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:10377711
- 负责人:
- 金额:$ 113.33万
- 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
- 来源:
- 关键词:
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/总结
问题的重要性:免疫治疗方法对大多数肿瘤是不成功的,
突变负荷(即,很少的新抗原引起强烈的T细胞活化)和很少的肿瘤浸润淋巴细胞
(“冷”肿瘤)。我们的临床前研究涉及多个小鼠模型,表明将辛德毕斯病毒
使用免疫调节抗体(Ab)(例如,至OX 40),导致
通过驱动活化的T细胞进入冷肿瘤来实现无退化生存。治疗改变了转录组
T细胞的特征和代谢程序,驱动高度活化的,终末分化的,
尽管存在抑制性肿瘤微环境(TME),但具有增强的肿瘤浸润能力的效应T细胞。
产品描述:我们建议开发创新的第三代SV载体,以驱动激活的T
细胞转化为“冷”肿瘤或肿瘤,如上皮性卵巢癌(EOC),其中TME中的许多因素
损害TIL的存在或活性。其中之一,CYN 103,将编码单链抗体(scFV),
OX 40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CYN 102的1期临床试验,
其编码NY-ESO-1,在具有化疗抗性的EOC的女性中,以确定其临床安全性。鉴于
CYN 102联合免疫调节Abs在临床前模型中具有疗效,我们将对此进行跟踪研究。
一项1b期临床试验,评估CYN 103在EOC女性中的安全性和最佳剂量。
产品的技术创新:“武装”SV载体,如CYN 103,它编码自己的
激动性/拮抗性scFV或小配体,可以潜在地克服减少免疫应答的固有限制。
抗体的功效,如差的组织或肿瘤转移率和有害的Fc效应子功能对肿瘤的潜在影响。
耗尽免疫细胞此外,批准的Ab价格昂贵,并且它们的副作用限制了它们的临床使用。
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,其中之一是CYN 103,
将携带双有效载荷,旨在针对EOC,用于计划的1b期试验。2.测试和比较
(i)CYN 103、(ii)仅编码NY-ESO-1的载体(CYN 102)和(iii)编码针对OX 40的scFV的载体的功效
仅在EOC的临床前同基因模型中。Milestone:CYN 103载体的产生。显示出相当
在EOC临床前模型中,CYN 102和抗OX 40的组合的抗肿瘤功效。
第二阶段(第二年和第三年):1。在药品生产质量管理规范条件下生产CYN 103。2.提交一份
CYN 103的研究性新药(IND)申请。Milestone:临床级GMP生产
CYN103。获得支持CYN 103 1b期试验IND所需的临床前和监管数据。
商业机会:EOC治疗在美国每年花费约50 - 60亿美元。市场规模和
对现有疗法产生耐药性的高可能性为像我们这样的新疗法创造了重要机会。
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)
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DANIEL MERUELO其他文献
DANIEL MERUELO的其他文献
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{{ 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:
$ 113.33万 - 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:
10417269 - 财政年份:2020
- 资助金额:
$ 113.33万 - 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:
$ 113.33万 - 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:
$ 113.33万 - 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:
$ 113.33万 - 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:
$ 113.33万 - 项目类别:
Sindbis Vectors For Advanced Pancreatic Cancer Therapy
用于先进胰腺癌治疗的 Sindbis 载体
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7229427 - 财政年份:2004
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$ 113.33万 - 项目类别:
IN VITRO INACTIVATION OF VIRUSES IN BLOOD COMPONENTS
血液成分中病毒的体外灭活
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2771384 - 财政年份:1995
- 资助金额:
$ 113.33万 - 项目类别:
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