Non-replicating rhabdovirus-derived particles (NRRPs) eradicate acute leukemia by direct cytolysis and induction of antitumor immunity

被引：20
作者：
Batenchuk, C. [1 ,2 ,3 ]
Le Boeuf, F. [1 ,3 ]
Stubbert, L. [1 ,3 ]
Falls, T. [1 ,3 ]
Atkins, H. L. [1 ,3 ,4 ]
Bell, J. C. [1 ,2 ,3 ]
Conrad, D. P. [1 ,3 ,5 ]
机构：
[1] Univ Ottawa, Ottawa Hosp, Res Inst, Ctr Canc Therapeut, Ottawa, ON K1H 8L6, Canada
[2] Univ Ottawa, Dept Biochem Immunol & Microbiol, Ottawa, ON K1H 8L6, Canada
[3] Univ Ottawa, Dept Med, Ottawa, ON K1H 8L6, Canada
[4] Univ Ottawa, Blood & Marrow Transplant Program, Ottawa, ON K1H 8L6, Canada
[5] Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON K1H 8L6, Canada
来源：
BLOOD CANCER JOURNAL | 2013年 / 3卷
基金：
加拿大自然科学与工程研究理事会;
关键词：
acute leukemia; oncolytic virus; non-replicative rhabdovirus-derived particles; NRRP; VESICULAR STOMATITIS-VIRUS; TUMOR-SPECIFIC DEFECTS; ONCOLYTIC VIRUSES; THERAPY; CANCER; REPLICATION; KINASE; AGE;
D O I：
10.1038/bcj.2013.23
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
摘要：
Rhabdoviruses (RVs) are currently being pursued as anticancer therapeutics for various tumor types, notably leukemia. However, modest virion production and limited spread between noncontiguous circulating leukemic cells requires high-dose administration of RVs, which exceeds the maximum tolerable dose of the live virus. Furthermore, in severely immunosuppressed leukemic patients, the potential for uncontrolled live virus spread may compromise the safety of a live virus approach. We hypothesized that the barriers to oncolytic virotherapy in liquid tumors may be overcome by administration of high-dose non-replicating RVs. We have developed a method to produce unique high-titer bioactive yet non-replicating rhabdovirus-derived particles (NRRPs). This novel biopharmaceutical is multimodal possessing direct cytolytic and immunomodulatory activity against acute leukemia. We demonstrate that NRRP resistance in normal cells is mediated by intact antiviral defences including interferon (IFN). This data was substantiated using murine models of blast crisis. The translational promise of NRRPs was demonstrated in clinical samples obtained from patients with high-burden multidrug-resistant acute myeloid leukemia. This is the first successful attempt to eradicate disseminated cancer using a non-replicating virus-derived agent, representing a paradigm shift in our understanding of oncolytic virus-based therapies and their application toward the treatment of acute leukemia.
引用
收藏
页码：e123 / e123
页数：7
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