Molecular Targeted Radionuclide Therapy for Tumor Immunomodulation and Enhancing Immunotherapy Response
Molecular Targeted Radionuclide Therapy for Tumor Immunomodulation and Enhancing Immunotherapy Response
批准号:
10416044
负责人:
Zachary Scott Morris
金额:
$245.38万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-09-14 至 2025-05-31
关键词:
Advisory CommitteesAgeAntigensAntitumor ResponseAwardBioinformaticsBiometryCancer PatientCanis familiarisCategoriesCellsClonal ExpansionCompanionsComplementComplexCore FacilityDataDevelopmentDiseaseDisseminated Malignant NeoplasmDistantDoseDose-RateEnsureExternal Beam Radiation TherapyFDA approvedFunding MechanismsImageImmuneImmune ToleranceImmune checkpoint inhibitorImmune systemImmunologicsImmunosuppressionImmunotherapyIndustry CollaborationInterferon Type IInvestigational TherapiesKnowledgeLeadershipLigandsLocationLow Dose RadiationMalignant NeoplasmsMediatingMethodsMicroscopicModalityModelingMolecular TargetMusMutationOncologyPatientsPharmaceutical PreparationsPredispositionProcessProgram Research Project GrantsProtocols documentationRadiationRadiation therapyRadiochemistryRadioisotopesRadiolabeledRadionuclide therapyRadiopharmaceuticalsRegimenResearchResourcesRoleSafetyServicesSiteT cell responseT-Cell ActivationT-LymphocyteTestingTherapeuticToxic effectTumor ImmunityTumor-infiltrating immune cellsVaccinesVeinsWhole-Body Irradiationadaptive immunityanti-tumor immune responseantigen-specific T cellsburden of illnesscancer immunotherapycancer therapycancer typeclinical translationclinically relevantcurative treatmentscytokinedosimetryexhaustionexperienceimmunogenicityimmunoregulationimprovedin situ vaccinein vivomultidisciplinaryneoantigensneoplastic cellnext generationnovelprogramsreceptorresearch clinical testingresearch facilityresponsesuccesstumortumor microenvironmentvector
中文摘要
项目总结--总体
该计划项目赠款将建立完全整合的跨学科研究和核心计划
对于从根本上理解两者之间复杂的相互作用所必需的设施
肿瘤治疗中迅速崛起的领域:1)靶向放射性核素治疗(TRT)和2)免疫治疗。我们的
首要目标是发展对免疫调节能力的详细的机械理解。
并评估和比较这些药物诱导合作治疗的能力
与免疫疗法相结合的相互作用。为了实现这一目标,我们将采用具有代表性的各种
TRT试剂在体内使用临床相关的小鼠肿瘤模型和伴犬进行放射治疗
会自发地患上癌症。我们将确定每个放射性核素的精确剂量学-,TRT
载体和肿瘤模型。这将促进剂量、剂量率和剂量范围依赖效应的研究。
宿主免疫系统,肿瘤浸润性免疫细胞,肿瘤微环境中细胞因子的表达,
肿瘤细胞的免疫敏感性、免疫抑制机制及抗原的研究进展
特异性适应性免疫。我们将通过测试广泛的
假设,通过调节肿瘤免疫耐受和所有肿瘤部位的功能免疫原性,TRT
会增加对某些癌症免疫疗法的反应。我们将在以下计划项目中对此进行测试:
项目1:用于剂量学指导的免疫调节的新型TRT
项目2:TRT增强肿瘤细胞免疫敏感性和对免疫检查点抑制剂的反应
项目3:将TRT与局部原位疫苗相结合以克服肿瘤中的免疫抑制
微环境与增强T细胞反应
项目4:使用肿瘤特异性疫苗进行TRT以刺激和扩大T细胞激活
这些高度整合的项目不仅将受益于彼此产生的方法和结果,
但他们还将直接受益于四个基本核心设施的专业知识和服务:1)高级
成像和剂量学核心(AIDC),2)放射性药物和放射化学核心(RPRC),3)生物统计学
和生物信息学核心(BBC),以及4)管理核心。与之相辅相成的是健全的制度设施。
这将使我们能够成功完成拟议的研究。我们的多学科团队汇集了
为实现我们提出的目标而调动这些资源所需的广泛专业知识。这些努力将
进一步受益于强有力的机构配对支持、强大的内部咨询委员会的领导,
宝贵的行业合作,以及外部咨询委员会的专业知识。因为迫在眉睫
我们的结果具有广阔的临床转化潜力,这些研究预示着改善治疗的机会
任何肿瘤患者,无论癌症类型、肿瘤部位、疾病负担或患者年龄。
英文摘要
PROJECT SUMMARY – OVERALL
This Program Project grant will establish the fully integrated interdisciplinary programs of research and core
facilities that are necessary to develop a fundamental understanding of the complex interplay between two
rapidly emerging fields in cancer therapy: 1) targeted radionuclide therapy (TRT) and 2) immunotherapy. Our
overarching objectives are to develop a detailed mechanistic understanding of the immunomodulatory capacity
of TRT agents and to evaluate and compare the ability of these agents to elicit cooperative therapeutic
interactions in combination with immunotherapies. To achieve this, we will employ a representative variety of
TRT agents to deliver radiation in vivo using clinically relevant murine tumor models and companion canines that
have spontaneously developed cancers. We will determine the precise dosimetry for each radionuclide-, TRT
vector-, and tumor model. This will facilitate studies of dose-, dose-rate-, and dose-range-dependent effects on
the host immune system, tumor infiltrating immune cells, cytokine expression in the tumor microenvironment,
immune susceptibility of tumor cells, mechanisms of immune suppression, and the development of antigen-
specific adaptive immunity. We will determine the functional consequences of these effects by testing the broad
hypothesis that, by modulating tumor immune tolerance and functional immunogenicity at all tumor sites, TRT
will increase response to certain cancer immunotherapies. We will test this in the following Program Projects:
Project 1: Novel TRTs for Dosimetry-Guided Immunomodulation
Project 2: TRT to enhance tumor cell immune susceptibility and response to immune checkpoint inhibitors
Project 3: Combining TRT with a localized in situ vaccine to overcome immune suppression in the tumor
microenvironment and augment T cell responses
Project 4: TRT with tumor-specific vaccine to stimulate and expand T-cell activation
These highly integrated projects will not only benefit from the methods and findings generated in one another,
but they also will directly benefit from the expertise and service of four essential Core Facilities: 1) Advanced
imaging and dosimetry core (AIDC), 2) Radiopharmaceutical and radiochemistry core (RPRC), 3) Biostatistics
and bioinformatics core (BBC), and 4) Administrative core. Complementing these are robust institutional facilities
that will enable successful completion of our proposed studies. Our multidisciplinary team brings together the
broad expertise needed to mobilize these resources in pursuit of our proposed objectives. These efforts will
further benefit from robust institutional matching support, leadership of a strong Internal Advisory Committee,
invaluable Industry collaborations, and expertise of an External Advisory Board. Because of the immediate and
broad potential for clinical translation of our results, these studies portend an opportunity to improve the treatment
of any oncology patient, regardless of cancer type, tumor location, burden of disease, or patient age.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Administrative-Core-001
-
批准号:10707579
-
项目类别:
-
资助金额:$7.0万
-
财政年份:2022
-
负责人:Zachary Scott Morris
-
依托单位:
Molecular Targeted Radionuclide Therapy for Tumor Immunomodulation and Enhancing Immunotherapy Response
-
批准号:10737774
-
项目类别:
-
资助金额:$7.45万
-
财政年份:2020
-
负责人:Zachary Scott Morris
-
依托单位:
Administrative-Core-001
-
批准号:10895779
-
项目类别:
-
资助金额:$7.45万
-
财政年份:2020
-
负责人:Zachary Scott Morris
-
依托单位:
Molecular Targeted Radionuclide Therapy to Enhance Tumor Cell Susceptibility and Response to Immune Checkpoint Inhibition
-
批准号:10672926
-
项目类别:
-
资助金额:$38.43万
-
财政年份:2020
-
负责人:Zachary Scott Morris
-
依托单位:
Molecular Targeted Radionuclide Therapy for Tumor Immunomodulation and Enhancing Immunotherapy Response
-
批准号:10672912
-
项目类别:
-
资助金额:$245.27万
-
财政年份:2020
-
负责人:Zachary Scott Morris
-
依托单位:
Molecular Targeted Radionuclide Therapy to Enhance Tumor Cell Susceptibility and Response to Immune Checkpoint Inhibition
-
批准号:10263247
-
项目类别:
-
资助金额:$39.2万
-
财政年份:2020
-
负责人:Zachary Scott Morris
-
依托单位:
Molecular Targeted Radionuclide Therapy for Tumor Immunomodulation and Enhancing Immunotherapy Response
-
批准号:10533542
-
项目类别:
-
资助金额:$7.0万
-
财政年份:2020
-
负责人:Zachary Scott Morris
-
依托单位:
Molecular Targeted Radionuclide Therapy to Enhance Tumor Cell Susceptibility and Response to Immune Checkpoint Inhibition
-
批准号:10024882
-
项目类别:
-
资助金额:$39.09万
-
财政年份:2020
-
负责人:Zachary Scott Morris
-
依托单位:
Molecular Targeted Radionuclide Therapy to Enhance Tumor Cell Susceptibility and Response to Immune Checkpoint Inhibition
-
批准号:10416046
-
项目类别:
-
资助金额:$38.43万
-
财政年份:2020
-
负责人:Zachary Scott Morris
-
依托单位:
Molecular Targeted Radionuclide Therapy for Tumor Immunomodulation and Enhancing Immunotherapy Response
-
批准号:10024878
-
项目类别:
-
资助金额:$249.09万
-
财政年份:2020
-
负责人:Zachary Scott Morris
-
依托单位:
Molecular Targeted Radionuclide Therapy for Tumor Immunomodulation and Enhancing Immunotherapy Response
-
批准号:10263244
-
项目类别:
-
资助金额:$250.85万
-
财政年份:2020
-
负责人:Zachary Scott Morris
-
依托单位:
Immunomodulation of the Tumor Microenvironment with Molecular Targeted Radiotherapy to Facilitate an Adaptive Anti-Tumor Immune Response to Combined Modality Immunotherapies
-
批准号:10459937
-
项目类别:
-
资助金额:$16.52万
-
财政年份:2018
-
负责人:Zachary Scott Morris
-
依托单位:
Immunomodulation of the Tumor Microenvironment with Molecular Targeted Radiotherapy to Facilitate an Adaptive Anti-Tumor Immune Response to Combined Modality Immunotherapies
-
批准号:10007582
-
项目类别:
-
资助金额:$76.5万
-
财政年份:2018
-
负责人:Zachary Scott Morris
-
依托单位:
Immunomodulation of the Tumor Microenvironment with Molecular Targeted Radiotherapy to Facilitate an Adaptive Anti-Tumor Immune Response to Combined Modality Immunotherapies
-
批准号:9788087
-
项目类别:
-
资助金额:$76.5万
-
财政年份:2018
-
负责人:Zachary Scott Morris
-
依托单位:
Immunomodulation of the Tumor Microenvironment with Molecular Targeted Radiotherapy to Facilitate an Adaptive Anti-Tumor Immune Response to Combined Modality Immunotherapies
-
批准号:10251058
-
项目类别:
-
资助金额:$76.5万
-
财政年份:2018
-
负责人:Zachary Scott Morris
-
依托单位:
Combining Radiation and Tumor-specific AntIbody Therapies to Elicit in Situ Tumor Vaccination
-
批准号:9351733
-
项目类别:
-
资助金额:$38.25万
-
财政年份:2017
-
负责人:Zachary Scott Morris
-
依托单位:
Combining Radiation and Tumor-specific AntIbody Therapies to Elicit in Situ Tumor Vaccination
-
批准号:10247598
-
项目类别:
-
资助金额:$38.25万
-
财政年份:2017
-
负责人:Zachary Scott Morris
-
依托单位:
Project 1: Priming and propagating immunity against head and neck cancer using targeted radionuclide therapy
-
批准号:10673970
-
项目类别:
-
资助金额:$36.49万
-
财政年份:2016
-
负责人:Zachary Scott Morris
-
依托单位:
Project 1: Priming and propagating immunity against head and neck cancer using targeted radionuclide therapy
-
批准号:10495293
-
项目类别:
-
资助金额:$36.74万
-
财政年份:2016
-
负责人:Zachary Scott Morris
-
依托单位:
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