Targeted radionuclide therapy for tumor immunomodulation and enhancing immunotherapy response
靶向放射性核素治疗肿瘤免疫调节和增强免疫治疗反应
基本信息
- 批准号:10387310
- 负责人:
- 金额:$ 3.72万
- 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:2022-01-01 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:90YApplications GrantsCD8-Positive T-LymphocytesCancer PatientCanis familiarisCellsChelating AgentsClinicalClinical TrialsCombination immunotherapyCombined Modality TherapyDataDendritic CellsDevelopmentDiseaseDisseminated Malignant NeoplasmDoseDose-LimitingExhibitsExternal Beam Radiation TherapyFoundationsGoalsHalf-LifeHead and Neck Squamous Cell CarcinomaImmuneImmune ToleranceImmune checkpoint inhibitorImmune responseImmunologicsImmunosuppressionImmunotherapeutic agentImmunotherapyIncidenceInfiltrationInterferon ActivationInterferon Type IInterferonsLigandsLinear Energy TransferLocationLymphocyteLymphopeniaMalignant NeoplasmsMetastatic toMethodsMicrometastasisMicroscopicModalityModelingMusMutationNeoplasm MetastasisOutcomePathway interactionsPatientsPositioning AttributePredispositionProductionPropertyProteinsPublic HealthRadiationRadiation therapyRadioisotopesRadionuclide therapyRecurrenceResourcesSiteSpatial DistributionStimulator of Interferon GenesSurfaceT-LymphocyteTherapeuticTissuesToxic effectTrainingTranslationsTreatment CostTreatment ProtocolsTumor ImmunityTumor-infiltrating immune cellsUniversitiesWisconsinanaloganti-CTLA4anti-PD-L1anti-tumor immune responsecancer therapycancer typecomparativeexhaustexhaustionexperimental studyimmunoregulationimprovedinsightmelanomamouse modelneoantigensneoplastic cellnovelnovel strategiesparticlephysical propertypreclinical studypreventprofessorradiation deliveryradiological imagingreceptorrecruitresearch clinical testingresponsesynergismtreatment responsetumortumor heterogeneitytumor microenvironment
项目摘要
Project Summary/Abstract
We aim to improve the cure rates for metastatic cancers. To achieve this we propose a combined modality
approach to stimulate and diversify an endogenous anti-tumor immune response at all tumor sites to recognize
and destroy tumor cells in a manner that will prevent recurrence and enable long-term cancer free survival.
Immune checkpoint inhibitors (ICI; e.g. anti-PD-L1), are a class of immunotherapies that modulate immune
tolerance of a tumor by blocking specific inhibitory receptor-ligand interactions on the surface of T cells and
thereby overcoming T cell inhibition or exhaustion. In patients with immunologically “hot” tumors, characterized
by a pre-existing but exhausted anti-tumor immune response, ICIs can restore efficacy to the anti-tumor immune
response, sometimes resulting in complete and durable tumor regression. However, ICIs have not shown clinical
benefit in the treatment of immunologically “cold” cancers that are characterized by low levels of T cell infiltrate
and low mutation burden resulting in few mutation-created neo-antigens. To overcome immunotherapy treatment
barriers posed by immunologically cold tumors, we propose to combine systemic delivery of ICIs with systemic
delivery of radiation by targeted radionuclide therapy (TRT). To date, nearly all approaches to combining
radiation and immunotherapy have used external beam radiotherapy (EBRT), which promotes tumor immune
cell infiltration through activation of type I interferon (IFN) responses. Administration of EBRT to multiple tumor
sites or to the whole body (to target radiographically occult or microscopic disease) would result in prohibitive
toxicity, including lymphopenia. TRT is a systemic method of delivering a therapeutic radionuclide to a tumor,
which poses an alternative option for delivery of immunomodulatory radiation to metastatic tumor sites without
causing immunosuppression. The Weichert lab at the University of Wisconsin-Madison has developed a novel
class of TRT, known as NM600, an alkylphosphocholine analog that is selectively taken up and retained in nearly
any tumor type in any location. Our broad hypothesis is that unique physical properties of radionuclides (e.g.
emission type, linear energy transfer, half-life, tissue range) differentially impact immunomodulation by TRT. In
this study, the immunomodulatory capacity of alpha- (225Ac) and beta- (90Y) particle emitting radionuclides will be
compared directly. In a project that builds upon the ongoing collaborative progress of the Morris and Weichert
labs, we will now determine the radionuclide-specific potency of combining TRT with immunotherapy to enhance
the immune response against immunologically cold tumors. In murine models, we will: 1) expand on preliminary
data showing potent synergy with the combination of TRT and ICI, 2) evaluate therapeutic mechanisms of TRT
and ICI using the intrinsic properties of 225Ac- and 90Y-NM600, focusing on type I IFN response activation and 3)
investigate potential enhanced tumor responses with the combination of two distinct radionuclides with ICI. The
insights and treatment regimens developed in these studies should enable rapid translation to clinical testing in
patients and potentially for any type of metastatic cancer.
项目总结/摘要
我们的目标是提高转移性癌症的治愈率。为了实现这一目标,我们提出了一种综合方式,
刺激所有肿瘤部位的内源性抗肿瘤免疫反应并使其多样化的方法,以识别
并以防止复发和实现长期无癌生存的方式破坏肿瘤细胞。
免疫检查点抑制剂(ICI;例如抗PD-L1)是一类调节免疫调节的免疫疗法。
- 通过阻断T细胞表面上的特异性抑制性受体-配体相互作用而产生的肿瘤耐受性,
从而克服T细胞抑制或耗竭。在具有免疫学“热”肿瘤的患者中,
通过预先存在但耗尽的抗肿瘤免疫应答,ICI可以恢复抗肿瘤免疫应答的功效。
反应,有时导致完全和持久的肿瘤消退。然而,ICIs尚未显示临床
有益于治疗以低水平T细胞浸润为特征的免疫学“冷”癌
和低突变负荷,导致很少的突变产生的新抗原。为了克服免疫治疗
由于免疫冷肿瘤造成的屏障,我们建议将联合收割机全身性ICI递送与全身性
通过靶向放射性核素治疗(TRT)的放射递送。到目前为止,几乎所有的结合方法
放射和免疫疗法使用外部束放射疗法(EBRT),其促进肿瘤免疫
通过激活I型干扰素(IFN)应答的细胞浸润。EBRT对多发性肿瘤的给药
部位或全身(针对放射学上的隐匿性或显微镜下疾病)将导致禁止性
毒性,包括淋巴细胞减少症。TRT是将治疗性放射性核素递送至肿瘤的全身方法,
这为将免疫调节放射递送到转移性肿瘤部位提供了一种替代选择,
导致免疫抑制。威斯康星大学麦迪逊分校的韦克特实验室开发了一种新的
TRT类,称为NM 600,是一种烷基磷酸胆碱类似物,选择性地吸收和保留在近
任何部位的任何肿瘤类型。我们广泛的假设是,放射性核素的独特物理性质(例如,
发射类型、线性能量转移、半衰期、组织范围)差异性地影响TRT的免疫调节。在
在这项研究中,α-(225 Ac)和β-(90 Y)粒子发射放射性核素的免疫调节能力将被
直接比较。在一个建立在莫里斯和韦切特正在进行的合作进展的项目中,
实验室,我们现在将确定放射性核素特异性结合TRT与免疫治疗的效力,以增强
对免疫冷肿瘤的免疫反应。在小鼠模型中,我们将:1)扩展初步的
显示TRT和ICI组合的有效协同作用的数据,2)评价TRT的治疗机制
和ICI,使用225 Ac-和90 Y-NM 600的固有特性,重点是I型IFN应答激活,和3)
研究用两种不同的放射性核素与ICI的组合潜在增强的肿瘤反应。的
这些研究中开发的见解和治疗方案应能够快速转化为临床试验,
患者和潜在的任何类型的转移性癌症。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Caroline Paula Anne Kerr其他文献
Caroline Paula Anne Kerr的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Caroline Paula Anne Kerr', 18)}}的其他基金
Targeted radionuclide therapy for tumor immunomodulation and enhancing immunotherapy response
靶向放射性核素治疗肿瘤免疫调节和增强免疫治疗反应
- 批准号:
10543064 - 财政年份:2022
- 资助金额:
$ 3.72万 - 项目类别: