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T-cell Responses to Individualized Neoantigen Therapy mRNA-4157 (V940) Alone or in Combination with Pembrolizumab in the Phase 1 KEYNOTE-603 Study. 个体化新抗原疗法 mRNA-4157 (V940) 单独或与 Pembrolizumab 联用的 T 细胞反应在 KEYNOTE-603 1 期研究中。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-24-0158
Justin F Gainor, Manish R Patel, Jeffrey S Weber, Martin Gutierrez, Julie E Bauman, Jeffrey M Clarke, Ricklie Julian, Aaron J Scott, Jessica L Geiger, Kedar Kirtane, Celine Robert-Tissot, Brandon Coder, Moomal Tasneem, Jing Sun, Wei Zheng, Lauren Gerbereux, Andressa Laino, Filippos Porichis, Jack Russella Pollard, Peijie Hou, Vasudha Sehgal, Xing Chen, Manju Morrissey, Hikmat N Daghestani, Igor Feldman, Lakshmi Srinivasan, Joshua P Frederick, Michelle Brown, Praveen Aanur, Robert Meehan, Howard A Burris

mRNA-4157 (V940) is an individualized neoantigen therapy targeting up to 34 patient-specific tumor neoantigens to induce T-cell responses and potentiate antitumor activity. We report mechanistic insights into the immunogenicity of mRNA-4157 via characterization of T-cell responses to neoantigens from the first-in-human, phase 1, KEYNOTE-603 study (NCT03313778) in patients with resected non-small cell lung cancer (Part A: 1-mg mRNA-4157, n = 4) or resected cutaneous melanoma (Part D: 1-mg mRNA-4157 + 200-mg pembrolizumab, n = 12). Safety, tolerability, and immunogenicity were assessed. All patients experienced ≥1 treatment-emergent adverse event; there were no grade 4/5 adverse events or dose-limiting toxicities. mRNA-4157 alone induced consistent de novo and strengthened preexisting T-cell responses to targeted neoantigens. Following combination therapy, sustained mRNA-4157-induced neoantigen-specific T-cell responses and expansion of cytotoxic CD8 and CD4 T cells were observed. These findings show the potential of a novel mRNA individualized neoantigen therapy approach in oncology. Significance: The safety and immunogenicity results from this phase 1 study of mRNA-4157 as adjuvant monotherapy or combination therapy with pembrolizumab show generation of de novo and enhancement of existing neoantigen-specific T-cell responses and provide mechanistic proof of concept to support further development of mRNA-4157 for patients with resected solid tumors. See related commentary by Berraondo et al., p. 2021.

mRNA-4157(V940)是一种个体化新抗原疗法(INT),它以多达34种患者特异性肿瘤新抗原为靶点,诱导T细胞反应并增强抗肿瘤活性。我们报告了在切除的非小细胞肺癌患者(A部分:1毫克mRNA-4157,n = 4)或切除的皮肤黑色素瘤患者(D部分:1毫克mRNA-4157 + 200毫克pembrolizumab,n = 12)中进行的首次人体1期KEYNOTE-603研究(NCT03313778)中T细胞对新抗原反应的表征,从机理上揭示了mRNA-4157的免疫原性。对安全性、耐受性和免疫原性进行了评估。所有患者都出现了≥1次治疗突发不良事件(AE);没有出现4/5级AE或剂量限制性毒性反应。联合治疗后,可观察到持续的mRNA-4157诱导的新抗原特异性T细胞反应以及细胞毒性CD8和CD4 T细胞的扩增。这些发现显示了新型 mRNA INT 方法在肿瘤学中的潜力。
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引用次数: 0
Targeting Noncoding cis-Regulatory Elements for Cancer Therapy in the Context of the 3D Genome. 在三维基因组背景下瞄准非编码顺式调控元件治疗癌症
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-24-0836
Kailong Li, Gong-Hong Wei, Yuxin Yin, Jiawen Feng

Significant efforts have been made to identify and validate oncoproteins and ncRNAs as therapeutic targets for cancer therapy; however, emerging observations suggest that noncoding cis-regulatory elements, which orchestrate the 3D organization of the genome and thus the transcriptional landscape, are potential therapeutic targets as well. In this commentary, we envisage that further efforts to decipher the noncoding cis-regulatory code and performing systematic surveys of functional noncoding cis-regulatory elements and recurrent 3D genome alterations in both cancerous and nonmalignant cells within tumor tissues will pave the way to the development of novel therapeutic strategies.

我们已经做出了巨大努力来识别和验证肿瘤蛋白和 ncRNA,并将其作为癌症治疗的靶点;然而,新出现的观察结果表明,非编码顺式调控元件也是潜在的治疗靶点,它们协调了基因组的三维组织,从而协调了转录格局。在这篇评论中,我们设想进一步努力破译非编码顺式调控密码,并对肿瘤组织内癌细胞和非癌细胞中的功能性非编码顺式调控元件和反复出现的三维基因组改变进行系统调查,这将为开发新型治疗策略铺平道路。
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引用次数: 0
The N6-methyladenosine Epitranscriptomic Landscape of Lung Adenocarcinoma. 肺腺癌的 N6-甲基腺苷表转录组图谱
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-23-1212
Shiyan Wang, Yong Zeng, Lin Zhu, Min Zhang, Lei Zhou, Weixiong Yang, Weishan Luo, Lina Wang, Yanming Liu, Helen Zhu, Xin Xu, Peiran Su, Xinyue Zhang, Musaddeque Ahmed, Wei Chen, Moliang Chen, Sujun Chen, Mykhaylo Slobodyanyuk, Zhongpeng Xie, Jiansheng Guan, Wen Zhang, Aafaque Ahmad Khan, Shingo Sakashita, Ni Liu, Nhu-An Pham, Paul C Boutros, Zunfu Ke, Michael F Moran, Zongwei Cai, Chao Cheng, Jun Yu, Ming S Tsao, Housheng H He

Comprehensive N6-methyladenosine (m6A) epitranscriptomic profiling of primary tumors remains largely uncharted. Here, we profiled the m6A epitranscriptome of 10 nonneoplastic lung tissues and 51 lung adenocarcinoma (LUAD) tumors, integrating the corresponding transcriptomic, proteomic, and extensive clinical annotations. We identified distinct clusters and genes that were exclusively linked to disease progression through m6A modifications. In comparison with nonneoplastic lung tissues, we identified 430 transcripts to be hypo-methylated and 222 to be hyper-methylated in tumors. Among these genes, EML4 emerged as a novel metastatic driver, displaying significant hypermethylation in tumors. m6A modification promoted the translation of EML4, leading to its widespread overexpression in primary tumors. Functionally, EML4 modulated cytoskeleton dynamics by interacting with ARPC1A, enhancing lamellipodia formation, cellular motility, local invasion, and metastasis. Clinically, high EML4 protein abundance correlated with features of metastasis. METTL3 small-molecule inhibitor markedly diminished both EML4 m6A and protein abundance and efficiently suppressed lung metastases in vivo. Significance: Our study reveals a dynamic and functional epitranscriptomic landscape in LUAD, offering a valuable resource for further research in the field. We identified EML4 hypermethylation as a key driver of tumor metastasis, highlighting a novel therapeutic strategy of targeting EML4 to prevent LUAD metastasis.

对原发性肿瘤进行全面的 m6A 表转录组分析在很大程度上仍是未知的。在这里,我们分析了 10 个非肿瘤性肺(NL)组织和 51 个肺腺癌(LUAD)肿瘤的 m6A 表转录组,整合了相应的转录组、蛋白质组和大量临床注释。我们发现了通过 m6A 修饰与疾病进展密切相关的基因簇和基因。与 NL 组织相比,我们发现肿瘤中有 430 个转录本发生低甲基化,222 个发生高甲基化。m6A修饰促进了EML4的翻译,导致其在原发性肿瘤中广泛过表达。在功能上,EML4通过与ARPC1A相互作用来调节细胞骨架动力学,从而增强纤毛形成、细胞运动、局部侵袭和转移。在临床上,高EML4蛋白丰度与转移特征相关。METTL3小分子抑制剂可显著降低EML4 m6A和蛋白丰度,并有效抑制体内肺转移。
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引用次数: 0
The SCRUM-MONSTAR Cancer-Omics Ecosystem: Striving for a Quantum Leap in Precision Medicine. SCRUM-MONSTAR 癌症-肿瘤生态系统:努力实现精准医学的飞跃。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-24-0206
Tadayoshi Hashimoto, Yoshiaki Nakamura, Takao Fujisawa, Mitsuho Imai, Taro Shibuki, Naoko Iida, Hiroshi Ozaki, Norio Nonomura, Chigusa Morizane, Hiroji Iwata, Susumu Okano, Wataru Yamagami, Naoya Yamazaki, Shigenori Kadowaki, Hiroya Taniguchi, Makoto Ueno, Shogen Boku, Eiji Oki, Yoshito Komatsu, Satoshi Yuki, Akitaka Makiyama, Tomoyuki Otsuka, Hiroki Hara, Naohiro Okano, Tomohiro Nishina, Yasutoshi Sakamoto, Izumi Miki, Shin Kobayashi, Junichiro Yuda, Shun-Ichiro Kageyama, Michiko Nagamine, Shingo Sakashita, Naoya Sakamoto, Riu Yamashita, Yoshikatsu Koga, Hideaki Bando, Genichiro Ishii, Takeshi Kuwata, Woong-Yang Park, Atsushi Ohtsu, Takayuki Yoshino

The SCRUM-Japan MONSTAR-SCREEN consortium is a nationwide molecular profiling project employing artificial intelligence-driven multiomics analyses for patients with advanced malignancies, aiming to develop novel therapeutics and diagnostics and deliver effective drugs to patients. Concurrently, studies assessing molecular residual disease-based precision medicine for resectable solid tumors, including CIRCULATE-Japan, are ongoing. The substantial data generated by these platforms are stored within a state-of-the-art supercomputing infrastructure, VAPOR CONE. Since 2015, our project has registered over 24,000 patients as of December 2023. Among 16,144 patients with advanced solid tumors enrolled in MONSTAR-SCREEN projects, 5.0% have participated in matched clinical trials, demonstrating a 29.2% objective response rate and 14.8-month median survival (95% CI, 13.4-16.3) for patients treated in the matched clinical trials. Notably, patients who received matched therapy demonstrated significantly prolonged overall survival compared with those who did not (hazard ratio 0.77; 95% confidence interval, 0.71-0.83). Significance: Our nationwide molecular profiling initiative played pivotal roles in facilitating the enrollment of patients with advanced solid tumors into matched clinical trials and highlighted the substantial survival benefits of patients treated with matched therapy. We aim to facilitate an industry-academia data-sharing infrastructure ecosystem, fostering new drug discovery paradigms and precision medicine.

SCRUM-Japan MONSTAR-SCREEN 联合体是一个全国性的分子图谱分析项目,采用人工智能驱动的多组学分析方法对晚期恶性肿瘤患者进行分析,旨在开发新型疗法和诊断方法,并向患者提供有效的药物。与此同时,包括 CIRCULATE-Japan 在内的针对可切除实体瘤的基于分子残留病的精准医疗评估研究也在进行中。这些平台产生的大量数据存储在最先进的超级计算基础设施VAPOR CONE中。自2015年以来,截至2023年12月,我们的项目已登记了超过24000名患者。在MONSTAR-SCREEN项目登记的16144名晚期实体瘤患者中,5.0%参加了匹配临床试验,结果显示,接受匹配临床试验治疗的患者客观反应率为29.2%,中位生存期为14.8个月(95%置信区间,13.4-16.3)。值得注意的是,与未接受匹配治疗的患者相比,接受匹配治疗的患者总生存期明显延长(危险比为 0.77;95% 置信区间为 0.71-0.83)。
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引用次数: 0
Exploring the Interplay of Diet, Obesity, Immune Function, and Cancer. 探索饮食、肥胖、免疫功能和癌症之间的相互作用。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-24-0834
Yumin Fu, Xinyu Guo, Linmao Sun, Tianming Cui, Jiabei Wang, Yao Liu, Lianxin Liu

This commentary provides an in-depth exploration of the intricate relationships among diet, obesity, immune function, and cancer, highlighting the potential role of dietary interventions as complementary therapies in cancer treatment. Multiple analyses underscore the importance of personalized dietary strategies in cancer management and identify opportunities for further research in this evolving field.

这篇评论深入探讨了饮食、肥胖、免疫功能和癌症之间错综复杂的关系,强调了饮食干预作为辅助疗法在癌症治疗中的潜在作用。多项分析强调了个性化饮食策略在癌症治疗中的重要性,并指出了在这一不断发展的领域开展进一步研究的机会。
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引用次数: 0
Beneath the Surface: Neoantigens beyond Chromosomal DNA Mutations. 表面之下染色体 DNA 突变之外的新抗原。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-24-0830
Shicheng Su

The conventional wisdom is that the overwhelming majority of neoantigens arise from chromosomal DNA mutations; however, recent studies show that posttranscriptional and posttranslational events can also generate neoantigens. This commentary provides an overview of known and potential sources of nonchromosomal neoantigens, emerging technologies, and clinical trials that may move this field forward to redefine immunologically "hot/cold" tumors and develop next-generation immunotherapeutic approaches.

传统观点认为,绝大多数新抗原来自染色体 DNA 突变;然而,最近的研究表明,转录后和翻译后事件也能产生新抗原。这篇评论概述了非染色体新抗原的已知和潜在来源、新兴技术和临床试验,它们可能会推动这一领域的发展,从而重新定义免疫学上的 "热/冷 "肿瘤,并开发出下一代免疫治疗方法。
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引用次数: 0
Combination Diagnostics: Adding Blood-Based ctDNA Screening to Low-Dose CT Imaging for Early Detection of Lung Cancer. 联合诊断:在低剂量 CT 成像中加入基于血液的 ctDNA 筛查以早期检测肺癌。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-24-1195
Daniel A Haber, Steven J Skates

Annual low-dose CT screening of individuals with a smoking history identifies early curable lung tumors and reduces cancer mortality by 20%, yet only a minority of eligible patients undergo such monitoring. Mazzone and colleagues apply a blood-based cfDNA fragmentomic assay as a high-sensitivity/low-specificity pre-screen to help stratify individuals who may benefit most from more definitive low-dose CT imaging. See related article by Mazzone et al., p. 2224.

每年对有吸烟史的人进行低剂量 CT 筛查可以发现早期可治愈的肺部肿瘤,并将癌症死亡率降低 20%,但只有少数符合条件的患者接受了这种监测。Mazzone 及其同事将基于血液的 cfDNA 片段组测定作为一种高灵敏度/低特异性的预筛查方法,帮助对可能从更明确的低剂量 CT 成像中获益最多的人进行分层。请参阅 Mazzone 等人的相关文章,第 2224 页。
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引用次数: 0
Early Cancer Detection Through Comprehensive Mapping of Dynamic Tumorigenesis. 通过全面绘制动态肿瘤发生图早期发现癌症
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-24-0831
Jiang Chang, Tongsen Zheng, Chen Wu

Current strategies for early cancer detection and diagnosis need updating to achieve greater precision, necessitating the creation of a comprehensive evolutionary map of tumorigenesis. This requires establishing high-quality prospective cohorts, systematically collecting samples for integrated spatiotemporal multiomics analyses, and efficiently translating laboratory findings into clinical applications.

目前的早期癌症检测和诊断策略需要更新,以实现更高的精确度,这就需要绘制一张全面的肿瘤发生进化图。这就需要建立高质量的前瞻性队列,系统地收集样本进行综合时空多组学分析,并有效地将实验室研究结果转化为临床应用。
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引用次数: 0
Advancing Cancer Prevention through an AI-Based Integration of Traditional and Western Medicine. 通过基于人工智能的中西医结合推进癌症预防。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-24-0832
Peng Zhang, Qian Zhang, Shao Li

Traditional Chinese medicine has accumulated a wealth of experiences in individualized cancer prevention and serves as a complement to Western medicine. We propose an artificial intelligence-based integration of traditional and Western medicine as a new paradigm for cancer prevention, encompassing cancer risk screening and preventive intervention, which will provide new solutions for cancer prevention and offer fresh perspectives for traditional medicine research worldwide.

中医药在癌症个体化预防方面积累了丰富的经验,是西医的补充。我们提出以人工智能为基础的中西医结合癌症预防新模式,包括癌症风险筛查和预防干预,这将为癌症预防提供新的解决方案,并为世界范围内的传统医学研究提供新的视角。
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引用次数: 0
The Far Side of Resistance to RAS Inhibitors. RAS 抑制剂耐药性的远方
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-24-1153
Michelangelo Marasco, Sandra Misale

In this issue, four articles highlight the critical role of nongenetic mechanisms and cell plasticity in mediating resistance to different classes of RAS inhibitors in pancreatic ductal adenocarcinoma and non-small cell lung cancer. See related article by Benitz et al., p. 2162 See related article by Dilly et al., p. 2135 See related article by Araujo et al., p. 2183 See related article by Singhal et al., p. 2122.

本期有四篇文章强调了非遗传机制和细胞可塑性在胰腺导管腺癌和非小细胞肺癌对不同类别 RAS 抑制剂产生耐药性方面的关键作用。见 Benitz 等人的相关文章,第 2162 页 见 Dilly 等人的相关文章,第 2135 页 见 Araujo 等人的相关文章,第 2183 页 见 Singhal 等人的相关文章,第 2122 页。
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引用次数: 0
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Cancer discovery
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