Enhanced oncolysis mediated by Coxsackievirus A21 in combination with doxorubicin hydrochloride

Abstract

Virotherapy is an emerging strategy for the treatment of cancer that utilizes both replication-competent and genetically modified viruses to selectively kill tumor cells. We have previously shown that Coxsackievirus A21 (CVA21), a common-cold producing enterovirus, is an effective oncolytic agent against human melanoma, prostate, and breast cancer xenografts in vivo. CVA21 specifically targets and lytically infects susceptible cells expressing the CVA21 cellular receptors, intercellular adhesion molecule-1 (ICAM-1) and decay-accelerating factor (DAF). Herein, the efficacy of CVA21 administered in combination with doxorubicin hydrochloride as a new therapeutic regimen for cancer was investigated. Flow cytometric analysis demonstrated that the human breast, colorectal, and pancreatic cancer cell lines examined expressed moderate levels of surface ICAM-1 and DAF, whilst a normal breast cell line expressed only minimal levels. When CVA21 was combined with doxorubicin hydrochloride, synergistically enhanced cell death was observed when CVA21 was administered both simultaneously or 24 h prior to doxorubicin hydrochloride exposure. Doxorubicin hydrochloride had no effect on CVA21 replication. Through the use of an orthotopic (MDA-MB-231-luc) xenograft SCID mouse model of human breast cancer we showed that a single intravenous injection of CVA21 in combination with an intraperitoneal injection of doxorubicin hydrochloride resulted in significantly greater tumor reduction compared to either agent alone. Overall, these findings highlight the exciting potential of CVA21, administered in combination with doxorubicin hydrochloride, as a new therapeutic regimen for cancer.

Coxsackievirus B3 Is an Oncolytic Virus with Immunostimulatory Properties That Is Active against Lung Adenocarcinoma

“…Therefore, they lack the genotoxicity caused by integration of the viral genome into the host DNA. In particular, enteroviruses, members of the Picornaviridae family, a diverse group of small RNA viruses have emerged as promising candidates for cancer treatment (6)(7)(8)(9). Their use has several therapeutic advantages: these viruses immediately induce robust cytolytic changes during cell-to-cell infection, they do not possess oncogenes that may lead to tumorigenesis, and they can be easily genetically manipulated by reverse genetics systems for the rescue of positivestrand RNA viruses from complementary DNA (10,11).…”

“…Furthermore, most nonpolio enteroviruses are common and highly prevalent and are mainly associated with asymptomatic infection or mild disease (12). Although CVA21 is reportedly a potent oncolytic enterovirus against miscellaneous human cancer cells (8,9,13), CVA21-treated mice died of lethal myositis with paralysis (14).…”

Short Overview of Clinical Trials With Current Immunotherapeutic Tools for Cancer Treatment

“…Большинство побочных явле-ний, наблюдавшихся при виротерапии, не были серьезными (не выше третьей степени тяжести), в основном -кратковременное гриппоподобное состояние [48]. Была показана способность ви-русов сенсибилизировать клетки опухоли к хи-миотерапии [39,42,79]. Во многих клинических испытаниях онколитические вирусы исполь- зуются в комбинации с химиотерапией, в част-ности: рекомбинантный онколитический вирус кори, кодирующий симпотер Na + /I -, (MV-NIS), в сочетании с циклофосфамидом использовался в КИ NCT00450814; онколитический вирус оспо-вакцины JX-594 в сочетании с сорафенибом -в КИ NCT01171651 и NCT02562755; аденовирус DNX2401 и темозоломид в КИ NCT01956734 и т.п.…”

Trial Watch:

“…(NCT02068794), as well as in subjects with head and neck squamous cell carcinoma, who are treated with MV-NIS i.t. (NCT01846091); (3) the intratumoral or intravenous administration of VCN-01, a replication-competent adenovirus expressing human sperm adhesion molecule 1 (SPAM1, best known as PH20 hyaluronidase), 249 is being assessed in individuals affected by advanced pancreatic cancer (NCT02045589) or other solid neoplasms (NCT02045602), respectively; (4) the biodistribution and shedding of intratumorally administered T-vec are being evaluated in melanoma patients (NCT02014441); (5) the safety and efficacy of Toca 511, an amphotropic replication-competent retrovirus genetically modified to express cytosine deaminase, 250 - 252 given as a standalone therapeutic intervention are being assessed in patients undergoing surgery for recurrent brain tumors (NCT01985256); (6) a naturally occurring variant of coxsackievirus, namely, coxsackievirus A21, 253 - 256 is being evaluated as a single agent for the systemic treatment of residual metastatic disease in subjects with NSCLC, melanoma, bladder carcinoma, and castration-resistant prostate cancer 257 (NCT02043665); (7) the intravesical instillation of CG0070, a conditionally replicating oncolytic adenovirus genetically modified to express GM-CSF, 108 , 258 is being investigated as a standalone therapeutic intervention in bladder carcinoma patients who failed Bacillus Calmette-Guérin (BCG)-based immunotherapy 259 , 260 (NCT00109655); (8) the clinical profile of ICOVIR-5 and DNX2401, 2 oncolytic adenoviruses engineered to replicate only in cells exhibiting alterations of the retinoblastoma 1 (RB1) signaling pathway, 261 - 266 is being assessed in subjects with advanced melanoma (NCT01864759) or other solid tumors (NCT01844661), in both scenarios as a standalone therapeutic intervention, as well as in patients with recurrent glioblastoma (in the context of temozolomide-based chemotherapy) (NCT01956734); (9) HSV-1716, a γ34.5-deficient variant of HSV, 267 - 270 is being tested in combination with dexamethasone (a glucocorticoid) in subjects with refractory or recurrent high-grade glioma that can be removed by surgery (NCT02031965); and (10) Pexa-Vec is being tested as a single therapeutic intervention in ovarian carcinoma patients (NCT02017678) (Table 1). …”

“…In the context of NCT00651157, a Phase II study testing Reolysin ® as a standalone therapeutic intervention in Stage IV melanoma patients, 225 serious adverse effects developed in a significant proportion of patients (50%) and no clinical activity was recorded (source http://clinicaltrials.gov/ct2/show/results/NCT00651157?term=NCT00651157&rank=1). Although both these trials have been completed, results are available neither for NCT01048892, a Phase I trial testing the Seneca Valley virus in combination with metronomic cyclophosphamide in patients with neuroendocrine tumors, nor for NCT01227551, 271 , 272 a Phase II study testing coxsackievirus A21 as a standalone therapeutic intervention in patients with advanced melanoma 253 - 256 . NCT01437280, a Phase I trial testing the safety and efficacy of a GM-CSF-encoding oncolytic adenovirus (CGTG-102) in patients with advanced tumors has been terminated prior to enrollment for undisclosed reasons 73 , 205 …”