Pub Date : 2024-06-20DOI: 10.1158/2159-8290.CD-24-0096
Sunil Acharya, Rafet Basar, May Daher, Hind Rafei, Ping Li, Nadima Uprety, Emily Ensley, Mayra Shanley, Bijender Kumar, Pinaki P Banerjee, Luciana Melo Garcia, Paul Lin, Vakul Mohanty, Kun Hee Kim, Xianli Jiang, Yuchen Pan, Ye Li, Bin Liu, Ana Karen Nunez Cortes, Chenyu Zhang, Mohsen Fathi, Ali Rezvan, Melisa J Montalvo, Sophia L Cha, Francia Reyes-Silva, Rejeena Shrestha, Xingliang Guo, Kiran Kundu, Alexander Biederstadt, Luis Muniz-Feliciano, Gary M Deyter, Mecit Kaplan, Xin Ru Jiang, Enli Liu, Antrix Jain, Janos Roszik, Natalie W Fowlkes, Luisa M Solis Soto, Maria Gabriela Raso, Joseph D Khoury, Pei Lin, Francisco Vega, Navin Varadarajan, Ken Chen, David Marin, Elizabeth J Shpall, Katayoun Rezvani
Multiple factors in the design of a chimeric antigen receptor (CAR) influence CAR T-cell activity, with costimulatory signals being a key component. Yet, the impact of costimulatory domains on the downstream signaling and subsequent functionality of CAR-engineered natural killer (NK) cells remains largely unexplored. Here, we evaluated the impact of various costimulatory domains on CAR-NK cell activity, using a CD70-targeting CAR. We found that CD28, a costimulatory molecule not inherently present in mature NK cells, significantly enhanced the antitumor efficacy and long-term cytotoxicity of CAR-NK cells both in vitro and in multiple xenograft models of hematologic and solid tumors. Mechanistically, we showed that CD28 linked to CD3Z creates a platform that recruits critical kinases, such as LCK and ZAP70, initiating a signaling cascade that enhances CAR-NK cell function. Our study provides insights into how CD28 costimulation enhances CAR-NK cell function and supports its incorporation in NK-based CARs for cancer immunotherapy.
嵌合抗原受体(CAR)设计中的多种因素会影响 CAR T 细胞的活性,其中成本调控信号是一个关键因素。然而,成本调控域对 CAR 工程自然杀伤(NK)细胞的下游信号转导和后续功能的影响在很大程度上仍未得到探讨。在这里,我们使用一种 CD70 靶向 CAR 评估了各种成本调控域对 CAR-NK 细胞活性的影响。我们发现,CD28是成熟NK细胞中并不固有的一种协同调控分子,它能显著增强CAR-NK细胞在体外以及多种血液肿瘤和实体瘤异种移植模型中的抗肿瘤疗效和长期细胞毒性。从机理上讲,我们发现 CD28 与 CD3Z 连接形成了一个平台,它能招募 LCK 和 ZAP70 等关键激酶,启动信号级联,增强 CAR-NK 细胞的功能。我们的研究深入揭示了 CD28 成本刺激如何增强 CAR-NK 细胞功能,并支持将其纳入基于 NK 的 CAR 用于癌症免疫疗法。
{"title":"CD28 costimulation augments CAR signaling in NK cells via the LCK/CD3Z/ZAP70 signaling axis.","authors":"Sunil Acharya, Rafet Basar, May Daher, Hind Rafei, Ping Li, Nadima Uprety, Emily Ensley, Mayra Shanley, Bijender Kumar, Pinaki P Banerjee, Luciana Melo Garcia, Paul Lin, Vakul Mohanty, Kun Hee Kim, Xianli Jiang, Yuchen Pan, Ye Li, Bin Liu, Ana Karen Nunez Cortes, Chenyu Zhang, Mohsen Fathi, Ali Rezvan, Melisa J Montalvo, Sophia L Cha, Francia Reyes-Silva, Rejeena Shrestha, Xingliang Guo, Kiran Kundu, Alexander Biederstadt, Luis Muniz-Feliciano, Gary M Deyter, Mecit Kaplan, Xin Ru Jiang, Enli Liu, Antrix Jain, Janos Roszik, Natalie W Fowlkes, Luisa M Solis Soto, Maria Gabriela Raso, Joseph D Khoury, Pei Lin, Francisco Vega, Navin Varadarajan, Ken Chen, David Marin, Elizabeth J Shpall, Katayoun Rezvani","doi":"10.1158/2159-8290.CD-24-0096","DOIUrl":"10.1158/2159-8290.CD-24-0096","url":null,"abstract":"<p><p>Multiple factors in the design of a chimeric antigen receptor (CAR) influence CAR T-cell activity, with costimulatory signals being a key component. Yet, the impact of costimulatory domains on the downstream signaling and subsequent functionality of CAR-engineered natural killer (NK) cells remains largely unexplored. Here, we evaluated the impact of various costimulatory domains on CAR-NK cell activity, using a CD70-targeting CAR. We found that CD28, a costimulatory molecule not inherently present in mature NK cells, significantly enhanced the antitumor efficacy and long-term cytotoxicity of CAR-NK cells both in vitro and in multiple xenograft models of hematologic and solid tumors. Mechanistically, we showed that CD28 linked to CD3Z creates a platform that recruits critical kinases, such as LCK and ZAP70, initiating a signaling cascade that enhances CAR-NK cell function. Our study provides insights into how CD28 costimulation enhances CAR-NK cell function and supports its incorporation in NK-based CARs for cancer immunotherapy.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-14DOI: 10.1158/2159-8290.CD-23-1379
Raghuvaran Shanmugam, Prativa Majee, Wei Shi, Mert Burak Ozturk, Thamil Selvan Vaiyapuri, Khaireen Idzham, Anandhkumar Raju, Seung Hee Shin, Kerem Fidan, Joo-Leng Low, Joelle Yi Heng Chua, Yap Choon Kong, Ong Yue Qi, Emile Tan, Aik Yong Chok, Isaac Seow-En, Ian Wee, Dominique Camat Macalinao, Dawn Qingqing Chong, Hong Yun Chang, Fiona Lee, Wei Qiang Leow, Maki Murata-Hori, Zhang Xiaoqian, Chia Shumei, Chris Soon Heng Tan, Ramanuj Dasgupta, Iain Beehuat Tan, Vinay Tergaonkar
Over-consumption of iron-rich red meat and hereditary or genetic iron overload are associated with increased risk of colorectal carcinogenesis, yet the mechanistic basis of how metal-mediated signaling leads to oncogenesis remains enigmatic. Using fresh colorectal cancer (CRC) samples we identify Pirin, an iron sensor, that overcomes a rate-limiting step in oncogenesis, by re-activating the dormant human-reverse-transcriptase (hTERT) subunit of telomerase holoenzyme in an iron-(Fe3+)-dependent-manner and thereby drives CRCs. Chemical genetic screens combined with isothermal-dose response fingerprinting and mass-spectrometry identified a small molecule SP2509, that specifically inhibits Pirin-mediated hTERT reactivation in CRCs by competing with iron-(Fe3+) binding. Our findings, first to document how metal ions reactivate telomerase, provide a molecular mechanism for the well-known association between red meat, and increased incidence of CRCs. Small molecules like SP2509 represent a novel modality to target telomerase that acts as driver of 90% human cancers and is yet to be targeted in clinic.
{"title":"Iron-(Fe3+) dependent reactivation of telomerase drives colorectal cancers.","authors":"Raghuvaran Shanmugam, Prativa Majee, Wei Shi, Mert Burak Ozturk, Thamil Selvan Vaiyapuri, Khaireen Idzham, Anandhkumar Raju, Seung Hee Shin, Kerem Fidan, Joo-Leng Low, Joelle Yi Heng Chua, Yap Choon Kong, Ong Yue Qi, Emile Tan, Aik Yong Chok, Isaac Seow-En, Ian Wee, Dominique Camat Macalinao, Dawn Qingqing Chong, Hong Yun Chang, Fiona Lee, Wei Qiang Leow, Maki Murata-Hori, Zhang Xiaoqian, Chia Shumei, Chris Soon Heng Tan, Ramanuj Dasgupta, Iain Beehuat Tan, Vinay Tergaonkar","doi":"10.1158/2159-8290.CD-23-1379","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-23-1379","url":null,"abstract":"<p><p>Over-consumption of iron-rich red meat and hereditary or genetic iron overload are associated with increased risk of colorectal carcinogenesis, yet the mechanistic basis of how metal-mediated signaling leads to oncogenesis remains enigmatic. Using fresh colorectal cancer (CRC) samples we identify Pirin, an iron sensor, that overcomes a rate-limiting step in oncogenesis, by re-activating the dormant human-reverse-transcriptase (hTERT) subunit of telomerase holoenzyme in an iron-(Fe3+)-dependent-manner and thereby drives CRCs. Chemical genetic screens combined with isothermal-dose response fingerprinting and mass-spectrometry identified a small molecule SP2509, that specifically inhibits Pirin-mediated hTERT reactivation in CRCs by competing with iron-(Fe3+) binding. Our findings, first to document how metal ions reactivate telomerase, provide a molecular mechanism for the well-known association between red meat, and increased incidence of CRCs. Small molecules like SP2509 represent a novel modality to target telomerase that acts as driver of 90% human cancers and is yet to be targeted in clinic.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":28.2,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141417873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-03DOI: 10.1158/2159-8290.CD-23-0996
Madison Darmofal, Shalabh Suman, Gurnit Atwal, Michael Toomey, Jie-Fu Chen, Jason C Chang, Efsevia Vakiani, Anna M Varghese, Anoop Balakrishnan Rema, Aijazuddin Syed, Nikolaus Schultz, Michael F Berger, Quaid Morris
Tumor type guides clinical treatment decisions in cancer, but histology-based diagnosis remains challenging. Genomic alterations are highly diagnostic of tumor type, and tumor-type classifiers trained on genomic features have been explored, but the most accurate methods are not clinically feasible, relying on features derived from whole-genome sequencing (WGS), or predicting across limited cancer types. We use genomic features from a data set of 39,787 solid tumors sequenced using a clinically targeted cancer gene panel to develop Genome-Derived-Diagnosis Ensemble (GDD-ENS): a hyperparameter ensemble for classifying tumor type using deep neural networks. GDD-ENS achieves 93% accuracy for high-confidence predictions across 38 cancer types, rivaling the performance of WGS-based methods. GDD-ENS can also guide diagnoses of rare type and cancers of unknown primary and incorporate patient-specific clinical information for improved predictions. Overall, integrating GDD-ENS into prospective clinical sequencing workflows could provide clinically relevant tumor-type predictions to guide treatment decisions in real time.
Significance: We describe a highly accurate tumor-type prediction model, designed specifically for clinical implementation. Our model relies only on widely used cancer gene panel sequencing data, predicts across 38 distinct cancer types, and supports integration of patient-specific nongenomic information for enhanced decision support in challenging diagnostic situations. See related commentary by Garg, p. 906. This article is featured in Selected Articles from This Issue, p. 897.
{"title":"Deep-Learning Model for Tumor-Type Prediction Using Targeted Clinical Genomic Sequencing Data.","authors":"Madison Darmofal, Shalabh Suman, Gurnit Atwal, Michael Toomey, Jie-Fu Chen, Jason C Chang, Efsevia Vakiani, Anna M Varghese, Anoop Balakrishnan Rema, Aijazuddin Syed, Nikolaus Schultz, Michael F Berger, Quaid Morris","doi":"10.1158/2159-8290.CD-23-0996","DOIUrl":"10.1158/2159-8290.CD-23-0996","url":null,"abstract":"<p><p>Tumor type guides clinical treatment decisions in cancer, but histology-based diagnosis remains challenging. Genomic alterations are highly diagnostic of tumor type, and tumor-type classifiers trained on genomic features have been explored, but the most accurate methods are not clinically feasible, relying on features derived from whole-genome sequencing (WGS), or predicting across limited cancer types. We use genomic features from a data set of 39,787 solid tumors sequenced using a clinically targeted cancer gene panel to develop Genome-Derived-Diagnosis Ensemble (GDD-ENS): a hyperparameter ensemble for classifying tumor type using deep neural networks. GDD-ENS achieves 93% accuracy for high-confidence predictions across 38 cancer types, rivaling the performance of WGS-based methods. GDD-ENS can also guide diagnoses of rare type and cancers of unknown primary and incorporate patient-specific clinical information for improved predictions. Overall, integrating GDD-ENS into prospective clinical sequencing workflows could provide clinically relevant tumor-type predictions to guide treatment decisions in real time.</p><p><strong>Significance: </strong>We describe a highly accurate tumor-type prediction model, designed specifically for clinical implementation. Our model relies only on widely used cancer gene panel sequencing data, predicts across 38 distinct cancer types, and supports integration of patient-specific nongenomic information for enhanced decision support in challenging diagnostic situations. See related commentary by Garg, p. 906. This article is featured in Selected Articles from This Issue, p. 897.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11145170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139982432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-03DOI: 10.1158/2159-8290.CD-24-0519
Peter J Mazzone, Peter B Bach, Jacob Carey, Caitlin A Schonewolf, Katalin Bognar, Manmeet S Ahluwalia, Marcia Cruz-Correa, David Gierada, Sonali Kotagiri, Kathryn Lloyd, Fabien Maldonado, Jesse D Ortendahl, Lecia V Sequist, Gerard A Silvestri, Nichole Tanner, Jeffrey C Thompson, Anil Vachani, Kwok-Kin Wong, Ali H Zaidi, Joseph Catallini, Ariel Gershman, Keith Lumbard, Laurel K Millberg, Jeff Nawrocki, Carter Portwood, Aakanksha Rangnekar, Carolina Campos Sheridan, Niti Trivedi, Tony Wu, Yuhua Zong, Lindsey Cotton, Allison Ryan, Christopher Cisar, Alessandro Leal, Nicholas C Dracopoli, Robert B Scharpf, Victor E Velculescu, Luke R G Pike
Lung cancer screening via annual low-dose computed tomography (LDCT) has poor adoption. We conducted a prospective case-control study among 958 individuals eligible for lung cancer screening to develop a blood-based lung cancer detection test that when positive is followed by an LDCT. Changes in genome-wide cell-free DNA (cfDNA) fragmentation profiles (fragmentomes) in peripheral blood reflected genomic and chromatin characteristics of lung cancer. We applied machine learning to fragmentome features to identify individuals who were more or less likely to have lung cancer. We trained the classifier using 576 cases and controls from study samples, and then validated it in a held-out group of 382 cases and controls. The validation demonstrated high sensitivity for lung cancer, and consistency across demographic groups and comorbid conditions. Applying test performance to the screening eligible population in a five-year model with modest utilization assumptions suggested the potential to prevent thousands of lung cancer deaths.
{"title":"Clinical validation of a cell-free DNA fragmentome assay for augmentation of lung cancer early detection.","authors":"Peter J Mazzone, Peter B Bach, Jacob Carey, Caitlin A Schonewolf, Katalin Bognar, Manmeet S Ahluwalia, Marcia Cruz-Correa, David Gierada, Sonali Kotagiri, Kathryn Lloyd, Fabien Maldonado, Jesse D Ortendahl, Lecia V Sequist, Gerard A Silvestri, Nichole Tanner, Jeffrey C Thompson, Anil Vachani, Kwok-Kin Wong, Ali H Zaidi, Joseph Catallini, Ariel Gershman, Keith Lumbard, Laurel K Millberg, Jeff Nawrocki, Carter Portwood, Aakanksha Rangnekar, Carolina Campos Sheridan, Niti Trivedi, Tony Wu, Yuhua Zong, Lindsey Cotton, Allison Ryan, Christopher Cisar, Alessandro Leal, Nicholas C Dracopoli, Robert B Scharpf, Victor E Velculescu, Luke R G Pike","doi":"10.1158/2159-8290.CD-24-0519","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0519","url":null,"abstract":"<p><p>Lung cancer screening via annual low-dose computed tomography (LDCT) has poor adoption. We conducted a prospective case-control study among 958 individuals eligible for lung cancer screening to develop a blood-based lung cancer detection test that when positive is followed by an LDCT. Changes in genome-wide cell-free DNA (cfDNA) fragmentation profiles (fragmentomes) in peripheral blood reflected genomic and chromatin characteristics of lung cancer. We applied machine learning to fragmentome features to identify individuals who were more or less likely to have lung cancer. We trained the classifier using 576 cases and controls from study samples, and then validated it in a held-out group of 382 cases and controls. The validation demonstrated high sensitivity for lung cancer, and consistency across demographic groups and comorbid conditions. Applying test performance to the screening eligible population in a five-year model with modest utilization assumptions suggested the potential to prevent thousands of lung cancer deaths.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":28.2,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Colorectal cancer is a highly heterogeneous disease, with well-characterized subtypes based on genome, DNA methylome, and transcriptome signatures. To chart the epigenetic landscape of colorectal cancers, we generated a high-quality single-cell chromatin accessibility atlas of epithelial cells for 29 patients. Abnormal chromatin states acquired in adenomas were largely retained in colorectal cancers, which were tightly accompanied by opposite changes of DNA methylation. Unsupervised analysis on malignant cells revealed two epigenetic subtypes, exactly matching the iCMS classification, and key iCMS-specific transcription factors (TFs) were identified, including HNF4A and PPARA for iCMS2 tumors and FOXA3 and MAFK for iCMS3 tumors. Notably, subtype-specific TFs bind to distinct target gene sets and contribute to both interpatient similarities and diversities for both chromatin accessibilities and RNA expressions. Moreover, we identified CpG-island methylator phenotypes and pinpointed chromatin state signatures and TF regulators for the CIMP-high subtype. Our work systematically revealed the epigenetic basis of the well-known iCMS and CIMP classifications of colorectal cancers.
Significance: Our work revealed the epigenetic basis of the well-known iCMS and CIMP classifications of colorectal cancers. Moreover, interpatient minor similarities and major diversities of chromatin accessibility signatures of TF target genes can faithfully explain the corresponding interpatient minor similarities and major diversities of RNA expression signatures of colorectal cancers, respectively. This article is featured in Selected Articles from This Issue, p. 897.
{"title":"Single-Cell Chromatin Accessibility Analysis Reveals the Epigenetic Basis and Signature Transcription Factors for the Molecular Subtypes of Colorectal Cancers.","authors":"Zhenyu Liu, Yuqiong Hu, Haoling Xie, Kexuan Chen, Lu Wen, Wei Fu, Xin Zhou, Fuchou Tang","doi":"10.1158/2159-8290.CD-23-1445","DOIUrl":"10.1158/2159-8290.CD-23-1445","url":null,"abstract":"<p><p>Colorectal cancer is a highly heterogeneous disease, with well-characterized subtypes based on genome, DNA methylome, and transcriptome signatures. To chart the epigenetic landscape of colorectal cancers, we generated a high-quality single-cell chromatin accessibility atlas of epithelial cells for 29 patients. Abnormal chromatin states acquired in adenomas were largely retained in colorectal cancers, which were tightly accompanied by opposite changes of DNA methylation. Unsupervised analysis on malignant cells revealed two epigenetic subtypes, exactly matching the iCMS classification, and key iCMS-specific transcription factors (TFs) were identified, including HNF4A and PPARA for iCMS2 tumors and FOXA3 and MAFK for iCMS3 tumors. Notably, subtype-specific TFs bind to distinct target gene sets and contribute to both interpatient similarities and diversities for both chromatin accessibilities and RNA expressions. Moreover, we identified CpG-island methylator phenotypes and pinpointed chromatin state signatures and TF regulators for the CIMP-high subtype. Our work systematically revealed the epigenetic basis of the well-known iCMS and CIMP classifications of colorectal cancers.</p><p><strong>Significance: </strong>Our work revealed the epigenetic basis of the well-known iCMS and CIMP classifications of colorectal cancers. Moreover, interpatient minor similarities and major diversities of chromatin accessibility signatures of TF target genes can faithfully explain the corresponding interpatient minor similarities and major diversities of RNA expression signatures of colorectal cancers, respectively. This article is featured in Selected Articles from This Issue, p. 897.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":28.2,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140038733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-03DOI: 10.1158/2159-8290.CD-24-0368
Yonina R Murciano-Goroff, Sean M Devlin, Alexia Iasonos, Alexander Drilon
Summary: Advances in cancer biology and diagnostics have led to the recognition of a multitude of rare cancer subtypes, emphasizing the pressing need for strategies to accelerate drug development for patients with these cancers. This paper addresses the unique challenges of dose finding in trials that accrue small numbers of patients with rare cancers; strategies for dose optimization are proposed, in line with evolving approaches to dose determination in the age of the US Food and Drug Administration's Project Optimus.
{"title":"Optimus-Era Dose Finding for Rare Cancers.","authors":"Yonina R Murciano-Goroff, Sean M Devlin, Alexia Iasonos, Alexander Drilon","doi":"10.1158/2159-8290.CD-24-0368","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0368","url":null,"abstract":"<p><strong>Summary: </strong>Advances in cancer biology and diagnostics have led to the recognition of a multitude of rare cancer subtypes, emphasizing the pressing need for strategies to accelerate drug development for patients with these cancers. This paper addresses the unique challenges of dose finding in trials that accrue small numbers of patients with rare cancers; strategies for dose optimization are proposed, in line with evolving approaches to dose determination in the age of the US Food and Drug Administration's Project Optimus.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":28.2,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-03DOI: 10.1158/2159-8290.CD-24-0374
Jessica J Lin, Justin F Gainor, Vincent K Lam, Christine M Lovly
Summary: Drug-tolerant residual disease (DTRD) after the initial maximal response to a systemic therapy can serve as a tumor reservoir for the development of acquired drug resistance and represents a major clinical challenge across various cancers and types of therapies. To unlock the next frontier in precision oncology, we propose a fundamental paradigm shift in the treatment of metastatic cancers with a sharpened focus towards defining, monitoring, and therapeutically targeting the DTRD state.
{"title":"Unlocking the Next Frontier in Precision Oncology: Addressing Drug-Tolerant Residual Disease.","authors":"Jessica J Lin, Justin F Gainor, Vincent K Lam, Christine M Lovly","doi":"10.1158/2159-8290.CD-24-0374","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0374","url":null,"abstract":"<p><strong>Summary: </strong>Drug-tolerant residual disease (DTRD) after the initial maximal response to a systemic therapy can serve as a tumor reservoir for the development of acquired drug resistance and represents a major clinical challenge across various cancers and types of therapies. To unlock the next frontier in precision oncology, we propose a fundamental paradigm shift in the treatment of metastatic cancers with a sharpened focus towards defining, monitoring, and therapeutically targeting the DTRD state.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":28.2,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-03DOI: 10.1158/2159-8290.CD-23-0913
Anthony Z Wang, Bryce L Mashimo, Maximilian O Schaettler, Ngima D Sherpa, Lydia A Leavitt, Alexandra J Livingstone, Saad M Khan, Mao Li, Markus I Anzaldua-Campos, Joseph D Bradley, Eric C Leuthardt, Albert H Kim, Joshua L Dowling, Michael R Chicoine, Pamela S Jones, Bryan D Choi, Daniel P Cahill, Bob S Carter, Allegra A Petti, Tanner M Johanns, Gavin P Dunn
Recent clinical trials have highlighted the limited efficacy of T cell-based immunotherapy in patients with glioblastoma (GBM). To better understand the characteristics of tumor-infiltrating lymphocytes (TIL) in GBM, we performed cellular indexing of transcriptomes and epitopes by sequencing and single-cell RNA sequencing with paired V(D)J sequencing, respectively, on TILs from two cohorts of patients totaling 15 patients with high-grade glioma, including GBM or astrocytoma, IDH-mutant, grade 4 (G4A). Analysis of the CD8+ TIL landscape reveals an enrichment of clonally expanded GZMK+ effector T cells in the tumor compared with matched blood, which was validated at the protein level. Furthermore, integration with other cancer types highlights the lack of a canonically exhausted CD8+ T-cell population in GBM TIL. These data suggest that GZMK+ effector T cells represent an important T-cell subset within the GBM microenvironment and may harbor potential therapeutic implications.
Significance: To understand the limited efficacy of immune-checkpoint blockade in GBM, we applied a multiomics approach to understand the TIL landscape. By highlighting the enrichment of GZMK+ effector T cells and the lack of exhausted T cells, we provide a new potential mechanism of resistance to immunotherapy in GBM. This article is featured in Selected Articles from This Issue, p. 897.
最近的临床试验表明,基于T细胞的免疫疗法对胶质母细胞瘤(GBM)患者的疗效有限。为了更好地了解 GBM 中肿瘤浸润淋巴细胞(TIL)的特征,我们对两组共 15 例高级别胶质瘤(包括 GBM 或星形细胞瘤、IDH 突变、4 级(G4A))患者的 TIL 分别进行了转录组和表位的细胞索引测序(CITE-seq)和单细胞 RNA 测序(scRNA-seq)以及配对 V(D)J 测序。对 CD8+ TIL 形态的分析表明,与匹配的血液相比,肿瘤中克隆扩增的 GZMK+ 效应 T 细胞富集,这在蛋白质水平上得到了验证。此外,与其他癌症类型的整合结果表明,GBM TIL 中缺乏典型衰竭的 CD8+ T 细胞群。这些数据表明,GZMK+效应T细胞代表了GBM微环境中一个重要的T细胞亚群,可能具有潜在的治疗意义。
{"title":"Glioblastoma-Infiltrating CD8+ T Cells Are Predominantly a Clonally Expanded GZMK+ Effector Population.","authors":"Anthony Z Wang, Bryce L Mashimo, Maximilian O Schaettler, Ngima D Sherpa, Lydia A Leavitt, Alexandra J Livingstone, Saad M Khan, Mao Li, Markus I Anzaldua-Campos, Joseph D Bradley, Eric C Leuthardt, Albert H Kim, Joshua L Dowling, Michael R Chicoine, Pamela S Jones, Bryan D Choi, Daniel P Cahill, Bob S Carter, Allegra A Petti, Tanner M Johanns, Gavin P Dunn","doi":"10.1158/2159-8290.CD-23-0913","DOIUrl":"10.1158/2159-8290.CD-23-0913","url":null,"abstract":"<p><p>Recent clinical trials have highlighted the limited efficacy of T cell-based immunotherapy in patients with glioblastoma (GBM). To better understand the characteristics of tumor-infiltrating lymphocytes (TIL) in GBM, we performed cellular indexing of transcriptomes and epitopes by sequencing and single-cell RNA sequencing with paired V(D)J sequencing, respectively, on TILs from two cohorts of patients totaling 15 patients with high-grade glioma, including GBM or astrocytoma, IDH-mutant, grade 4 (G4A). Analysis of the CD8+ TIL landscape reveals an enrichment of clonally expanded GZMK+ effector T cells in the tumor compared with matched blood, which was validated at the protein level. Furthermore, integration with other cancer types highlights the lack of a canonically exhausted CD8+ T-cell population in GBM TIL. These data suggest that GZMK+ effector T cells represent an important T-cell subset within the GBM microenvironment and may harbor potential therapeutic implications.</p><p><strong>Significance: </strong>To understand the limited efficacy of immune-checkpoint blockade in GBM, we applied a multiomics approach to understand the TIL landscape. By highlighting the enrichment of GZMK+ effector T cells and the lack of exhausted T cells, we provide a new potential mechanism of resistance to immunotherapy in GBM. This article is featured in Selected Articles from This Issue, p. 897.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139982433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-03DOI: 10.1158/2159-8290.CD-24-0186
Rachel L Paolini, George P Souroullas
Summary: In this issue, a study by Kazansky and colleagues explored resistance mechanisms after EZH2 inhibition in malignant rhabdoid tumors (MRT) and epithelioid sarcomas (ES). The study identified genetic alterations in EZH2 itself, along with alterations that converge on RB1-E2F-mediated cell-cycle control, and demonstrated that inhibition of cell-cycle kinases, such as Aurora Kinase B (AURKB) could bypass EZH2 inhibitor resistance to enhance treatment efficacy. See related article by Kazansky et al., p. 965 (6).
{"title":"The Cell Cycle: a Key to Unlock EZH2-targeted Therapy Resistance.","authors":"Rachel L Paolini, George P Souroullas","doi":"10.1158/2159-8290.CD-24-0186","DOIUrl":"10.1158/2159-8290.CD-24-0186","url":null,"abstract":"<p><strong>Summary: </strong>In this issue, a study by Kazansky and colleagues explored resistance mechanisms after EZH2 inhibition in malignant rhabdoid tumors (MRT) and epithelioid sarcomas (ES). The study identified genetic alterations in EZH2 itself, along with alterations that converge on RB1-E2F-mediated cell-cycle control, and demonstrated that inhibition of cell-cycle kinases, such as Aurora Kinase B (AURKB) could bypass EZH2 inhibitor resistance to enhance treatment efficacy. See related article by Kazansky et al., p. 965 (6).</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-03DOI: 10.1158/2159-8290.CD-23-1060
Eric Y Stutheit-Zhao, Enrique Sanz-Garcia, Zhihui Amy Liu, Derek Wong, Kayla Marsh, Albiruni R Abdul Razak, Anna Spreafico, Philippe L Bedard, Aaron R Hansen, Stephanie Lheureux, Dax Torti, Bernard Lam, Shih Yu Cindy Yang, Justin Burgener, Ping Luo, Yong Zeng, Nicholas Cheng, Philip Awadalla, Scott V Bratman, Pamela S Ohashi, Trevor J Pugh, Lillian L Siu
Early kinetics of circulating tumor DNA (ctDNA) in plasma predict response to pembrolizumab but typically requires sequencing of matched tumor tissue or fixed gene panels. We analyzed genome-wide methylation and fragment-length profiles using cell-free methylated DNA immunoprecipitation and sequencing (cfMeDIP-seq) in 204 plasma samples from 87 patients before and during treatment with pembrolizumab from a pan-cancer phase II investigator-initiated trial (INSPIRE). We trained a pan-cancer methylation signature using independent methylation array data from The Cancer Genome Atlas to quantify cancer-specific methylation (CSM) and fragment-length score (FLS) for each sample. CSM and FLS are strongly correlated with tumor-informed ctDNA levels. Early kinetics of CSM predict overall survival and progression-free survival, independently of tumor type, PD-L1, and tumor mutation burden. Early kinetics of FLS are associated with overall survival independently of CSM. Our tumor-naïve mutation-agnostic ctDNA approach integrating methylomics and fragmentomics could predict outcomes in patients treated with pembrolizumab.
Significance: Analysis of methylation and fragment length in plasma using cfMeDIP-seq provides a tumor-naive approach to measure ctDNA with results comparable with a tumor-informed bespoke ctDNA. Early kinetics within the first weeks of treatment in methylation and fragment quantity can predict outcomes with pembrolizumab in patients with various advanced solid tumors. This article is featured in Selected Articles from This Issue, p. 897.
血浆中循环肿瘤DNA(ctDNA)的早期动力学可预测对pembrolizumab的反应,但通常需要对匹配的肿瘤组织或固定基因组进行测序。我们利用无细胞甲基化DNA免疫沉淀和测序技术(cfMeDIP-seq)分析了泛癌症II期研究者发起试验(INSPIRE)中87名患者在使用pembrolizumab治疗前和治疗期间的204份血浆样本的全基因组甲基化和片段长度谱。我们利用癌症基因组图谱(The Cancer Genome Atlas)中的独立甲基化阵列数据训练了泛癌症甲基化特征,以量化每个样本的癌症特异性甲基化(CSM)和片段长度评分(FLS)。CSM和FLS与肿瘤信息ctDNA水平密切相关。CSM的早期动力学可预测总生存期和无进展生存期,与肿瘤类型、PD-L1和肿瘤突变负荷无关。FLS的早期动力学与总生存期相关,与CSM无关。我们整合了甲基组学和片段组学的肿瘤基因突变诊断 ctDNA 方法可以预测接受 pembrolizumab 治疗的患者的预后。
{"title":"Early Changes in Tumor-Naive Cell-Free Methylomes and Fragmentomes Predict Outcomes in Pembrolizumab-Treated Solid Tumors.","authors":"Eric Y Stutheit-Zhao, Enrique Sanz-Garcia, Zhihui Amy Liu, Derek Wong, Kayla Marsh, Albiruni R Abdul Razak, Anna Spreafico, Philippe L Bedard, Aaron R Hansen, Stephanie Lheureux, Dax Torti, Bernard Lam, Shih Yu Cindy Yang, Justin Burgener, Ping Luo, Yong Zeng, Nicholas Cheng, Philip Awadalla, Scott V Bratman, Pamela S Ohashi, Trevor J Pugh, Lillian L Siu","doi":"10.1158/2159-8290.CD-23-1060","DOIUrl":"10.1158/2159-8290.CD-23-1060","url":null,"abstract":"<p><p>Early kinetics of circulating tumor DNA (ctDNA) in plasma predict response to pembrolizumab but typically requires sequencing of matched tumor tissue or fixed gene panels. We analyzed genome-wide methylation and fragment-length profiles using cell-free methylated DNA immunoprecipitation and sequencing (cfMeDIP-seq) in 204 plasma samples from 87 patients before and during treatment with pembrolizumab from a pan-cancer phase II investigator-initiated trial (INSPIRE). We trained a pan-cancer methylation signature using independent methylation array data from The Cancer Genome Atlas to quantify cancer-specific methylation (CSM) and fragment-length score (FLS) for each sample. CSM and FLS are strongly correlated with tumor-informed ctDNA levels. Early kinetics of CSM predict overall survival and progression-free survival, independently of tumor type, PD-L1, and tumor mutation burden. Early kinetics of FLS are associated with overall survival independently of CSM. Our tumor-naïve mutation-agnostic ctDNA approach integrating methylomics and fragmentomics could predict outcomes in patients treated with pembrolizumab.</p><p><strong>Significance: </strong>Analysis of methylation and fragment length in plasma using cfMeDIP-seq provides a tumor-naive approach to measure ctDNA with results comparable with a tumor-informed bespoke ctDNA. Early kinetics within the first weeks of treatment in methylation and fragment quantity can predict outcomes with pembrolizumab in patients with various advanced solid tumors. This article is featured in Selected Articles from This Issue, p. 897.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":28.2,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11145176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139930163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}