Abstract
BackgroundDespite availability of efficient treatment regimens for early stage colorectal cancer, treatment regimens for late stage colorectal cancer are generally not effective and thus need improvement. Oncolytic virotherapy using replication-competent vaccinia virus (VACV) strains is a promising new strategy for therapy of a variety of human cancers.MethodsOncolytic efficacy of replication-competent vaccinia virus GLV-1h68 was analyzed in both, cell cultures and subcutaneous xenograft tumor models.ResultsIn this study we demonstrated for the first time that the replication-competent recombinant VACV GLV-1h68 efficiently infected, replicated in, and subsequently lysed various human colorectal cancer lines (Colo 205, HCT-15, HCT-116, HT-29, and SW-620) derived from patients at all four stages of disease. Additionally, in tumor xenograft models in athymic nude mice, a single injection of intravenously administered GLV-1h68 significantly inhibited tumor growth of two different human colorectal cell line tumors (Duke’s type A-stage HCT-116 and Duke’s type C-stage SW-620), significantly improving survival compared to untreated mice. Expression of the viral marker gene ruc-gfp allowed for real-time analysis of the virus infection in cell cultures and in mice. GLV-1h68 treatment was well-tolerated in all animals and viral replication was confined to the tumor. GLV-1h68 treatment elicited a significant up-regulation of murine immune-related antigens like IFN-γ, IP-10, MCP-1, MCP-3, MCP-5, RANTES and TNF-γ and a greater infiltration of macrophages and NK cells in tumors as compared to untreated controls.ConclusionThe anti-tumor activity observed against colorectal cancer cells in these studies was a result of direct viral oncolysis by GLV-1h68 and inflammation-mediated innate immune responses. The therapeutic effects occurred in tumors regardless of the stage of disease from which the cells were derived. Thus, the recombinant vaccinia virus GLV-1h68 has the potential to treat colorectal cancers independently of the stage of progression.
Highlights
Despite availability of efficient treatment regimens for early stage colorectal cancer, treatment regimens for late stage colorectal cancer are generally not effective and need improvement
Replication and cytotoxicity of GLV-1h68 in human colorectal cancer cell lines The replication of recombinant vaccinia virus GLV-1h68 was analyzed in different human colorectal cancer cells in culture (Colo 205, HCT-15, HCT-116, HT-29 and SW-620)
In this study we demonstrated that GLV-1h68 infected and killed colorectal cancer cells derived both from primary tumors (HCT-116, Duke’s type A, HT-29, Duke’s type B and HCT-15, Duke’s type C) and metastatic sites (SW-620, Duke’s type C and Colo 205, Duke’s type D) in culture and in vivo (Table 3)
Summary
Despite availability of efficient treatment regimens for early stage colorectal cancer, treatment regimens for late stage colorectal cancer are generally not effective and need improvement. According to the American Cancer Society, cancer is the second leading cause of death, with an estimated total of 577,190 deaths worldwide in 2012. Colon cancers identified at early (I & II) stages of the disease are highly treatable and can oftentimes be cured with surgical resection being the standard therapy [2]. Cases of surgical excision and chemotherapy still show recurrence rates between 40-60% in the first three years, with high recurrence rates at later stages of the disease, likely caused by chemoresistant cancerinitiating cells [4,5]. Newer and more efficient treatment regimens are needed to reduce the still considerably high treatment failure rates, especially in recurring cases or the late stages of colorectal cancer disease
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