RESUMO
BACKGROUND/AIM: Breast cancer is the most common cancer in women worldwide, and triple-negative breast cancer (TNBC) is highly refractory to current standard therapies. Oncolytic virotherapy has recently gathered attention as a new treatment candidate for refractory cancers. MATERIALS AND METHODS: We previously developed a new Coxsackievirus B3 (CVB3) virotherapy targeting lung cancers, and demonstrated that miRNA target sequence insertion into CVB3 reduced its pathogenicity, retaining its original oncolytic activity. In this study, we examined the oncolytic effects of CVB3 against breast cancer cells including TNBC cells. RESULTS: CVB3 infection killed breast cancer cells in a time- and titer-dependent manner, and induced apoptosis. Nude mice transplanted with human TNBC cells were successfully treated with both CVB3-WT and CVB3-HP. Importantly, mice treated with CVB3-HP showed very few adverse events. CONCLUSION: CVB3-HP is a strong oncolytic virus candidate for breast cancer, including TNBC, due to its remarkable oncolytic efficacy and improved safety profile.
Assuntos
Neoplasias da Mama/genética , Enterovirus Humano B/genética , Terapia Genética , Vetores Genéticos/genética , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Animais , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Células Cultivadas , Efeito Citopatogênico Viral , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Expressão Gênica , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Vetores Genéticos/efeitos adversos , Humanos , Imuno-Histoquímica , Camundongos , Terapia Viral Oncolítica/métodos , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Oncolytic virotherapies have emerged as new modalities for cancer treatment. We previously reported that coxsackievirus B3 (CVB3) is a novel oncolytic virus (OV) with a strong ability to lyse human non-small cell lung cancer cells; however, its non-specific toxicity against normal cells remains to be resolved. To improve its safety profile, microRNA target sequences complementary to miR-34a/c, which is expressed preferentially in normal cells, were inserted into the 5' UTR or 3' UTR of the CVB3 genome. In the presence of miR-34a/c, the gene-modified CVB3 could not replicate in normal cells. We also found that the pathogenicity of CVB3 was reduced to a greater extent by targeting miR-34a than miR-34c; in addition, it was more effective to insert the target sequences into the 3' UTR rather than the 5' UTR of the viral genome. Ultimately, we developed a double-miR-34a targeting virus (53a-CVB) by inserting miR-34a targets in both the 5' UTR and 3' UTR of the virus. 53a-CVB was minimally toxic to cells in normal tissue, but maintained nearly its full oncolytic activity in mice xenografted with human lung cancer. 53a-CVB is the first miR-34-regulated OV and represents a promising platform for the development of safe and effective anti-cancer therapies.
RESUMO
Recently, the active development of oncolytic virotherapy has gathered attention. Enterovirus research seeks to better understand its pathogenicity. In particular, coxsackievirus A21 (CVA21) is a promising candidate for oncolytic virotherapy, and thus is the focus of many clinical trials. We have reported that coxsackievirus B3 (CVB3) had potent oncolytic activity for cancer, and induced immunogenic cell death of CVB3-infected cells. We then genetically engineered wild type CVB3 and successfully produced a novel recombinant CVB3-miRT, improving its safety by the introducing an organ-specific miRNA target sequence. We also developed the production method of CVB3 agent, and are conducting a clinical trial of CVB3 therapy for cancer patients. In this report, we review recent clinical progress in oncolytic virotherapy of CVA21 and clinical development of our CVB3.
Assuntos
Adjuvantes Imunológicos/genética , Enterovirus/genética , Terapia Viral Oncolítica , Animais , Morte Celular , Ensaios Clínicos como Assunto , Humanos , MicroRNAs/genéticaRESUMO
Although various therapies are available to treat cancers, including surgery, chemotherapy, and radiotherapy, cancer has been the leading cause of death in Japan for the last 30 years, and new therapeutic modalities are urgently needed. As a new modality, there has recently been great interest in oncolytic virotherapy, with measles virus being a candidate virus expected to show strong antitumor effects. The efficacy of virotherapy, however, was strongly limited by the host immune response in previous clinical trials. To enhance and prolong the antitumor activity of virotherapy, we combined the use of two newly developed tools: the genetically engineered measles virus (MV-NPL) and the multilayer virus-coating method of layer-by-layer deposition of ionic polymers. We compared the oncolytic effects of this polymer-coated MV-NPL with the naked MV-NPL, both in vitro and in vivo. In the presence of anti-MV neutralizing antibodies, the polymer-coated virus showed more enhanced oncolytic activity than did the naked MV-NPL in vitro. We also examined antitumor activities in virus-treated mice. Complement-dependent cytotoxicity and antitumor activities were higher in mice treated with polymer-coated MV-NPL than in mice treated with the naked virus. This novel, polymer-coated MV-NPL is promising for clinical cancer therapy in the future.
