Applications of coxsackievirus A21 in oncology

Abstract

The clinical management of cancer continues to be dominated by macroscopic surgical resection, radiotherapy, and cytotoxic drugs. The major challenge facing oncology is to achieve more selective, less toxic and effective methods of targeting disseminated tumors, a challenge oncolytic virotherapy may be well-placed to meet. Characterization of coxsackievirus A21 (CVA21) receptor-based mechanism of virus internalization and lysis in the last decade has suggested promise for CVA21 as a virotherapy against malignancies which overexpress those receptors. Preclinical studies have demonstrated proof of principle, and with the results of early clinical trials awaited, CVA21 may be one of the few viruses to demonstrate benefit for patients. This review outlines the potential of CVA21 as an oncolytic agent, describing the therapeutic development of CVA21 in preclinical studies and early stage clinical trials. Preclinical evidence supports the potential use of CVA21 across a range of malignancies. Malignant melanoma is the most intensively studied cancer, and may represent a “test case” for future development of the virus. Although there are theoretical barriers to the clinical utility of oncolytic viruses like CVA21, whether these will block the efficacy of the virus in clinical practice remains to be established, and is a question which can only be answered by appropriate trials. As these data become available, the rapid journey of CVA21 from animal studies to clinical trials may offer a model for the translation of other oncolytic virotherapies from laboratory to clinic.

Viral Vector-Based Melanoma Gene Therapy

“…Upregulation of ICAM-1 in melanoma is well studied, and it has been considered a relevant marker in disease prognosis [160]. It has been suggested that ICAM-1 is responsible for metastasis generation, as it facilitates cell-cell interactions between malignant melanocytes and circulating lymphocytes [95]. Upregulation of ICAM-1 in melanoma could be a potential target for CVA21 therapy as has been reported [158].…”

Development of oncolytic virotherapy: from genetic modification to combination therapy

“…Coxsackievirus A21 (CVA21) is a promising OV that depends on highly expressed receptor molecules on the surface of tumor cells, intercellular adhesion molecule-1 (ICAM-1, also named CD54), and decay-accelerating factor to preferentially enter, replicate in, and kill tumor cells. CVA21 exhibited antitumor efficacy in multiple cancers, including melanoma, prostate cancer, and multiple myeloma [30]. A CVA21-based OV (CAVATAK ® ) has been assessed in clinical trials for the treatment of malignant melanoma, bladder cancer [58], and uveal melanoma with liver metastases [59].…”

<p>Virus–Receptor Interactions and Virus Neutralization: Insights for Oncolytic Virus Development</p>

“…Most oncolytic viruses exert anti-tumor activity by penetrating the tumor cells, establishing a lytic cycle and ultimately causing the activation of cell death pathways. While some OVs have the natural capacity to infect specific tumors through receptor-mediated internalization, 14,[16][17][18] most OVs have been engineered to enhance their tumor selectivity and to reduce virulence in normal cells. 12,13,19,20 Even though natural receptors responsible for oncolytic viral entry are expressed on non-malignant cells thereby allowing a successful infection, [21][22][23] OVs often require a defect in innate immunity to successfully infect and propagate, which is only present in tumor cells but not in healthy cells.…”