Actively engaging NK cells during virotherapy to induce neoantigen-specific antitumor immunity
在病毒治疗过程中积极参与 NK 细胞诱导新抗原特异性抗肿瘤免疫
基本信息
- 批准号:10646382
- 负责人:
- 金额:$ 37.66万
- 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:2022-06-15 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:Activated Natural Killer CellCD8 receptorCD8-Positive T-LymphocytesCell MaturationClinicClinicalColon CarcinomaCross PresentationDataDendritic CellsDevelopmentDiseaseERBB2 geneEffectivenessEnsureEpidermal Growth Factor ReceptorEventFCGR3B geneFutureHerpesvirus 1HomingHuman Herpesvirus 2ImmuneImmune systemImmunityIn VitroInfiltrationInjectionsInterleukin-2MacrophageMalignant NeoplasmsMalignant neoplasm of lungMeasurableMediatingNatural Killer CellsNoduleOncolyticOncolytic virusesOutcomePatientsProceduresReceptor ActivationRouteSeriesSimplexvirusSiteSolid NeoplasmSystemSystemic diseaseT-LymphocyteTestingTherapeuticTherapeutic EffectTranslatingTreatment EfficacyTumor AntigensTumor ImmunityVirotherapyVirusXCL1 geneantigen-specific T cellsantitumor effectarmcancer immunotherapycell killingchemokineclinical applicationclinical practicecombinatorialdesigndraining lymph nodeeffective therapyexperimental studyimprovedin vivoindividual patientjoint destructionmelanomamigrationneoantigensneoplastic cellneutralizing antibodynovelnovel strategiesoncolysisoncolytic virotherapyreceptorsystemic barriertumortumor microenvironment
项目摘要
PROJECT SUMMARY
Significant progress in recent years on the development of oncolytic virotherapy has led to the FDA approval
of a type I herpes simplex virus (HSV-1) based oncolytic virus (Talimogene Laherparepvec or T-VEC) for the
treatment of advanced melanoma. However, it has become increasingly clear that there is a need to further
improve the current version of OV for a better clinical benefit. Our lab has constructed a HSV-2 based oncolytic
virus - FusOn-H2, the first of its kind, by a novel mechanism. Our recent studies showed that arming FusOn-
H2 with a chimeric NK engager (C-NK-E) that can engage the infiltrated natural killer (NK) cells with tumor
cells could significantly enhance the effectiveness of this virotherapy. Moreover, we observed that tumor
destruction by the joint effect of the direct oncolysis and the engaged NK cells led to a measurable elicitation
of neoantigen-specific antitumor immunity. Based on these exciting findings, we propose to develop a three-
pronged strategy to enhance the antitumor efficacy of FusOn-H2 via combinatorial immuno-oncolytic
virotherapy (IOV). The antitumor activities from this strategic three-pronged IOV come in waves in a sequential
order. The first wave comes immediately and it derives primarily from the virus-mediated direct oncolysis. The
second wave comes from the NK-mediated tumor cell killing enabled jointly by the virotherapy-trigged NK cell
infiltration and the released C-NK-E from the armed virus. The third wave is the outcome of a series of chain
events that ultimately result in induction and homing of neoantigen-specific T cells. Our major hypothesis is
that this three-pronged strategy will act in a consequential and concerted way to significantly enhance the
therapeutic efficacy of this IOV. We have designed three specific aims to test our major hypothesis. In Aim 1,
we will dissect the mechanism of C-NK-E-armed virus in generating neoantigen-specific immunity and to
design additional strategies to further potentiate this effect. Neoantigens are attractive targets for cancer
immunotherapy, but there lacks a simple and effective way of delivering them. In principle, OV offers a simple
means to release these neoantigens in individual patients, and our proposed strategy will ensure their efficient
and timely presentation to the host’s immune system without the need for additional procedures. In Aim 2, we
will investigate if combining C-NK-Es that engage two different activation receptors can further potentiate the
NK cell killing and neoantigen-specific T cell immunity. In Aim 3, we will demonstrate that the three-pronged
IOV can produce an efficient therapeutic effect against metastatic diseases by the systemic delivery route.
We have recently developed novel strategies to overcome key obstacles for systemic delivery - the rapid
clearance by the macrophage system and the neutralizing antibodies. We hypothesize that the combination
of the high potency of the three-pronged IOV with the improved systemic delivery will lead to effective
treatment of metastatic diseases. Our studies in this proposal thus overcome the two major hurdles hindering
OV - the relatively weak therapeutic activity and lack of means for effective systemic delivery, and the
developed strategy can be translated into the clinic in the near future.
项目摘要
近年来,溶瘤病毒疗法的发展取得了重大进展,已获得FDA批准
- 基于I型单纯疱疹病毒(HSV-1)的溶瘤病毒(Laherparepvec或T-VEC),
治疗晚期黑色素瘤然而,越来越清楚的是,需要进一步
改进当前版本的OV,以获得更好的临床受益。本实验室构建了一种基于HSV-2的溶瘤病毒,
病毒- FusOn-H2,第一个通过一种新的机制。我们最近的研究表明,武装扶桑-
H2与嵌合NK细胞结合剂(C-NK-E),其可以使浸润的自然杀伤(NK)细胞与肿瘤细胞结合。
细胞可以显著增强这种病毒疗法的有效性。此外,我们观察到,
直接溶瘤和参与的NK细胞的联合作用的破坏导致了可测量的激发
新抗原特异性抗肿瘤免疫。基于这些令人兴奋的发现,我们建议开发一个三-
通过组合免疫溶瘤增强FusOn-H2的抗肿瘤功效的多管齐下的策略
病毒疗法(IOV)。这种战略性三管齐下的IOV的抗肿瘤活性依次呈波浪状
秩序第一波立即到来,它主要来自病毒介导的直接溶瘤。的
第二波来自NK介导的肿瘤细胞杀伤,由病毒治疗激活的NK细胞共同实现
以及武装病毒释放的C-NK-E第三次浪潮是一系列连锁反应的结果
最终导致新抗原特异性T细胞的诱导和归巢的事件。我们的主要假设是
这一三管齐下的战略将以相应和协调一致的方式发挥作用,
这种IOV的治疗效果。我们设计了三个具体目标来检验我们的主要假设。在目标1中,
我们将剖析C-NK-E武装病毒产生新抗原特异性免疫的机制,并
设计额外的策略来进一步加强这种效果。新抗原是癌症的有吸引力的靶点
免疫疗法,但缺乏一个简单而有效的方式来提供它们。原则上,OV提供了一个简单的
意味着在个体患者中释放这些新抗原,我们提出的策略将确保它们的有效性。
并及时呈递给宿主的免疫系统,而不需要额外的程序。在目标2中,
将研究结合两种不同激活受体的C-NK-Es是否能进一步增强
NK细胞杀伤和新抗原特异性T细胞免疫。在目标3中,我们将证明三管齐下
IOV可以通过全身递送途径产生针对转移性疾病的有效治疗效果。
我们最近制定了新的战略,以克服系统交付的关键障碍-快速
通过巨噬细胞系统和中和抗体清除。我们假设
具有改善的全身递送的三管齐下的IOV的高效力将导致有效的
转移性疾病的治疗。因此,我们在该提案中的研究克服了阻碍
OV -治疗活性相对较弱,缺乏有效的全身递送手段,
制定的战略可以在不久的将来转化为临床。
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 }}
SHAUN XIAOLIU ZHANG其他文献
SHAUN XIAOLIU ZHANG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('SHAUN XIAOLIU ZHANG', 18)}}的其他基金
Actively engaging NK cells during virotherapy to induce neoantigen-specific antitumor immunity
在病毒治疗过程中积极参与 NK 细胞诱导新抗原特异性抗肿瘤免疫
- 批准号:
10405290 - 财政年份:2022
- 资助金额:
$ 37.66万 - 项目类别:
Reconstruction of an oncolytic HSV vector for systemic delivery
重建用于全身递送的溶瘤 HSV 载体
- 批准号:
9891964 - 财政年份:2016
- 资助金额:
$ 37.66万 - 项目类别:
Reconstruction of an oncolytic HSV vector for systemic delivery
重建用于全身递送的溶瘤 HSV 载体
- 批准号:
9076933 - 财政年份:2016
- 资助金额:
$ 37.66万 - 项目类别:
Reconstruction of an oncolytic HSV vector for systemic delivery
重建用于全身递送的溶瘤 HSV 载体
- 批准号:
9265809 - 财政年份:2016
- 资助金额:
$ 37.66万 - 项目类别:
Novel Strategies to Potentiate a Ras-targeted Oncolytic Herpes Simplex Virus
增强 Ras 靶向溶瘤单纯疱疹病毒的新策略
- 批准号:
9033087 - 财政年份:2015
- 资助金额:
$ 37.66万 - 项目类别:
Development of an HSV-2 based oncolytic virus
基于 HSV-2 的溶瘤病毒的开发
- 批准号:
8196839 - 财政年份:2008
- 资助金额:
$ 37.66万 - 项目类别:
Development of an HSV-2 based oncolytic virus
基于 HSV-2 的溶瘤病毒的开发
- 批准号:
8391742 - 财政年份:2008
- 资助金额:
$ 37.66万 - 项目类别:
Development of an HSV-2 based oncolytic virus
基于 HSV-2 的溶瘤病毒的开发
- 批准号:
8528758 - 财政年份:2008
- 资助金额:
$ 37.66万 - 项目类别:
Development of an HSV-2 based oncolytic virus
基于 HSV-2 的溶瘤病毒的开发
- 批准号:
7579620 - 财政年份:2008
- 资助金额:
$ 37.66万 - 项目类别:
Development of an HSV-2 based oncolytic virus
基于 HSV-2 的溶瘤病毒的开发
- 批准号:
7925372 - 财政年份:2008
- 资助金额:
$ 37.66万 - 项目类别: