An engineered oncolytic herpes virus expressing a full-length α-CD47 mAb for the treatment of GBM

一种表达全长 α-CD47 mAb 的工程溶瘤疱疹病毒,用于治疗 GBM

基本信息

  • 批准号:
    10696185
  • 负责人:
  • 金额:
    $ 15.52万
  • 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:
    2021-09-13 至 2026-08-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY – PROJECT 1 The combination of oncolytic virotherapy (OV) and monoclonal antibody (mAb) immunotherapy has great potential for the treatment of glioblastoma (GBM), the most common malignant brain tumor without a cure. An OV carrying a mAb-coding gene can produce and release the mAb drug specifically at the tumor site as a safe, effective, and innovative delivery system. Prior to our study, this approach has not been previously explored using herpes simplex virus 1-based OV (oHSV). CD47 is a transmembrane protein widely expressed on cancer cells including GBM. It acts as a “don’t eat me” signal by functioning as a ligand to signal regulatory protein-α (SIRPα) expressed on macrophages, resulting in inhibition of phagocytosis. We have generated an oHSV that expresses a full-length anti-CD47 mAb on an IgG1 scaffold (OV-αCD47-G1) that is capable of inducing antibody- dependent cellular phagocytosis (ADCP) by macrophages and antibody-dependent cellular cytotoxicity (ADCC) by natural killer cells to eradicate GBM cells in vitro and in vivo, in addition to blockade of the CD47-SIRPα “don’t eat me” signaling pathway in macrophages. We have demonstrated that our novel OV-αCD47-G1 significantly improves the survival of GBM-bearing mice in orthotopic, immunocompetent, and immunodeficient models. Our central hypothesis is that OV-αCD47-G1 will be safe and effective at improving GBM treatment and its anti- tumor activity in the brain will be reflected by markers in the peripheral blood. Importantly, we have optimized and manufactured GMP-grade OV-αCD47-G1 to conduct the proposed studies and will initiate a phase I clinical trial for adults with GBM. In this proposal, we will evaluate both the systemic and regional immune responses in vivo following clinical-grade OV-αCD47-G1 administration and identify markers in the circulation that correlate with anti-tumor activity in the brain in GBM animal models (Aim 1); we will perform Investigational New Drug (IND)-enabling in vivo safety and efficacy studies using clinical-grade OV-αCD47-G1 (Aim 2); and we will determine the safety of administering a single intracerebral infusion of OV-αCD47-G1 in adult patients with recurrent GBM (Aim 3). To accomplish these objectives, we will utilize immunocompetent and immunocompromised GBM mouse models for our correlative and preclinical studies evaluating OV-αCD47-G1 prior to the phase I clinical trial. Upon conclusion, we will understand how to optimize OV-αCD47-G1 therapy to cure GBM. Further insight into this process, as will result from the implementation and completion of this proposal, is impactful as it will ultimately lead to a reduction in mortality for adults suffering from GBM.
项目总结-项目1

项目成果

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Jianhua Yu其他文献

Jianhua Yu的其他文献

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{{ truncateString('Jianhua Yu', 18)}}的其他基金

An engineered oncolytic herpes virus expressing a full-length α-CD47 mAb for the treatment of GBM
一种表达全长 α-CD47 mAb 的工程溶瘤疱疹病毒,用于治疗 GBM
  • 批准号:
    10488216
  • 财政年份:
    2021
  • 资助金额:
    $ 15.52万
  • 项目类别:
An engineered oncolytic herpes virus expressing a full-length α-CD47 mAb for the treatment of GBM
一种表达全长 α-CD47 mAb 的工程溶瘤疱疹病毒,用于治疗 GBM
  • 批准号:
    10306304
  • 财政年份:
    2021
  • 资助金额:
    $ 15.52万
  • 项目类别:
Characterizing and Targeting the Novel IL-15- AKT-XBP1s Pathway in NK Cells
NK 细胞中新型 IL-15-AKT-XBP1s 通路的表征和靶向
  • 批准号:
    10304873
  • 财政年份:
    2019
  • 资助金额:
    $ 15.52万
  • 项目类别:
Characterizing and Targeting the Novel IL-15- AKT-XBP1s Pathway in NK Cells
NK 细胞中新型 IL-15-AKT-XBP1s 通路的表征和靶向
  • 批准号:
    10063858
  • 财政年份:
    2019
  • 资助金额:
    $ 15.52万
  • 项目类别:
Characterizing and Targeting the Novel IL-15- AKT-XBP1s Pathway in NK Cells
NK 细胞中新型 IL-15-AKT-XBP1s 通路的表征和靶向
  • 批准号:
    9917605
  • 财政年份:
    2019
  • 资助金额:
    $ 15.52万
  • 项目类别:
scFvPD1-FLT3 CAR T Cells for the Treatment of Relapsed Acute Myeloid Leukemia
scFvPD1-FLT3 CAR T 细胞用于治疗复发性急性髓系白血病
  • 批准号:
    9765792
  • 财政年份:
    2019
  • 资助金额:
    $ 15.52万
  • 项目类别:
Characterizing and Targeting the Novel IL-15- AKT-XBP1s Pathway in NK Cells
NK 细胞中新型 IL-15-AKT-XBP1s 通路的表征和靶向
  • 批准号:
    10520016
  • 财政年份:
    2019
  • 资助金额:
    $ 15.52万
  • 项目类别:
Overcoming Barriers of Virotherapy by Next-Generation oHSV Expressing E-Cadherin
通过表达 E-钙粘蛋白的下一代 oHSV 克服病毒治疗的障碍
  • 批准号:
    9921509
  • 财政年份:
    2018
  • 资助金额:
    $ 15.52万
  • 项目类别:
Overcoming Barriers of Virotherapy by Next-Generation oHSV Expressing E-Cadherin
通过表达 E-钙粘蛋白的下一代 oHSV 克服病毒治疗的障碍
  • 批准号:
    10544483
  • 财政年份:
    2018
  • 资助金额:
    $ 15.52万
  • 项目类别:
Elucidate and Modulate Cell Signaling in NK Cells for Glioma Treatment
阐明和调节 NK 细胞中的细胞信号传导用于神经胶质瘤治疗
  • 批准号:
    9240181
  • 财政年份:
    2017
  • 资助金额:
    $ 15.52万
  • 项目类别:

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EphA6 酪氨酸激酶作为成人胶质母细胞瘤基于 BMP 的治疗的潜在生物标志物
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  • 财政年份:
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