Vaccinia Virus-mediated Expression of Human Erythropoietin in Tumors Enhances Virotherapy and Alleviates Cancer-related Anemia in Mice

Abstract

Recombinant human erythropoietin (rhEPO), a glycoprotein hormone regulating red blood cell (RBC) formation, is used for the treatment of cancer-related anemia. The effect of rhEPO on tumor growth, however, remains controversial. Here, we report the construction and characterization of the recombinant vaccinia virus (VACV) GLV-1h210, expressing hEPO. GLV-1h210 was shown to replicate in and kill A549 lung cancer cells in culture efficiently. In mice bearing A549 lung cancer xenografts, treatment with a single intravenous dose of GLV-1h210 resulted in tumor-specific production and secretion of functional hEPO, which exerted an effect on RBC progenitors and precursors in the mouse bone marrow, leading to a significant increase in the number of RBCs and in the level of hemoglobin. Furthermore, virally expressed hEPO, but not exogenously added rhEPO, enhanced virus-mediated green fluorescent protein (GFP) expression in tumors and subsequently accelerated tumor regression when compared with the treatment with the parental virus GLV-1h68 or GLV-1h209 that expressed a nonfunctional hEPO protein. Moreover, intratumorally expressed hEPO caused enlarged tumoral microvessels, likely facilitating virus spreading. Taken together, VACV-mediated intratumorally expressed hEPO not only enhanced oncolytic virotherapy but also simultaneously alleviated cancer-related anemia.

Progress in clinical oncolytic virus-based therapy for hepatocellular carcinoma

“…The majority of approaches to arming OVs can equally be applied in the treatment of any solid malignancy. Exceptions include recombinant human erythropoietin (rhEPO), which was recently engineered into an oncolytic Lister strain vaccinia virus (GLV-1h210) and tested in lung cancer xenografts (Nguyen et al, 2013). rhEPO is essential for erythropoiesis and significantly improves quality of life in anaemic cancer patients, but is associated with angiogenesis, limiting its use in highly vascularized tumours such as HCC (Yasuda et al, 2003;Crawford et al, 2002).…”

Oncolytic Poxviruses

“…However, other animal studies showed no evidence of such deleterious effects (83–85). A recombinant GLV-1h210 expressing hEPO was constructed, and the effects of intratumorally expressed hEPO on tumor growth were examined in xenografted mice bearing human lung cancer (86). Insertion of the hEPO gene did not compromise virus replication (86).…”

“…A recombinant GLV-1h210 expressing hEPO was constructed, and the effects of intratumorally expressed hEPO on tumor growth were examined in xenografted mice bearing human lung cancer (86). Insertion of the hEPO gene did not compromise virus replication (86). Intravenous injection of GLV-1h210 resulted in tumor-specific production and secretion of functional hEPO, which significantly increased red blood cell numbers and hemoglobin levels (86).…”

“…Insertion of the hEPO gene did not compromise virus replication (86). Intravenous injection of GLV-1h210 resulted in tumor-specific production and secretion of functional hEPO, which significantly increased red blood cell numbers and hemoglobin levels (86). Mice receiving GLV-1h210 exhibited enhanced tumor regression compared with mice injected with GLV-1h68 (86).…”

“…Intravenous injection of GLV-1h210 resulted in tumor-specific production and secretion of functional hEPO, which significantly increased red blood cell numbers and hemoglobin levels (86). Mice receiving GLV-1h210 exhibited enhanced tumor regression compared with mice injected with GLV-1h68 (86). The enhanced efficacy of GLV-1h210 most likely resulted from localized hEPO expression enlarging tumor vessels and thereby facilitating virus spread within the tumor (86).…”