A novel and effective immunotherapeutic approach for tumors with a low mutational load and few tumor-infiltrating lymphocytes, such as ovarian cancer

针对突变负荷低、肿瘤浸润淋巴细胞少的肿瘤(例如卵巢癌)的一种新颖有效的免疫治疗方法

基本信息

  • 批准号:
    10417269
  • 负责人:
  • 金额:
    $ 86.67万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-07-09 至 2022-12-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT/SUMMARY Significance of the problem: Immunotherapeutic approaches are unsuccessful for most tumors with low mutational loads (i.e., few neoantigens eliciting robust T-cell activation) and few tumor-infiltrating lymphocytes (“cold” tumors). Our preclinical studies involving multiple mouse models indicate that combining a Sindbis virus (SV)–based immunotherapeutic approach with immunomodulatory antibodies (Abs) (e.g., to OX40), leads to regression-free survival by driving activated T cells into cold tumors. The treatment changes the transcriptome signature and metabolic program of T cells, driving the development of highly activated, terminally differentiated, effector T cells with enhanced tumor infiltration capacity despite a repressive tumor microenvironment (TME). Description of the product: We propose to develop innovative third-generation SV vectors to drive activated T cells into “cold” tumors or tumors such as epithelial ovarian cancer (EOC), where a number of factors in the TME impair the presence or activity of TILs. One of these, CYN103, will encode a single-chain antibody (scFV) to OX40 and the full-length tumor-associated antigen (TAA) NY-ESO-1, expressed in about 40% of EOC cells. Therapeutic development: Early in 2020 Cynvec will begin a Phase 1 clinical trial of a SV vector, CYN102, which encodes NY-ESO-1 in women with chemotherapy-resistant EOC to establish its clinical safety. Given that CYN102 in combination with immunomodulatory Abs has curative effects in preclinical models, we will follow this trial with a Phase 1b trial to evaluate the safety and optimal dosing of CYN103 in women with EOC. Technical innovation of the product: “Armed” SV vectors like CYN103, which encode their own agonistic/antagonistic scFVs or small ligands, can potentially overcome the inherent limitations that curtail efficacy of Abs, such as poor tissue or tumor penetrance and the potential of detrimental Fc-effector functions to deplete immune cells. Also, approved Abs are expensive, and their side effects limit their clinical use. Phase I (Year 1): 1. Engineer third-generation SV vectors for cancer immunotherapy, one of which, CYN103, will carry a dual payload designed to target EOC for use in planned Phase 1b trial. 2. Test and compare the efficacy of (i) CYN103, (ii) a vector encoding NY-ESO-1 only (CYN102), and (iii) a vector encoding scFV to OX40 only in a preclinical syngeneic model of EOC. Milestones: Generation of the CYN103 vector. Show equivalent anti-tumor efficacy in an EOC preclinical model to the combination of CYN102 and anti-OX40. Phase II (Years 2 & 3): 1. Produce CYN103 under Good Manufacturing Practice conditions. 2. Submit an Investigational New Drug (IND) application for CYN103. Milestones: GMP production of clinical grade CYN103. Obtain the preclinical and regulatory data needed to support an IND for a Phase 1b trial of CYN103. Commercial opportunity: EOC treatment in the US costs ~$5–6 billion annually. The size of the market and the high likelihood of resistance to existing therapies create a significant opportunity for novel therapies like ours.
摘要/摘要 问题的意义:免疫治疗方法对大多数低密度的肿瘤是不成功的 突变负荷(即很少的新抗原能激发强大的T细胞激活)和极少的肿瘤浸润性淋巴细胞 (“冷”瘤)。我们涉及多个小鼠模型的临床前研究表明,结合辛德比斯病毒 使用免疫调节抗体(如针对OX40)的(SV)免疫治疗方法可导致 通过驱使激活的T细胞进入冷肿瘤而实现无退化生存。治疗改变转录组 T细胞的信号和代谢程序,驱动高度激活的,终末分化的, 尽管肿瘤微环境(TME)受到抑制,但效应T细胞仍具有增强的肿瘤渗透能力。 产品描述:我们计划开发创新的第三代SV载体来驱动激活的T 细胞转化为“冷”瘤或上皮性卵巢癌(EOC)等肿瘤时,TME中的一些因素 损害TIL的存在或活动。其中一种名为CyN103的病毒将编码一种单链抗体(ScFv)来对抗 OX40和全长肿瘤相关抗原(TAA)NY-ESO-1在约40%的EOC细胞中表达。 治疗开发:2020年初,Cynvec将开始SV载体CYN102的第一阶段临床试验, 该基因编码NY-ESO-1用于化疗耐药的卵巢癌患者,以确定其临床安全性。考虑到 CYN102联合免疫调节性抗体在临床前模型中有疗效,我们将遵循以下原则 1b期试验,以评估CyN103在女性EoC患者中的安全性和最佳剂量。 该产品的技术创新:像CYN103一样,对自己的SV载体进行编码的武装SV载体 激动型/拮抗型单链抗体或小配体,可以潜在地克服 单抗的疗效,如不良的组织或肿瘤穿透性以及有害的Fc效应功能潜在地 消耗免疫细胞。此外,批准的单抗价格昂贵,其副作用限制了其临床应用。 第一阶段(第一年):1.设计用于癌症免疫治疗的第三代SV载体,其中之一,CYN103, 将携带双有效载荷,旨在针对EOC在计划的1B阶段试验中使用。2.测试和比较 (I)CyN103,(Ii)仅编码NY-Eso-1的载体(CyN102),和(Iii)编码ScFv至OX40的载体的有效性 仅在EOC的临床前同基因模型中。里程碑:CYN103载体的产生。显示等效项 在EOC临床前模型中,CYN102和抗OX40联合应用的抗肿瘤效果。 第二阶段(第2年和第3年):1.在良好的生产实践条件下生产CYN103。2.提交 研究用新药(IND)申请CYN103。里程碑:临床级别的GMP生产 CYN103号。获得支持CYN103 1b期试验IND所需的临床前和监管数据。 商业机会:在美国,EOC治疗每年花费约50-60亿美元。市场的规模和 对现有疗法产生抵抗的高可能性为我们这样的新疗法创造了一个重要的机会。

项目成果

期刊论文数量(3)
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 }}

DANIEL MERUELO其他文献

DANIEL MERUELO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('DANIEL MERUELO', 18)}}的其他基金

A novel and effective immunotherapeutic approach for tumors with a low mutational load and few tumor-infiltrating lymphocytes, such as ovarian cancer
针对突变负荷低、肿瘤浸润淋巴细胞少的肿瘤(例如卵巢癌)的一种新颖有效的免疫治疗方法
  • 批准号:
    10004922
  • 财政年份:
    2020
  • 资助金额:
    $ 86.67万
  • 项目类别:
A novel and effective immunotherapeutic approach for tumors with a low mutational load and few tumor-infiltrating lymphocytes, such as ovarian cancer
针对突变负荷低、肿瘤浸润淋巴细胞少的肿瘤(例如卵巢癌)的一种新颖有效的免疫治疗方法
  • 批准号:
    10377711
  • 财政年份:
    2020
  • 资助金额:
    $ 86.67万
  • 项目类别:
Sindbis Vectors For Advanced Pancreatic Cancer Therapy
用于先进胰腺癌治疗的 Sindbis 载体
  • 批准号:
    7413987
  • 财政年份:
    2004
  • 资助金额:
    $ 86.67万
  • 项目类别:
Sindbis Vectors For Advanced Pancreatic Cancer Therapy
用于先进胰腺癌治疗的 Sindbis 载体
  • 批准号:
    7075406
  • 财政年份:
    2004
  • 资助金额:
    $ 86.67万
  • 项目类别:
Sindbis Vectors For Advanced Pancreatic Cancer Therapy
用于先进胰腺癌治疗的 Sindbis 载体
  • 批准号:
    6827190
  • 财政年份:
    2004
  • 资助金额:
    $ 86.67万
  • 项目类别:
Sindbis Vectors For Advanced Pancreatic Cancer Therapy
用于先进胰腺癌治疗的 Sindbis 载体
  • 批准号:
    6908073
  • 财政年份:
    2004
  • 资助金额:
    $ 86.67万
  • 项目类别:
Sindbis Vectors For Advanced Pancreatic Cancer Therapy
用于先进胰腺癌治疗的 Sindbis 载体
  • 批准号:
    7229427
  • 财政年份:
    2004
  • 资助金额:
    $ 86.67万
  • 项目类别:
TARGETED IN VIVO GENE THERAPY FOR BRAIN TUMORS
针对脑肿瘤的体内基因治疗
  • 批准号:
    2112480
  • 财政年份:
    1995
  • 资助金额:
    $ 86.67万
  • 项目类别:
TARGETED IN VIVO GENE THERAPY FOR BRAIN TUMORS
针对脑肿瘤的体内基因治疗
  • 批准号:
    2458202
  • 财政年份:
    1995
  • 资助金额:
    $ 86.67万
  • 项目类别:
IN VITRO INACTIVATION OF VIRUSES IN BLOOD COMPONENTS
血液成分中病毒的体外灭活
  • 批准号:
    2771384
  • 财政年份:
    1995
  • 资助金额:
    $ 86.67万
  • 项目类别:

相似海外基金

Quantification of Neurovasculature Changes in a Post-Hemorrhagic Stroke Animal-Model
出血性中风后动物模型中神经血管变化的量化
  • 批准号:
    495434
  • 财政年份:
    2023
  • 资助金额:
    $ 86.67万
  • 项目类别:
Bioactive Injectable Cell Scaffold for Meniscus Injury Repair in a Large Animal Model
用于大型动物模型半月板损伤修复的生物活性可注射细胞支架
  • 批准号:
    10586596
  • 财政年份:
    2023
  • 资助金额:
    $ 86.67万
  • 项目类别:
A Comparison of Treatment Strategies for Recovery of Swallow and Swallow-Respiratory Coupling Following a Prolonged Liquid Diet in a Young Animal Model
幼年动物模型中长期流质饮食后吞咽恢复和吞咽呼吸耦合治疗策略的比较
  • 批准号:
    10590479
  • 财政年份:
    2023
  • 资助金额:
    $ 86.67万
  • 项目类别:
Small animal model for evaluating the impacts of cleft lip repairing scar on craniofacial growth and development
评价唇裂修复疤痕对颅面生长发育影响的小动物模型
  • 批准号:
    10642519
  • 财政年份:
    2023
  • 资助金额:
    $ 86.67万
  • 项目类别:
Diurnal grass rats as a novel animal model of seasonal affective disorder
昼夜草鼠作为季节性情感障碍的新型动物模型
  • 批准号:
    23K06011
  • 财政年份:
    2023
  • 资助金额:
    $ 86.67万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Longitudinal Ocular Changes in Naturally Occurring Glaucoma Animal Model
自然发生的青光眼动物模型的纵向眼部变化
  • 批准号:
    10682117
  • 财政年份:
    2023
  • 资助金额:
    $ 86.67万
  • 项目类别:
A whole animal model for investigation of ingested nanoplastic mixtures and effects on genomic integrity and health
用于研究摄入的纳米塑料混合物及其对基因组完整性和健康影响的整体动物模型
  • 批准号:
    10708517
  • 财政年份:
    2023
  • 资助金额:
    $ 86.67万
  • 项目类别:
A Novel Large Animal Model for Studying the Developmental Potential and Function of LGR5 Stem Cells in Vivo and in Vitro
用于研究 LGR5 干细胞体内外发育潜力和功能的新型大型动物模型
  • 批准号:
    10575566
  • 财政年份:
    2023
  • 资助金额:
    $ 86.67万
  • 项目类别:
Elucidating the pathogenesis of a novel animal model mimicking chronic entrapment neuropathy
阐明模拟慢性卡压性神经病的新型动物模型的发病机制
  • 批准号:
    23K15696
  • 财政年份:
    2023
  • 资助金额:
    $ 86.67万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
The effect of anti-oxidant on swallowing function in an animal model of dysphagia
抗氧化剂对吞咽困难动物模型吞咽功能的影响
  • 批准号:
    23K15867
  • 财政年份:
    2023
  • 资助金额:
    $ 86.67万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了