Jingyuan Zhang, Zhen Guo

et al.

Journal for ImmunoTherapy of Cancer, Journal Year: 2024, Volume and Issue: 12(1), P. e008229 - e008229

Published: Jan. 1, 2024

Background The optimal dosages, timing, and treatment sequencing for standard-of-care neoadjuvant chemoradiotherapy necessitate re-evaluation when used in conjunction with immune checkpoint inhibitors patients resectable, locally advanced esophageal squamous cell carcinoma (RLaESCC). SCALE-1 phase Ib study aimed to evaluate the safety efficacy of short-course radiotherapy combined chemotherapy toripalimab this patient population. Methods RLaESCC clinical stages cT3-4aN0M0/cT1-4aN+M0 received paclitaxel (135 mg/m 2 ), carboplatin (area under curve=5), (240 mg) every 3 weeks two cycles. Short-course (30 Gy 12 fractions; 5 days per week) was administered between immune-chemotherapy (nICT) doses. Esophagectomies were scheduled 4–6 after completing treatment. primary endpoint safety, secondary endpoints including pathological complete response (pCR) rate, postoperative complications, progression-free survival (PFS), overall (OS). Exploratory biomarker analysis gene expression profiles via nCounter platform. Results Of 23 enrolled, all completed radiotherapy, while 21 cases finished full nICT doses Common grade 3/4 adverse events included neutropenia (57%), leukopenia (39%), skin rash (30%). No or higher esophagitis pneumonitis occured. Twenty underwent surgery, 11 achieved pCR (55%). Two (10%) experienced IIIb surgical complications. At database lock, a 2-year PFS rate 63.8% (95% CI 43.4% 84.2%) OS 78% 64.9% 91.1%) achieved. Tumor microenvironment indicated that tumors exhibited significantly pretreatment T-cell-inflamed score post-treatment reshaping antitumor immunity. Conclusions Combining demonstrated favorable promising patients. Trial registration number ChiCTR2100045104.

Language: Английский

Multicenter, single-arm, phase II trial of camrelizumab and chemotherapy as neoadjuvant treatment for locally advanced esophageal squamous cell carcinoma DOI Creative Commons
Jun Liu, Yang Yang, Zhichao Liu

et al.

Journal for ImmunoTherapy of Cancer, Journal Year: 2022, Volume and Issue: 10(3), P. e004291 - e004291

Published: March 1, 2022

Camrelizumab and chemotherapy demonstrated durable antitumor activity with a manageable safety profile as first-line treatment in patients advanced esophageal squamous cell carcinoma (ESCC). This study aimed to evaluate the efficacy of camrelizumab plus neoadjuvant chemotherapy, using pathologically complete response (pCR) primary endpoint, for locally ESCC.Patients but resectable thoracic ESCC, staged T1b-4a, N2-3 (≥3 stations), M0 or M1 lymph node metastasis (confined supraclavicular nodes) were enrolled. Eligible received intravenous (200 mg, day 1) nab-paclitaxel (100 mg/m2, 1, 8, 15) carboplatin (area under curve 5 mg/mL/min, each 21-days cycle, two cycles before surgery. The endpoint is pCR rate per-protocol population. Safety was assessed modified intention-to-treat population that treated at least one dose camrelizumab.From November 20, 2019 December 22, 2020, 60 55 (91.7%) completed full two-cycle successfully. 51 underwent surgery R0 resection achieved 50 (98.0%) patients. (ypT0N0) identified 20 (39.2%) (9.8%) had tumor residual disease nodes alone (ypT0N+). 58 (96.7%) any-grade treatment-related adverse events (TRAEs), most common being leukocytopenia (86.7%). 34 (56.7%) grade 3 worse, patient (1.7%) occurred event. There no in-hospital postoperative 30-day well 90-day mortality.The robust confirmed without unexpected signals. Our findings established promising ESCC.ChiCTR1900026240.

Language: Английский

Citations

173
Tislelizumab combined with chemotherapy as neoadjuvant therapy for surgically resectable esophageal cancer: A prospective, single-arm, phase II study (TD-NICE) DOI
Xiaolong Yan, Hongtao Duan,

Yunfeng Ni

et al.

International Journal of Surgery, Journal Year: 2022, Volume and Issue: 103, P. 106680 - 106680

Published: May 18, 2022

Language: Английский

Citations

140
Predictive biomarkers of immunotherapy response with pharmacological applications in solid tumors DOI Creative Commons
Szonja Anna Kovács, János Tibor Fekete, Balázs Győrffy

et al.

Acta Pharmacologica Sinica, Journal Year: 2023, Volume and Issue: 44(9), P. 1879 - 1889

Published: April 13, 2023

Immune-checkpoint inhibitors show promising effects in the treatment of multiple tumor types. Biomarkers are biological indicators used to select patients for a systemic anticancer treatment, but there only few clinically useful biomarkers such as PD-L1 expression and mutational burden, which can be predict immunotherapy response. In this study, we established database consisting both gene clinical data identify response anti-PD-1, anti-PD-L1, anti-CTLA-4 immunotherapies. A GEO screening was executed datasets with simultaneously available transcriptomic regardless cancer type. The restricted studies involving administration anti-PD-1 (nivolumab, pembrolizumab), anti-PD-L1 (atezolizumab, durvalumab) or (ipilimumab) agents. Receiver operating characteristic (ROC) analysis Mann-Whitney test were across all genes features related therapy consisted 1434 tissue samples from 19 esophageal, gastric, head neck, lung, urothelial cancers, plus melanoma. strongest druggable candidates linked resistance SPIN1 (AUC = 0.682, P 9.1E-12), SRC 0.667, 5.9E-10), SETD7 0.663, 1.0E-09), FGFR3 0.657, 3.7E-09), YAP1 0.655, 6.0E-09), TEAD3 0.649, 4.1E-08) BCL2 0.634, 9.7E-08). cohort, BLCAP 0.735, 2.1E-06) most candidate. No therapeutically relevant target found predictive cohort. group, able confirm significant correlation survival mismatch-repair MLH1 MSH6. web platform further validation new biomarker set up at https://www.rocplot.com/immune . summary, investigate large cohort solid samples. Our results could help patient cohorts eligible immunotherapy.

Language: Английский

Citations

88
Machine learning-based identification of tumor-infiltrating immune cell-associated lncRNAs for improving outcomes and immunotherapy responses in patients with low-grade glioma DOI Creative Commons
Nan Zhang, Hao Zhang,

Wantao Wu

et al.

Theranostics, Journal Year: 2022, Volume and Issue: 12(13), P. 5931 - 5948

Published: Jan. 1, 2022

Rationale: Accumulating evidence demonstrated that long noncoding RNAs (lncRNAs) involved in the regulation of immune system and displayed a cell-type-specific pattern cell subsets. Given vital role tumor-infiltrating lymphocytes effective immunotherapy, we explored cell-associated lncRNA (TIIClncRNA) low-grade glioma (LGG), which has never been uncovered yet. Methods: This study utilized novel computational framework 10 machine learning algorithms (101 combinations) to screen out TIIClncRNAs by integratively analyzing sequencing data purified cells, LGG lines, bulk tissues. Results: The established TIIClnc signature based on 16 most potent could predict outcomes public datasets Xiangya in-house dataset with decent efficiency showed better performance when compared 95 published signatures. was strongly correlated characteristics, including microsatellite instability, tumor mutation burden, interferon γ, exhibited more active immunologic process. Furthermore, predicted superior immunotherapy response multiple across cancer types. Notably, positive correlation between CD8, PD-1, PD-L1 verified dataset. Conclusions: enabled precise selection population who were potential beneficiaries immunotherapy.

Language: Английский

Citations

84
Evaluation of Clinical and Safety Outcomes of Neoadjuvant Immunotherapy Combined With Chemotherapy for Patients With Resectable Esophageal Cancer DOI Creative Commons
Fan Ge, Zhenyu Huo, Xiuyu Cai

et al.

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

Citations

72
Toripalimab Plus Paclitaxel and Carboplatin as Neoadjuvant Therapy in Locally Advanced Resectable Esophageal Squamous Cell Carcinoma DOI Creative Commons
Wenwu He, Xuefeng Leng, Tianqin Mao

et al.

The Oncologist, Journal Year: 2022, Volume and Issue: 27(1), P. e18 - e28

Published: Jan. 1, 2022

Immune checkpoint inhibitors (ICIs) are effective in the treatment of advanced esophageal squamous cell carcinoma (ESCC); however, their efficacy locally resectable ESCC and potential predictive biomarkers have limited data.In this study, patients were enrolled received neoadjuvant toripalimab (240 mg, day 1) plus paclitaxel (135 mg/m2, carboplatin (area under curve 5 mg/mL per min, each 3-week cycle for 2 cycles, followed by esophagectomy planned 4-6 weeks after preoperative therapy. The primary endpoints safety, feasibility, major pathological response (MPR) rate; secondary complete (pCR) rate, disease-free survival (DFS), overall (OS). Association between molecular signatures/tumor immune microenvironment was also explored.Twenty enrolled. Treatment-related adverse events (AEs) occurred all (100%), 4 (22.2%) experienced grade 3 or higher treatment-related AEs. Sixteen underwent surgery without surgical delay, R0 resection rate 87.5% (14/16). Among 16 patients, MPR 43.8% (7/16) pCR 18.8% (3/16). abundance CD8+ T cells specimens increased (P = .0093), accompanied a decreased proportion M2-type tumor-associated macrophages .036) responders upon Responders associated with baseline gene expression levels CXCL5 .03) lower CCL19 .017) UMODL1 .03).The combination is safe, feasible, ESCC, indicating its as ESCC.NCT04177797.

Language: Английский

Citations

71
Toripalimab combined with definitive chemoradiotherapy in locally advanced oesophageal squamous cell carcinoma (EC-CRT-001): a single-arm, phase 2 trial DOI
Yujia Zhu, Jing Wen, Qiaoqiao Li

et al.

The Lancet Oncology, Journal Year: 2023, Volume and Issue: 24(4), P. 371 - 382

Published: March 27, 2023

Language: Английский

Citations

50
Neoadjuvant adebrelimab in locally advanced resectable esophageal squamous cell carcinoma: a phase 1b trial DOI Creative Commons
Jun Yin, Jingnan Yuan, Yunjin Li

et al.

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(8), P. 2068 - 2078

Published: July 24, 2023

Abstract Overall survival (OS) benefits of neoadjuvant immunotherapy remain elusive in locally advanced esophageal squamous cell carcinomas (ESCC). Here, we reported the results a phase 1b trial PD-L1 blockade with adebrelimab resectable ESCC. Patients received two doses followed by surgery. The primary endpoints were safety and feasibility; secondary included pathologic complete response (pCR) OS. Our data showed feasibility had been met. Common treatment-related adverse events anorexia (32%) fatigue (16%), without grade 3 or more events. Of 30 patients enrolled trial, 25 underwent successful resection surgery delay 24% major responses including pCR rate 8%. 2-year OS was 92%. Responsive an immune-enriched tumor microenvironment phenotype, whereas nonresponsive greater infiltration cancer-associated fibroblasts at baseline. Clonotypic dynamics pre-existing intratumoral T cells hallmark responsive patients. These findings provide rational for anti-PD-L1 monotherapy as therapeutic strategy ClinicalTrials.gov identifier: NCT04215471 .

Language: Английский

Citations

46
Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/gastroesophageal junction cancer: a phase Ib trial and ctDNA analyses DOI Creative Commons
Ronan J. Kelly, Blair V. Landon, Ali H. Zaidi

et al.

Nature Medicine, Journal Year: 2024, Volume and Issue: 30(4), P. 1023 - 1034

Published: March 19, 2024

Abstract Gastroesophageal cancer dynamics and drivers of clinical responses with immune checkpoint inhibitors (ICI) remain poorly understood. Potential synergistic activity dual programmed cell death protein 1 (PD-1) lymphocyte-activation gene 3 (LAG-3) inhibition may help improve immunotherapy for these tumors. We report a phase Ib trial that evaluated neoadjuvant nivolumab (Arm A, n = 16) or nivolumab–relatlimab B, in combination chemoradiotherapy 32 patients resectable stage II/stage III gastroesophageal together an in-depth evaluation pathological, molecular functional responses. Primary endpoint was safety; the secondary feasibility; exploratory endpoints included pathological complete (pCR) major response (MPR), recurrence-free survival (RFS) overall (OS). The study met its primary safety Arm although B required modification to mitigate toxicity. pCR MPR rates were 40% 53.5% A 21.4% 57.1% B. Most common adverse events fatigue, nausea, thrombocytopenia dermatitis. Overall, 2-year RFS OS 72.5% 82.6%, respectively. Higher baseline ligand (PD-L1) LAG-3 expression associated deeper Exploratory analyses circulating tumor DNA (ctDNA) showed undetectable ctDNA post-ICI induction, preoperatively postoperatively had significantly longer OS; clearance reflective neoantigen-specific T Our findings provide insights into profile combined PD-1 blockade highlight potential analysis dynamically assess systemic burden during ICI open therapeutic window future intervention. ClinicalTrials.gov registration: NCT03044613 .

Language: Английский

Citations

37
Purine metabolism in lung adenocarcinoma: A single‐cell analysis revealing prognostic and immunotherapeutic insights DOI Creative Commons
Pengpeng Zhang,

Shengbin Pei,

Guangyao Zhou

et al.

Journal of Cellular and Molecular Medicine, Journal Year: 2024, Volume and Issue: 28(8)

Published: April 1, 2024

Abstract Lung adenocarcinoma (LUAD) is a prevalent subtype of lung cancer, yet the contribution purine metabolism (PM) to its pathogenesis remains poorly elucidated. PM, critical component intracellular nucleotide synthesis and energy metabolism, hypothesized exert significant influence on LUAD development. Herein, we employed single‐cell analysis investigate role PM within tumour microenvironment (TME) LUAD. scoring (PMS) across distinct cell types was determined using AUCell, UCell, singscore AddModuleScore algorithms. Subsequently, explored communication networks among cells high‐ low‐PMS groups, establishing robust PM‐associated signature (PAS) utilizing comprehensive dataset comprising samples from TCGA five GEO datasets. Our findings revealed that high‐PMS group exhibited intensified interactions, while PAS, constructed PM‐related genes, demonstrated precise prognostic predictive capability. Notably, datasets indicated low‐PAS patients superior prognosis. Furthermore, displayed increased immune infiltration elevated CD8A expression, coupled with reduced PD‐L1 expression. Moreover, data eight publicly available immunotherapy cohorts suggested enhanced outcomes in group. These results underscore close association between PAS immunity, offering insights into genomic alterations, chemotherapy drug sensitivity responses The newly established holds promise as valuable tool for selecting populations likely benefit future clinical stratification efforts.

Language: Английский

Citations

23