STING agonist-expressing BCG for bladder cancer
表达 STING 激动剂的 BCG 用于治疗膀胱癌
基本信息
- 批准号:10668536
- 负责人:
- 金额:$ 109.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAgonistAmericanAnimalsAntibiotic ResistanceAntibioticsAntitumor ResponseAttenuated VaccinesAutophagocytosisBCG LiveBacillus Calmette-Guerin TherapyBacteremiaBacteriaBacterial VaccinesBiological AssayCOVID-19Cancer PatientCarcinoma in SituCell ReprogrammingCellsCessation of lifeClinical ResearchClinical TrialsComplementDNA cassetteDataDevelopmentDiagnosisDiseaseDoseDrug KineticsEffectivenessEnsureEpigenetic ProcessEquationExcisionFermentationGenerationsGenesGeneticGrowthIRF3 geneImmuneImmunityImmunotherapyIn VitroIndividualInfectionInflammatoryInflammatory Response PathwayInterferonsLeftLegal patentLightLiquid substanceMacrophageMalignant NeoplasmsMalignant neoplasm of urinary bladderMethodsModelingMucous MembraneMusMyeloid CellsNewly DiagnosedPantothenic AcidPathway interactionsPatientsPhagocytosisPhasePhenotypePlasmidsPositioning AttributePreparationProductionPromoter RegionsRecombinantsRecurrenceRecurrent diseaseRelapseResistanceResourcesReverse Transcriptase Polymerase Chain ReactionSafetyStandardizationStimulator of Interferon GenesSubmucosaTherapeuticTimeTrainingTransurethral ResectionTreatment CostTumor ImmunityViral PhysiologyWorkanti-tumor immune responseantitumor effectauxotrophycancer immunotherapyclinical efficacycytokineeffector T cellhead-to-head comparisonimprovedintravesicalmanufacturemenmetabolomicsmicrobialmicroorganismnext generationnon-muscle invasive bladder cancernovelnovel therapeuticsoverexpressionphase 3 studypreventprogression riskprototyperecruitresistance genesafety studysmall moleculestandard of caresuccesstumortumor eradicationtumor microenvironment
项目摘要
Abstract
More than 80,000 Americans are diagnosed with bladder cancer each year, and more than 17,000 die from the
disease. Approximately 75% of new bladder cancer patients present with non-muscle invasive bladder cancer
(NMIBC). Not only is NMIBC associated with high recurrence rates (>50%) and risk of progression, but 30% of
patients are unresponsive to the standard of care treatment: transurethral resection with intravesical Bacillus
Calmette-Guérin (BCG) instillation, the only approved microbial therapeutic for cancer. These individuals are left
with limited therapeutic options. While there have been efforts to generate improved recombinant BCG (rBCG)
strains, such efforts have not yet yielded demonstrable improvement over traditional BCG. With very few
advances in treatment over the past two decades for early stage disease and a limited pipeline of therapeutics
in development, there is a major unmet need for improved treatments for NMIBC. To address this need,
OncoSTING is developing OS-101, a breakthrough rBCG immunotherapy that overexpresses a potent Stimulator
of IFN Genes (STING) agonist. STING agonists potentiate anti-tumor responses through the innate immune
STING-IRF3-NF-κB pathway. While other companies are developing small molecule STING agonists as novel
anti-cancer immunotherapies, OncoSTING is the only company developing STING agonist delivery by a
live bacterial vaccine—BCG—that itself is a well-known immunotherapy already in use for the treatment
of bladder cancer, thus offering the benefits of both. Because it is a live bacteria, OS-101 allows for
continuous and prolonged delivery of the STING agonist to the tumor microenvironment. Compared with wild
type BCG, OS-101 demonstrates superior antitumor efficacy in models of NMIBC; more potent pro-inflammatory
cytokine responses; greater myeloid cell reprogramming, producing an M1 shift with enhanced
phagocytosis/autophagy; more pronounced epigenetic changes in key cytokine promoter regions; and
metabolomic changes favoring antitumor immunity. In Phase I of this Fast Track project, OncoSTING will create
a next-generation, antibiotic resistance-free version of 0S-101 using a novel, patent-pending method. The current
rBCG prototype, OS-101, relies on a bacterial plasmid that is maintained using an antibiotic resistance cassette.
However, Phase 3 studies will require the removal of antibiotic resistance genes. The efficacy of the new
construct, called OS-151, will then be confirmed in four relevant bioassays. In Phase II, OS-151 will be compared
to ADU-S100 (Aduro's small molecule STING agonist which is in current clinical trials) and wild type BCG in
relevant models of bladder cancer. Pre-IND, pharmacokinetic and safety studies of OS-151 will also be
conducted, and optimization work will ensure production of OS-151 at scale. Finally, tumor repetitive dosing
studies and rechallenge studies will be carried out in mouse syngeneic models. Once approved, OS-151 will first
be used to treat patients with BCG-unresponsive NMIBC, with potential to expand to other cancer indications.
摘要
每年有超过8万美国人被诊断出患有膀胱癌,超过1.7万人死于膀胱癌
疾病。约75%的新发膀胱癌患者存在非肌肉浸润性膀胱癌
(NMIBC)。NMIBC不仅与高复发率(50%)和进展风险有关,而且30%的
患者对标准的护理治疗无反应:经尿道膀胱内杆菌电切术
卡介苗(BCG)滴注,是唯一被批准的癌症微生物疗法。这些人被留了下来
治疗选择有限。虽然一直在努力产生改良的重组卡介苗(RBCG)
但是,与传统的卡介苗相比,这些努力尚未产生明显的改善。只有很少的
过去二十年来早期疾病的治疗进展和有限的治疗方法
在发展中,对改善NMIBC治疗的主要需求尚未得到满足。为了满足这一需求,
OncoSTING正在开发OS-101,这是一种突破性的rBCG免疫疗法,过度表达一种有效的刺激因子
干扰素基因(刺激性)激动剂。STING激动剂通过先天免疫增强抗肿瘤反应
STING-IRF3-NF-κB途径。而其他公司正在开发小分子刺痛激动剂作为新的
抗癌免疫疗法,OncoSTING是唯一一家通过
活细菌疫苗-卡介苗-本身就是一种众所周知的免疫疗法,已经在治疗中使用
对膀胱癌的治疗,因此提供了两者的好处。因为它是一种活细菌,OS-101允许
持续和长时间地将刺激剂输送到肿瘤微环境。与野性相比
BCG型OS-101在NMIBC模型中显示出优越的抗肿瘤效果;更强的促炎作用
细胞因子反应;更大的髓系细胞重新编程,产生M1移位
吞噬/自噬;关键细胞因子启动子区域更明显的表观遗传变化;以及
有利于抗肿瘤免疫的代谢变化。在这个快速通道项目的第一阶段,OncoSTING将创建
使用一种新的、正在申请专利的方法的下一代、无抗生素耐药性的0S-101版本。海流
RBCG原型OS-101依赖于使用抗生素耐药盒维持的细菌质粒。
然而,第三阶段的研究将需要移除抗生素耐药性基因。新技术的功效
构建,称为OS-151,然后将在四个相关的生物检测中得到确认。在第二阶段,将比较OS-151
对Adu-S100(目前正在进行临床试验的Aduro的小分子刺痛激动剂)和野生型卡介苗
膀胱癌相关模型的建立。还将进行OS-151的IND前、药代动力学和安全性研究
正在进行,优化工作将确保OS-151的规模化生产。最后,肿瘤重复给药
研究和再挑战研究将在小鼠同基因模型中进行。一旦获得批准,OS-151将首先
用于治疗对卡介苗无反应的NMIBC患者,有可能扩展到其他癌症适应症。
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 }}
Todd Wallach其他文献
Todd Wallach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('Todd Wallach', 18)}}的其他基金
STING agonist-expressing BCG for bladder cancer
表达 STING 激动剂的 BCG 用于治疗膀胱癌
- 批准号:
10618561 - 财政年份:2021
- 资助金额:
$ 109.3万 - 项目类别:
相似国自然基金
Agonist-GPR119-Gs复合物的结构生物学研究
- 批准号:32000851
- 批准年份:2020
- 资助金额:24.0 万元
- 项目类别:青年科学基金项目
相似海外基金
S1PR1 agonistによる脳血液関門制御を介した脳梗塞の新規治療法開発
S1PR1激动剂调节血脑屏障治疗脑梗塞新方法的开发
- 批准号:
24K12256 - 财政年份:2024
- 资助金额:
$ 109.3万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
AHR agonistによるSLE皮疹の新たな治療薬の開発
使用 AHR 激动剂开发治疗 SLE 皮疹的新疗法
- 批准号:
24K19176 - 财政年份:2024
- 资助金额:
$ 109.3万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Evaluation of a specific LXR/PPAR agonist for treatment of Alzheimer's disease
特定 LXR/PPAR 激动剂治疗阿尔茨海默病的评估
- 批准号:
10578068 - 财政年份:2023
- 资助金额:
$ 109.3万 - 项目类别:
AUGMENTING THE QUALITY AND DURATION OF THE IMMUNE RESPONSE WITH A NOVEL TLR2 AGONIST-ALUMINUM COMBINATION ADJUVANT
使用新型 TLR2 激动剂-铝组合佐剂增强免疫反应的质量和持续时间
- 批准号:
10933287 - 财政年份:2023
- 资助金额:
$ 109.3万 - 项目类别:
Targeting breast cancer microenvironment with small molecule agonist of relaxin receptor
用松弛素受体小分子激动剂靶向乳腺癌微环境
- 批准号:
10650593 - 财政年份:2023
- 资助金额:
$ 109.3万 - 项目类别:
AMPKa agonist in attenuating CPT1A inhibition and alcoholic chronic pancreatitis
AMPKa 激动剂减轻 CPT1A 抑制和酒精性慢性胰腺炎
- 批准号:
10649275 - 财政年份:2023
- 资助金额:
$ 109.3万 - 项目类别:
Investigating mechanisms underpinning outcomes in people on opioid agonist treatment for OUD: Disentangling sleep and circadian rhythm influences on craving and emotion regulation
研究阿片类激动剂治疗 OUD 患者结果的机制:解开睡眠和昼夜节律对渴望和情绪调节的影响
- 批准号:
10784209 - 财政年份:2023
- 资助金额:
$ 109.3万 - 项目类别:
A randomized double-blind placebo controlled Phase 1 SAD study in male and female healthy volunteers to assess safety, pharmacokinetics, and transient biomarker changes by the ABCA1 agonist CS6253
在男性和女性健康志愿者中进行的一项随机双盲安慰剂对照 1 期 SAD 研究,旨在评估 ABCA1 激动剂 CS6253 的安全性、药代动力学和短暂生物标志物变化
- 批准号:
10734158 - 财政年份:2023
- 资助金额:
$ 109.3万 - 项目类别:
A novel nanobody-based agonist-redirected checkpoint (ARC) molecule, aPD1-Fc-OX40L, for cancer immunotherapy
一种基于纳米抗体的新型激动剂重定向检查点 (ARC) 分子 aPD1-Fc-OX40L,用于癌症免疫治疗
- 批准号:
10580259 - 财政年份:2023
- 资助金额:
$ 109.3万 - 项目类别:
Identification and characterization of a plant growth promoter from wild plants: is this a novel plant hormone agonist?
野生植物中植物生长促进剂的鉴定和表征:这是一种新型植物激素激动剂吗?
- 批准号:
23K05057 - 财政年份:2023
- 资助金额:
$ 109.3万 - 项目类别:
Grant-in-Aid for Scientific Research (C)














{{item.name}}会员




