Development of New Oncolytic Virotherapy Targeting Breast Cancer Using Coxsackievirus B3

Sagara, Miyako; Miyamoto, Shohei; Itoh, S.; Soda, Yasushi; Tani, Kenzaburo

doi:10.21873/anticanres.14753

Cited by 17 publications

(24 citation statements)

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“…In a xenograft model of colorectal carcinoma, virus replication was completely abrogated within both target tissues and both organs were protected from virus-induced pathology, while the growth of colorectal carcinomas was still significantly inhibited. Similar results were obtained by Sagara et al [ 108 ], who generated a CVB3 strain with the miR-TS of miR- 1 and of the pancreas-specific miR-217. The virus was successfully de-targeted from the heart and pancreas of nude mice, while breast cancer growth was still significantly inhibited.…”

Section: Improvement Of the Safety Of Oncolytic Cvb3 By Microrna-mediated Regulation Of Virus Replicationsupporting

confidence: 89%

“…Nevertheless, several studies recently demonstrated that miR-TS can also be inserted into the 3 -UTR of CVB3 without affecting virus propagation. This was achieved by placing the miR-TS immediately downstream of the stop codon of the CVB3 polyprotein [74,103,[107][108][109]. This approach apparently prevents the destruction of critical secondary structures within the 3 -UTR of the virus.…”

Section: Improvement Of the Safety Of Oncolytic Cvb3 By Microrna-mediated Regulation Of Virus Replicationmentioning

confidence: 99%

“…This involved the insertion of miR-TS in a forward orientation to target the plus-strand genome or in a reverse orientation to target the minus-strand replication intermediate of CVB3. All CVB3 containing miR-TS in their plus-strand genome were sensitive to the corresponding miRs [74,103,105,[107][108][109]137]. The miR-targeting of the viral minus-strand is particularly attractive, as CVB3 generates only few minus-strand RNA intermediates during genome replication, which function as template for generating lots of plus-strand RNA genomes [141].…”

Section: Improvement Of the Safety Of Oncolytic Cvb3 By Microrna-mediated Regulation Of Virus Replicationmentioning

confidence: 99%

“…In vitro data have shown an impressive reduction in miR-TS-bearing CVB3 replication of up to 10 5 -fold in cells endogenously expressing their cognate miRs, which was corroborated in vivo. Even after the application of high doses of virus and the use of highly virulent virus strains, a complete to nearly complete abrogation of CVB3 replication and organ toxicity in tissues expressing corresponding miRs was observed in several studies [74,103,105,[107][108][109]. However, it should be mentioned that the degree of attenuation seemed to be affected by several factors, such as the absolute level of miR expression in normal tissues [107], the miR-TS copy number [103] and the route of viral application [105].…”

Section: Improvement Of the Safety Of Oncolytic Cvb3 By Microrna-mediated Regulation Of Virus Replicationmentioning

confidence: 99%

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Coxsackievirus B3—Its Potential as an Oncolytic Virus

Geisler

Hazini

Heimann

et al. 2021

Viruses

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Oncolytic virotherapy represents one of the most advanced strategies to treat otherwise untreatable types of cancer. Despite encouraging developments in recent years, the limited fraction of patients responding to therapy has demonstrated the need to search for new suitable viruses. Coxsackievirus B3 (CVB3) is a promising novel candidate with particularly valuable features. Its entry receptor, the coxsackievirus and adenovirus receptor (CAR), and heparan sulfate, which is used for cellular entry by some CVB3 variants, are highly expressed on various cancer types. Consequently, CVB3 has broad anti-tumor activity, as shown in various xenograft and syngeneic mouse tumor models. In addition to direct tumor cell killing the virus induces a strong immune response against the tumor, which contributes to a substantial increase in the efficiency of the treatment. The toxicity of oncolytic CVB3 in healthy tissues is variable and depends on the virus strain. It can be abrogated by genetic engineering the virus with target sites of microRNAs. In this review, we present an overview of the current status of the development of CVB3 as an oncolytic virus and outline which steps still need to be accomplished to develop CVB3 as a therapeutic agent for clinical use in cancer treatment.

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Section: Improvement Of the Safety Of Oncolytic Cvb3 By Microrna-mediated Regulation Of Virus Replicationsupporting

confidence: 89%

Section: Improvement Of the Safety Of Oncolytic Cvb3 By Microrna-mediated Regulation Of Virus Replicationmentioning

confidence: 99%

Section: Improvement Of the Safety Of Oncolytic Cvb3 By Microrna-mediated Regulation Of Virus Replicationmentioning

confidence: 99%

Section: Improvement Of the Safety Of Oncolytic Cvb3 By Microrna-mediated Regulation Of Virus Replicationmentioning

confidence: 99%

See 2 more Smart Citations

Coxsackievirus B3—Its Potential as an Oncolytic Virus

Geisler

Hazini

Heimann

et al. 2021

Viruses

View full text Add to dashboard Cite

show abstract

“…Several studies demonstrated that side effects induced by oncolytic CVB3 can be prevented by insertion of target sites of microRNAs (miR-TS) into the virus genome. In fact, CVB3-induced pancreatitis and myocarditis was ablated by equipping the viral genome with miR-TS of tissue-specific microRNAs, such as the pancreas-specific expressed miR-375 and heart specific miR-1 or pancreas-specific miR-217 and miR-1 [17,19] or by using miR-TS of tumor suppressor miR-34a [18] or miR-143 and miR-145 [20].…”

Section: Introductionmentioning

confidence: 99%

Application Route and Immune Status of the Host Determine Safety and Oncolytic Activity of Oncolytic Coxsackievirus B3 Variant PD-H

Hazini

Dieringer

Klingel³

et al. 2021

Viruses

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The coxsackievirus B3 strain PD-0 has been proposed as a new oncolytic virus for the treatment of colorectal carcinoma. Here, we generated a cDNA clone of PD-0 and analyzed the virus PD-H, newly generated from this cDNA, in xenografted and syngenic models of colorectal cancer. Replication and cytotoxic assays revealed that PD-H replicated and lysed colorectal carcinoma cell lines in vitro as well as PD-0. Intratumoral injection of PD-H into subcutaneous DLD-1 tumors in nude mice resulted in strong inhibition of tumor growth and significantly prolonged the survival of the animals, but virus-induced systemic infection was observed in one of the six animals. In a syngenic mouse model of subcutaneously growing Colon-26 tumors, intratumoral administration of PD-H led to a significant reduction of tumor growth, the prolongation of animal survival, the prevention of tumor-induced cachexia, and the elevation of CD3+ and dendritic cells in the tumor microenvironment. No virus-induced side effects were observed. After intraperitoneal application, PD-H induced weak pancreatitis and myocarditis in immunocompetent mice. By equipping the virus with target sites of miR-375, which is specifically expressed in the pancreas, organ infections were prevented. Moreover, employment of this virus in a syngenic mouse model of CT-26 peritoneal carcinomatosis resulted in a significant reduction in tumor growth and an increase in animal survival. The results demonstrate that the immune status of the host, the route of virus application, and the engineering of the virus with target sites of suitable microRNAs are crucial for the use of PD-H as an oncolytic virus.

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