Spatiotemporal Tumor Analytics for Guiding Sequential Targeted-Inhibitor: Immunotherapy Combinations (ST-Analytics)
用于指导序贯靶向抑制剂的时空肿瘤分析:免疫治疗组合(ST-Analytics)
基本信息
- 批准号:10526101
- 负责人:
- 金额:$ 270.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-22 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdoptive Cell TransfersAlgorithmsAutomobile DrivingBiologicalBiopsyCell physiologyCellsClinicalClinical DataClinical TrialsClinical Trials DesignCombination immunotherapyCombined Modality TherapyCommunitiesCoupledDataDatabasesDevelopmentDisadvantagedDisease modelDistalDoseEducation and OutreachEducational ModelsEnvironmentEnvironment DesignEpigenetic ProcessEvaluationGenetic TranscriptionImmuneImmune systemImmunologic FactorsImmunooncologyImmunotherapyIndividualInternshipsK-12 EducationKineticsKnowledgeLeadLeadershipMalignant NeoplasmsMeasurementMetastatic malignant neoplasm to brainMitogen-Activated Protein Kinase InhibitorModelingNatureNeoplasm MetastasisOutcomePatientsPharmaceutical PreparationsPilot ProjectsPlayPrimary NeoplasmProteomicsResearchResearch PersonnelResearch Project GrantsResistanceResourcesRoleScienceScience, Technology, Engineering and Mathematics EducationScientistSelf-ExaminationSeriesStructureSystemSystems BiologyTherapeuticTimeTissuesVisualWorkbasebiobankcancer immunotherapycombinatorialcomputing resourcesdemographicsdesignimmune checkpoint blockadein silicoin vivoinhibitorinhibitor therapymedical schoolsmelanomamodel designmouse modelmultiple omicsoutreachoutreach programpreventprogramsrecruitspatiotemporaltooltranscriptomicstumortumor-immune system interactions
项目摘要
Overall Project Summary
The proposed U54 program Spatiotemporal Tumor Analytics for Guiding Sequential Targeted-Inhibitor --
Immunotherapy Combinations (ST-Analytics) is designed to develop the recent conceptual advance that
targeted inhibitor + cancer immunotherapy (IT) combination treatments may yield significantly greater patient
benefit if those treatments are administered in sequence rather than simultaneously. Analysis of retrospective
clinical data coupled with in vivo therapeutic modeling using syngeneic models of murine melanoma strongly
support this concept. In fact, the picture that has emerged in melanoma is that immune factors can play a strong
role in driving resistance to MAPK inhibitor (MAPKi) therapy, and that lead-in immune checkpoint blockade (ICB)
can ‘prime’ both the primary tumor and distal metastases (including brain metastases) for eradication when the
IT is subsequently combined with MAPKi. This observation opens the doors for immune based strategies, such
as ICB or adoptive cell therapy (ACT), as sequential combinatorial agents to prevent MAPKi resistance.
However, this concept introduces a number of new variables, including dosing, sequence, and timing. This can
make the design and execution of clinical trials that can yield statistically significant outcomes impractical. This
is the scientific and translational problem we address in the proposed ST-Analytics U54.
The ST-Analytics U54 center is populated by leading scientists at the ISB, the UCLA Geffen School of Medicine,
and Yale, and is comprised of two research projects and two research cores, with each project integrating both
state-of-the-art experimentation and computational work. This structure is further designed to bring together the
scientific, experimental, and computational and administrative resources to develop a data base that captures
the kinetics of lead-in monotherapy tumor priming, and apply that data base to the development of predictive in
silico models that can inform the design of such targeted inhibitor – immunotherapy sequence combinations for
clinical trials. This requires close integration and cycles of iteration between of state-of-the-art experimentation,
leading edge computation, and realistic disease models, continuously calibrated through the analysis of highly
relevant, biopsied patient tumors. The resulting science also provides exciting opportunities for high impact
STEM outreach. We propose to act on those opportunities by leveraging a long-standing systems education
outreach program at ISB that already has impacted K-12 STEM education in all 50 states, and places an
emphasis on those communities that have been historically under-represented in STEM.
项目总体概要
拟议的 U54 计划用于指导序贯靶向抑制剂的时空肿瘤分析——
免疫疗法组合(ST-Analytics)旨在开发最新的概念进展,
靶向抑制剂+癌症免疫疗法(IT)联合治疗可能会显着提高患者的治疗效果
如果这些治疗按顺序而不是同时进行,就会受益。回顾性分析
临床数据与使用小鼠黑色素瘤同基因模型的体内治疗模型相结合,强烈
支持这个概念。事实上,在黑色素瘤中出现的情况是,免疫因素可以发挥强大的作用
在驱动 MAPK 抑制剂 (MAPKi) 治疗耐药性中的作用,并导致免疫检查点阻断 (ICB)
当根除原发肿瘤和远端转移瘤(包括脑转移瘤)时,可以“启动”根除
IT 随后与 MAPKi 相结合。这一观察结果为基于免疫的策略打开了大门,例如
如 ICB 或过继细胞疗法 (ACT),作为序贯组合药物以预防 MAPKi 耐药。
然而,这个概念引入了许多新的变量,包括剂量、顺序和时间。这个可以
使得能够产生具有统计学意义的结果的临床试验的设计和执行变得不切实际。这
是我们在提议的 ST-Analytics U54 中解决的科学和转化问题。
ST-Analytics U54 中心由 ISB、加州大学洛杉矶分校格芬医学院、
和耶鲁大学,由两个研究项目和两个研究核心组成,每个项目都整合了
最先进的实验和计算工作。该结构进一步设计为将
科学、实验、计算和管理资源,以开发一个捕获数据的数据库
引入单一疗法肿瘤启动的动力学,并将该数据库应用于预测性肿瘤的开发
计算机模型可以为此类靶向抑制剂的设计提供信息 - 免疫治疗序列组合
临床试验。这需要最先进的实验之间的紧密集成和迭代周期,
领先的计算和现实的疾病模型,通过高度的分析不断校准
相关的、活检的患者肿瘤。由此产生的科学也为高影响力提供了令人兴奋的机会
STEM 外展。我们建议通过利用长期的系统教育来抓住这些机会
ISB 的外展计划已经影响了所有 50 个州的 K-12 STEM 教育,并在
重点关注那些历来在 STEM 领域代表性不足的社区。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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James R. Heath其他文献
Correction: Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19
- DOI:
10.1186/s13073-023-01278-0 - 发表时间:
2024-01-06 - 期刊:
- 影响因子:11.200
- 作者:
Daniela Matuozzo;Estelle Talouarn;Astrid Marchal;Peng Zhang;Jeremy Manry;Yoann Seeleuthner;Yu Zhang;Alexandre Bolze;Matthieu Chaldebas;Baptiste Milisavljevic;Adrian Gervais;Paul Bastard;Takaki Asano;Lucy Bizien;Federica Barzaghi;Hassan Abolhassani;Ahmad Abou Tayoun;Alessandro Aiuti;Ilad Alavi Darazam;Luis M. Allende;Rebeca Alonso-Arias;Andrés Augusto Arias;Gokhan Aytekin;Peter Bergman;Simone Bondesan;Yenan T. Bryceson;Ingrid G. Bustos;Oscar Cabrera-Marante;Sheila Carcel;Paola Carrera;Giorgio Casari;Khalil Chaïbi;Roger Colobran;Antonio Condino-Neto;Laura E. Covill;Ottavia M. Delmonte;Loubna El Zein;Carlos Flores;Peter K. Gregersen;Marta Gut;Filomeen Haerynck;Rabih Halwani;Selda Hancerli;Lennart Hammarström;Nevin Hatipoğlu;Adem Karbuz;Sevgi Keles;Christèle Kyheng;Rafael Leon-Lopez;Jose Luis Franco;Davood Mansouri;Javier Martinez-Picado;Ozge Metin Akcan;Isabelle Migeotte;Pierre-Emmanuel Morange;Guillaume Morelle;Andrea Martin-Nalda;Giuseppe Novelli;Antonio Novelli;Tayfun Ozcelik;Figen Palabiyik;Qiang Pan-Hammarström;Rebeca Pérez de Diego;Laura Planas-Serra;Daniel E. Pleguezuelo;Carolina Prando;Aurora Pujol;Luis Felipe Reyes;Jacques G. Rivière;Carlos Rodriguez-Gallego;Julian Rojas;Patrizia Rovere-Querini;Agatha Schlüter;Mohammad Shahrooei;Ali Sobh;Pere Soler-Palacin;Yacine Tandjaoui-Lambiotte;Imran Tipu;Cristina Tresoldi;Jesus Troya;Diederik van de Beek;Mayana Zatz;Pawel Zawadzki;Saleh Zaid Al-Muhsen;Mohammed Faraj Alosaimi;Fahad M. Alsohime;Hagit Baris-Feldman;Manish J. Butte;Stefan N. Constantinescu;Megan A. Cooper;Clifton L. Dalgard;Jacques Fellay;James R. Heath;Yu-Lung Lau;Richard P. Lifton;Tom Maniatis;Trine H. Mogensen;Horst von Bernuth;Alban Lermine;Michel Vidaud;Anne Boland;Jean-François Deleuze;Robert Nussbaum;Amanda Kahn-Kirby;France Mentre;Sarah Tubiana;Guy Gorochov;Florence Tubach;Pierre Hausfater;Isabelle Meyts;Shen-Ying Zhang;Anne Puel;Luigi D. Notarangelo;Stephanie Boisson-Dupuis;Helen C. Su;Bertrand Boisson;Emmanuelle Jouanguy;Jean-Laurent Casanova;Qian Zhang;Laurent Abel;Aurélie Cobat - 通讯作者:
Aurélie Cobat
C60's smallest cousin
C60 的最小“亲戚”
- DOI:
10.1038/31579 - 发表时间:
1998-06-25 - 期刊:
- 影响因子:48.500
- 作者:
James R. Heath - 通讯作者:
James R. Heath
Protein Catalyzed Capture (PCC) Agents for Antigen Targeting.
用于抗原靶向的蛋白质催化捕获 (PCC) 试剂。
- DOI:
- 发表时间:
2022 - 期刊:
- 影响因子:0
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Planar Patch-Clamp Electrodes for Single Cell and Neural Network Studies
- DOI:
10.1016/j.bpj.2009.12.3287 - 发表时间:
2010-01-01 - 期刊:
- 影响因子:
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Stereochemical engineering of a peptide macrocycle allosteric inhibitor of phospho-Akt2 controls cell penetration by fine-tuning macrocycle-cell membrane interactions
磷酸 Akt2 肽大环变构抑制剂的立体化学工程通过微调大环 - 细胞膜相互作用来控制细胞渗透
- DOI:
10.26434/chemrxiv-2021-kldh7 - 发表时间:
2021 - 期刊:
- 影响因子:5.9
- 作者:
Arundhati Nag;A. Mafi;Samir R Das;Mary Beth Yu;Belen Alvarez;W. Goddard;James R. Heath - 通讯作者:
James R. Heath
James R. Heath的其他文献
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{{ truncateString('James R. Heath', 18)}}的其他基金
Spatiotemporal Tumor Analytics for Guiding Sequential Targeted-Inhibitor: Immunotherapy Combinations (ST-Analytics)
用于指导序贯靶向抑制剂的时空肿瘤分析:免疫治疗组合(ST-Analytics)
- 批准号:
10708901 - 财政年份:2022
- 资助金额:
$ 270.26万 - 项目类别:
PROJECT 1: TIME-Based Spatiotemporal Cancer Immunograms Predictive for Immunotherapy-Targeted Therapy Sequential Combinations
项目 1:基于时间的时空癌症免疫图预测免疫治疗靶向治疗顺序组合
- 批准号:
10907268 - 财政年份:2022
- 资助金额:
$ 270.26万 - 项目类别:
PROJECT 1: TIME-Based Spatiotemporal Cancer Immunograms Predictive for Immunotherapy-Targeted Therapy Sequential Combinations
项目 1:基于时间的时空癌症免疫图预测免疫治疗靶向治疗顺序组合
- 批准号:
10526103 - 财政年份:2022
- 资助金额:
$ 270.26万 - 项目类别:
PROJECT 1: TIME-Based Spatiotemporal Cancer Immunograms Predictive for Immunotherapy-Targeted Therapy Sequential Combinations
项目 1:基于时间的时空癌症免疫图预测免疫治疗靶向治疗顺序组合
- 批准号:
10708924 - 财政年份:2022
- 资助金额:
$ 270.26万 - 项目类别:
Data-driven Patient-Specific Agent Based Models of Metastatic Melanoma for Immunotherapy Response Prediction
用于免疫治疗反应预测的数据驱动的基于患者特异性药物的转移性黑色素瘤模型
- 批准号:
10831325 - 财政年份:2022
- 资助金额:
$ 270.26万 - 项目类别:
Nano and biomolecular engineered technologies for neoantigen-specific T cell capture and characterization
用于新抗原特异性 T 细胞捕获和表征的纳米和生物分子工程技术
- 批准号:
10297588 - 财政年份:2021
- 资助金额:
$ 270.26万 - 项目类别:
Nano and biomolecular engineered technologies for neoantigen-specific T cell capture and characterization
用于新抗原特异性 T 细胞捕获和表征的纳米和生物分子工程技术
- 批准号:
10489832 - 财政年份:2021
- 资助金额:
$ 270.26万 - 项目类别:
Nano and biomolecular engineered technologies for neoantigen-specific T cell capture and characterization
用于新抗原特异性 T 细胞捕获和表征的纳米和生物分子工程技术
- 批准号:
10673935 - 财政年份:2021
- 资助金额:
$ 270.26万 - 项目类别:














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