文章：

非复制的横纹肌病毒衍生颗粒（NRRPs）通过直接细胞溶解和诱导抗肿瘤免疫来根除急性白血病

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

原文发布日期：2013-07-12

DOI: 10.1038/bcj.2013.23

类型: Original Article

开放获取: 是

英文摘要：

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.

摘要翻译： 

弹状病毒（RVs）目前被用作多种肿瘤类型的抗癌治疗剂，尤其是白血病。然而，由于病毒颗粒产量不高以及在非接触性循环白血病细胞间传播有限，需要大剂量施用弹状病毒，这超出了活病毒的最大耐受剂量。此外，在严重免疫抑制的白血病患者中，活病毒不受控制传播的可能性可能会影响活病毒方法的安全性。我们假设，通过施用高剂量的非复制性弹状病毒，可以克服液态肿瘤中溶瘤病毒治疗的障碍。我们开发了一种方法，可以生产独特的高滴度、具有生物活性但不复制的弹状病毒衍生颗粒（NRRPs）。这种新型生物药物具有多模式作用，对急性白血病具有直接的细胞溶解和免疫调节活性。我们证明，正常细胞对NRRPs的抵抗是由完整的抗病毒防御机制（包括干扰素（IFN））介导的。这一数据通过使用爆发性危象的小鼠模型得到了证实。NRRPs的转化前景在从高负荷、多药耐药急性髓系白血病患者获得的临床样本中得到了验证。这是首次成功尝试使用非复制性病毒衍生剂根除播散性癌症，代表了我们对基于溶瘤病毒的疗法及其在急性白血病治疗中应用的理解的范式转变。

原文链接：

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