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：
Grant McFadden
金额：
$ 16.06万
依托单位：
DNATRIX, INC.
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

来源：
https://reporter.nih.gov/project-details/8698922
关键词：
Acute Myelocytic Leukemia Animal Model Animals Aspirate substance Autologous Autologous Stem Cell Transplantation Autologous Transplantation B-Lymphocytes Binding Blood Platelets Bone Marrow Bone Marrow Cells Bone Marrow Transplantation Buffers CD34 gene Cancer Relapse Cancerous Cell Line Cells Clinical Cloning Vectors Data Development Disease Dose Drug Formulations Engraftment Ensure Exposure to Florida Future Goals Hematopoietic Hematopoietic Neoplasms Hematopoietic Stem Cell Transplantation Hematopoietic System Hematopoietic stem cells High Dose Chemotherapy Human IL2RA gene Immune Immune system Infusion procedures Intention Letters Life Malignant Neoplasms Mediating Methodology Methods Modeling Monozygotic twins Multiple Myeloma Mus Myeloablative Chemotherapy Myxoma virus Oncolytic Oryctolagus cuniculus Outcome Patients Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phase Phase I Clinical Trials Plasma Cells Poxviridae Procedures Publishing Reagent Recurrent disease Relapse Reporting Residual Cancers Residual state Resistance Safety Sampling Small Business Technology Transfer Research Source Specimen Stem cell transplant Stem cells T-Lymphocyte Testing Therapeutic Time Transplant Recipients Transplantation Tropism Viral Virotherapy Virus Virus Diseases Xenograft procedure cancer cell chemotherapy human stem cells improved in vitro testing in vivo novel particle pre-clinical prevent public health relevance purge reconstitution standard of care stem treatment strategy

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）治疗的临床结果。多发性骨髓瘤是一种克隆性浆细胞恶性肿瘤，迄今为止几乎所有治疗策略都对它产生抵抗。目前，多发性骨髓瘤患者的标准治疗是采用高剂量化疗，然后进行自体干细胞移植（ASTC）。尽管 ASCT 通常可以延长符合条件的患者的无病间隔，但疾病通常会复发。这种癌症复发是由两种来源之一或两者所衍生的细胞介导的：保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，当使用 MYXV 预处理原发性 MM 患者 ASTC 样本时，发现能够删除所有残留的 MM 细胞，同时完全保留在异种移植动物模型中重建受体免疫系统所需的正常人类干细胞。 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趋向性，并且正在被开发为一种病毒溶瘤剂，用于治疗多种癌症。我们建议在移植前对 ASCT 移植物进行离体 MYXV 治疗将降低 MM 疾病的复发率。在这一 I 期 STTR 申请中，提出了三个具体目标，以推进 MYXV 的开发，作为一种安全的治疗药物，用于在 MM 患者 ASCT 之前用于离体清除癌细胞：（1）通过体外测试评估安全性MYXV 与原代人移植骨髓细胞和外周血单核细胞的相互作用。 (2) 评估选择用于临床开发的特定 MYXV 载体克隆以及在适当的动物模型中的清除方法。该目标的目的是复制将向 FDA 提出的人体 I 期临床试验的精确临床离体清除策略。（3）优化MYXV离体治疗人骨髓或外周血单核细胞的程序，为支持未来的人体临床安全性试验提供所需的临床前数据。需要优化的各种因素包括确保产品稳定性并与离体处理兼容的 MYXV 库存配方、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例、离体孵化期间病毒和细胞的情况，以及 MYXV 的最小和最大有效剂量和无作用剂量。