Systemic delivery of an oncolytic adenovirus targeting TGFβ to enhance anti-PD-1 and anti-CTLA-4 therapy for triple negative breast cancer

全身递送靶向 TGFβ 的溶瘤腺病毒,以增强三阴性乳腺癌的抗 PD-1 和抗 CTLA-4 治疗

基本信息

  • 批准号:
    10117795
  • 负责人:
  • 金额:
    $ 39.51万
  • 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:
    2021-03-01 至 2026-02-28
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY The development of novel therapies for the treatment of breast cancer is a major unmet need. In recent years, immune checkpoint inhibitors including anti-PD-1, anti-PD-L1 and anti-CTLA-4 have shown promise as antitumor agents, and are approved for the treatment of several malignancies. Clinical trials in breast cancer patients have shown that about 20% of triple negative breast cancers (TNBC) respond favorably to anti-PD-1 antibodies and Atezolizumab, an anti-PD-L1 antibody in combination with nab-paclitaxel (Abraxane) is now FDA approved for advanced stage TNBC patients with positive PDL-1 expression. However, many TNBC patients are resistant to anti-PD-1/PDL-1 and anti-CTLA-4 treatments which could be due to weak immunogenicity of the tumors and poor inflammatory but highly immune suppressive tumor microenvironment. In recent years TGFβ has been shown to be a strong immune suppressor and can potentially produce a tumor microenvironment that is resistant to anti-PD-1 and anti-CTLA-4 therapy. To overcome resistance to anti-PD-1 and anti-CTLA-4 we have developed adenoviruses (Ad) expressing sTGFβRIIFc (soluble TGFβ receptor II fused with human IgG Fc). sTGFβRIIFc acts as a TGFβ decoy, and can inhibit TGFβ pathways. Initially, we created Ad5 based Ad.sT expressing sTGFβRIIFc. To reduce hepatic/systemic toxicity associated with systemic delivery of Ad.sT, we created mHAd.sT, a liver-detargeted virus, by replacing hypervariable regions (HVRs) (1-7) of Ad.sT with Ad48 HVRs. To enhance tumor specificity, we have now created mHAdLyp.sT by introducing LyP-1 peptide, a 9-amino acid long tumor homing-cell peptide, into the HI loop of the mHAd.sT fiber. In this proposal, we will test the hypotheses that systemic administration of mHAdLyp.sT in mice bearing 4T1 triple negative mammary tumors will result in reduced hepatic/systemic toxicity but produce high levels of sTGFβRIIFc and inhibit TGFβ pathways. This will alter the tumor microenvironment, induce tumor immunity, and overcome resistance to anti-PD-1 and anti-CTLA-4., and examine the expression profiles of TGFβ-1, TGFβ-1 regulated genes, and PD-1 and CTLA-4 signaling pathways. We will examine immuno-phenotypes in tumors, peripheral blood and spleen (Aim 1). Next, we will examine mHAdLyp.sT, anti-PD-1 and anti-CTLA-4 combination therapies in mouse tumor models. We will conduct RNA-Seq analysis of the whole transcriptomes, and examine the role of immune activation in mediating the anti-tumor responses (Aim 2). We will test the hypothesis that systemic administration of mHLypAd.sT, in combination with anti-PD-1 and anti- CTLA-4 in mice with pre-established metastases will be effective (Aim 3). To guide us for the combination therapy trials with mHAdLyp.sT, anti-PD-1 and anti-CTLA-4, we will examine human TNBC tumors by Nanostring technology for RNA profiling, and will further examine the TGFβ-1 and other relevant biomarkers and TILS in human TNBC tumors. We will also screen the human population for the Ad neutralizing antibodies titers (Aim 4). We believe that our research described here is critical to bring forward our oncolytic virus mHAdLyp.sT targeting TGFβ in combination with anti-PD-1 and anti-CTLA-4 for clinical evaluation in TNBC patients.
项目总结

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 }}

Weidong Xu其他文献

Weidong Xu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('Weidong Xu', 18)}}的其他基金

Systemic delivery of an oncolytic adenovirus targeting TGFβ to enhance anti-PD-1 and anti-CTLA-4 therapy for triple negative breast cancer
全身递送靶向 TGFβ 的溶瘤腺病毒,以增强三阴性乳腺癌的抗 PD-1 和抗 CTLA-4 治疗
  • 批准号:
    10565945
  • 财政年份:
    2021
  • 资助金额:
    $ 39.51万
  • 项目类别:
Systemic delivery of an oncolytic adenovirus targeting TGFβ to enhance anti-PD-1 and anti-CTLA-4 therapy for triple negative breast cancer
全身递送靶向 TGFβ 的溶瘤腺病毒,以增强三阴性乳腺癌的抗 PD-1 和抗 CTLA-4 治疗
  • 批准号:
    10357928
  • 财政年份:
    2021
  • 资助金额:
    $ 39.51万
  • 项目类别:
Targeted Delivery of siRNA Nanoparticles to Prevent HIV-1 Transmission
靶向递送 siRNA 纳米颗粒以预防 HIV-1 传播
  • 批准号:
    7554936
  • 财政年份:
    2008
  • 资助金额:
    $ 39.51万
  • 项目类别:

相似海外基金

Transient tissue ‘priming’ via FAK inhibition to impair pancreatic cancer progression and improve sensitivity to gemcitabine/Abraxane
通过 FAK 抑制作用的瞬时组织“启动”可损害胰腺癌进展并提高对吉西他滨/Abraxane 的敏感性
  • 批准号:
    nhmrc : 1140125
  • 财政年份:
    2018
  • 资助金额:
    $ 39.51万
  • 项目类别:
    Project Grants
Transient tissue ‘priming’ via FAK inhibition to impair pancreatic cancer progression and improve sensitivity to gemcitabine/Abraxane
通过 FAK 抑制作用的瞬时组织“启动”可损害胰腺癌进展并提高对吉西他滨/Abraxane 的敏感性
  • 批准号:
    nhmrc : GNT1140125
  • 财政年份:
    2018
  • 资助金额:
    $ 39.51万
  • 项目类别:
    Project Grants
Single-cell optical window imaging in CDK1-FRET biosensor mice to assess tissue stiffness and optimise delivery and therapeutic response to Gemcitabine/Abraxane in pancreatic cancer.
CDK1-FRET 生物传感器小鼠的单细胞光学窗口成像可评估胰腺癌中的组织硬度并优化吉西他滨/Abraxane 的递送和治疗反应。
  • 批准号:
    nhmrc : GNT1105640
  • 财政年份:
    2016
  • 资助金额:
    $ 39.51万
  • 项目类别:
    Project Grants
Single-cell optical window imaging in CDK1-FRET biosensor mice to assess tissue stiffness and optimise delivery and therapeutic response to Gemcitabine/Abraxane in pancreatic cancer.
CDK1-FRET 生物传感器小鼠的单细胞光学窗口成像可评估胰腺癌中的组织硬度并优化吉西他滨/Abraxane 的递送和治疗反应。
  • 批准号:
    nhmrc : 1105640
  • 财政年份:
    2016
  • 资助金额:
    $ 39.51万
  • 项目类别:
    Project Grants
Phase II Study of Topical Imiquimod and Weekly Abraxane for the Treatment of Brea
局部用咪喹莫特和每周 Abraxane 治疗 Brea 的 II 期研究
  • 批准号:
    8090410
  • 财政年份:
    2009
  • 资助金额:
    $ 39.51万
  • 项目类别:
Phase II Study of Topical Imiquimod and Weekly Abraxane for the Treatment of Brea
局部用咪喹莫特和每周 Abraxane 治疗 Brea 的 II 期研究
  • 批准号:
    7631940
  • 财政年份:
    2009
  • 资助金额:
    $ 39.51万
  • 项目类别:
CLINICAL TRIAL: PHASE I TRIAL OF ABRAXANE IN COMBINATION WITH GEMCITABINE IN SOL
临床试验:ABRAXANE 与吉西他滨在 SOL 中联合使用的 I 期试验
  • 批准号:
    7716859
  • 财政年份:
    2008
  • 资助金额:
    $ 39.51万
  • 项目类别:
LCCC 0412: PHASE I CARBOPLATIN AND ABRAXANE IN PATIENTS WITH SOLID TUMORS
LCCC 0412:I 期卡铂和 ABRAXANE 用于实体瘤患者
  • 批准号:
    7625597
  • 财政年份:
    2006
  • 资助金额:
    $ 39.51万
  • 项目类别:
PHASE I TRIAL OF ABRAXANE IN COMBINATION WITH GEMCITABINE IN SOLID TUMORS
ABRAXANE 联合吉西他滨治疗实体瘤的 I 期试验
  • 批准号:
    7625658
  • 财政年份:
    2006
  • 资助金额:
    $ 39.51万
  • 项目类别:
LCCC 0412: PHASE I CARBOPLATIN AND ABRAXANE IN PATIENTS WITH SOLID TUMORS
LCCC 0412:I 期卡铂和 ABRAXANE 用于实体瘤患者
  • 批准号:
    7377549
  • 财政年份:
    2005
  • 资助金额:
    $ 39.51万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了