Ex vivo purging strategy for treatment of multiple myeloma

治疗多发性骨髓瘤的离体清除策略

基本信息

  • 批准号:
    8698922
  • 负责人:
  • 金额:
    $ 16.06万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-06-01 至 2015-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The ultimate goal of this application is to develop a novel ex vivo purging method using myxoma virus (MYXV), a rabbit-specific poxvirus, to improve the clinical outcomes in treatment of multiple myeloma (MM). MM is a clonal plasma cell malignancy that has to date resisted essentially all therapeutic strategies. Currently, the standard of care for patients with MM is treatment with high-dose chemotherapy followed by autologous stem cell transplantation (ASTC). Although ASCT can often increase the disease-free interval for eligible patients, the disease generally relapses. This cancer relapse is mediated by cells derived from one or both of two sources: myeloma cells remaining within patient's hematopoietic system that resist the chemotherapy, and/or residual myeloma cells that contaminate the autologous stem cell graft sample. Recently, MYXV, when used to pre-treat primary MM patient ASTC samples, was found to be able to delete all residual MM cells while completely sparing the normal human stem cells needed to reconstitute the recipient immune system in a xenotransplantation animal model. MYXV is completely nonpathogenic to humans or mice, but has a natural tropism for a variety of human cancer cells and is being developed as a viral oncolytic agent for the treatment of a variety of cancers. We propose that ex vivo MYXV treatment of ASCT grafts prior to transplant will reduce MM disease relapse rates. In this Phase I STTR application, three specific aims are proposed to progress the development of MYXV as a safe therapeutic drug for the ex vivo purging of cancer cells to be used before ASCT in MM patients: (1) Evaluate safety by in vitro testing the interaction of MYXV with primary human transplant bone marrow cells and peripheral blood mononuclear cells. (2) To assess the specific MYXV vector clone chosen for clinical development and the purging methodology in an appropriate animal model. The intention of this Aim is to replicate in toto the exact clinical ex vivo purging strategy that will be proposed to the FDA for the human Phase I clinical trial. (3) Optimize the procedures for the ex vivo treatment of human bone marrow or peripheral blood mononuclear cells with MYXV to provide preclinical data required to support a future human clinical safety trial. The various factors to be optimized include the formulation for the MYXV stocks that ensures product stability and is compatibility with ex vivo treatment, the incubation buffer and conditions, the ratio of MXYV particles or infectious units to total nucleated cells in the transplant, the concentration of virus and cells during ex vivo incubation, and the minimum and maximally effective and no- effect doses of MYXV.
描述(由申请人提供): 本申请的最终目标是开发一种使用粘液瘤病毒(MYXV)(一种兔特异性痘病毒)的新型离体清除方法,以改善多发性骨髓瘤(MM)治疗的临床结局。MM是一种克隆性浆细胞恶性肿瘤,迄今为止基本上抵抗所有治疗策略。目前,MM患者的标准治疗是高剂量化疗,然后进行自体干细胞移植(ASTC)。虽然ASCT通常可以延长符合条件的患者的无病间期,但疾病通常会复发。这种癌症复发是由来源于两种来源之一或两者的细胞介导的:残留在患者造血系统内的抵抗化疗的骨髓瘤细胞,和/或污染自体干细胞移植物样品的残留骨髓瘤细胞。最近,发现MYXV在用于预处理原发性MM患者ASTC样品时能够删除所有残留的MM细胞,同时完全保留异种移植动物模型中重建受体免疫系统所需的正常人干细胞。MYXV对人类或小鼠完全无致病性,但对多种人类癌细胞具有天然向性,并且正在开发作为用于治疗多种癌症的病毒溶瘤剂。我们建议在移植前对ASCT移植物进行离体MYXV治疗将降低MM疾病复发率。在该I期STTR申请中,提出了三个具体目标,以推进MYXV作为一种安全治疗药物的开发,用于在MM患者ASCT前离体清除癌细胞:(1)通过体外测试MYXV与原代人移植骨髓细胞和外周血单核细胞的相互作用来评价安全性。(2)在适当的动物模型中评估选择用于临床开发的特定MYXV载体克隆和清除方法。该目的旨在完全复制将向FDA提出的用于人体I期临床试验的确切临床离体清除策略。(3)优化MYXV体外处理人骨髓或外周血单核细胞的程序,以提供支持未来人体临床安全性试验所需的临床前数据。待优化的各种因素包括确保产品稳定性并与离体处理相容的MYXV储备液的配方、孵育缓冲液和条件、移植物中MXYV颗粒或感染单位与总有核细胞的比率、离体孵育期间病毒和细胞的浓度以及MYXV的最小和最大有效和无效剂量。

项目成果

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Grant McFadden其他文献

Grant McFadden的其他文献

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{{ truncateString('Grant McFadden', 18)}}的其他基金

Unravelling the mechanisms of virus host species jump
揭示病毒宿主物种跳跃的机制
  • 批准号:
    10289093
  • 财政年份:
    2021
  • 资助金额:
    $ 16.06万
  • 项目类别:
Studies in Poxvirus Host Range Genes and Tropism
痘病毒宿主范围基因和趋向性研究
  • 批准号:
    9384142
  • 财政年份:
    2016
  • 资助金额:
    $ 16.06万
  • 项目类别:
Manipulation of inflammasomes and NF-kB signaling in human myeloid cells by Myxom
Myxom 操纵人骨髓细胞中的炎症小体和 NF-kB 信号传导
  • 批准号:
    8501735
  • 财政年份:
    2013
  • 资助金额:
    $ 16.06万
  • 项目类别:
Manipulation of inflammasomes and NF-kB signaling in human myeloid cells by Myxom
Myxom 操纵人骨髓细胞中的炎症小体和 NF-kB 信号传导
  • 批准号:
    8967138
  • 财政年份:
    2013
  • 资助金额:
    $ 16.06万
  • 项目类别:
Manipulation of inflammasomes and NF-kB signaling in human myeloid cells by Myxom
Myxom 操纵人骨髓细胞中的炎症小体和 NF-kB 信号传导
  • 批准号:
    8601041
  • 财政年份:
    2013
  • 资助金额:
    $ 16.06万
  • 项目类别:
Manipulation of inflammasomes and NF-kB signaling in human myeloid cells by Myxom
Myxom 操纵人骨髓细胞中的炎症小体和 NF-kB 信号传导
  • 批准号:
    9382931
  • 财政年份:
    2013
  • 资助金额:
    $ 16.06万
  • 项目类别:
Virotherapy for pancreatic cancer with wildtype and armed Myxoma viruses
使用野生型和武装粘液瘤病毒对胰腺癌进行病毒疗法
  • 批准号:
    8044924
  • 财政年份:
    2011
  • 资助金额:
    $ 16.06万
  • 项目类别:
Virotherapy for pancreatic cancer with wildtype and armed Myxoma viruses
使用野生型和武装粘液瘤病毒对胰腺癌进行病毒疗法
  • 批准号:
    8208977
  • 财政年份:
    2011
  • 资助金额:
    $ 16.06万
  • 项目类别:
Myxoma Virus (MV) Oncolysis for treating human cancer
粘液瘤病毒 (MV) 溶瘤治疗人类癌症
  • 批准号:
    8413599
  • 财政年份:
    2010
  • 资助金额:
    $ 16.06万
  • 项目类别:
Myxoma Virus (MV) Oncolysis for treating human cancer
粘液瘤病毒 (MV) 溶瘤治疗人类癌症
  • 批准号:
    8603761
  • 财政年份:
    2010
  • 资助金额:
    $ 16.06万
  • 项目类别:

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