Oncolytic myxoma virus: The path to clinic
Introduction
Cancer remains a major public health problem worldwide. For example, one out of four deaths in the United States is due to cancer [1]. Current standards of cancer therapy include resection surgery (if applicable), radiation, chemotherapy, immunotherapy, and/or biological therapy. However, available treatments for many common cancers remain noncurative and in many cases prolong survival rates only in the short term. Therefore, development of more efficacious treatments is much needed in order to significantly prolong the lives of cancer patients and eventually cure a wider spectrum of cancers. One of the newer and promising cancer therapeutic strategies is oncolytic virotherapy, and the first candidate viruses are rapidly approaching licensure in North America and Europe [2]. Successful oncolytic virotherapy in the clinic will possess two closely inter-related properties: the ability to destroy cancer cells directly but also the capacity to enhance acquired immune responses against tumor antigens, i.e., oncolytic virotherapy and anti-tumor immunostimulation are inextricably linked to each other. In general terms, a replication-competent virus, which spares normal tissues but selectively replicates in cancer cells, is used to specifically infect and eliminate cancerous tissues [3]. Viruses with demonstrated oncolytic potential include numerous candidates that are relatively nonpathogenic to humans but have a biologic proclivity to replicate selectively in human cancer cells. Examples of viruses that are in various stages of clinical and preclinical development include measles virus, vesicular stomatitis virus, adenovirus, reovirus, herpes simplex virus and two poxviruses, vaccinia virus and myxoma virus (MYXV) (reviewed in [4], [5], [6], [7], [8], [9]). Vaccinia virus, a prototypic member of the Poxviridae family, has been widely developed as a vaccination platform, and more recently is being tested as an oncolytic virotherapeutic in Phase II clinical trials for various late stage cancers, including liver cancer and malignancies that metastasize to the liver [4], [10], [11], [12], [13], [14]. Vaccinia virus, long used in the worldwide vaccination program against smallpox, is of unknown origin in terms of its evolutionary host, but has been tested extensively in humans.
In general, poxviruses infect a wide range of hosts including humans, monkeys, mice, rabbits and insects, but individual members can be highly species-specific in terms of the hosts that they can infect [15], [16]. For example, vaccinia virus infects a wide variety of vertebrate hosts whereas MYXV is completely restricted to lagomorphs and is only pathogenic in the European rabbit [17], [18], [19]. MYXV is the prototypic member of the Leporipoxvirus genus within the Poxviridae family [20], [21], [22]. The MYXV Lausanne strain genome is 161.8 kbp in size, encoding about 171 genes [23]. The central region of the genome encodes less than 100 genes that are highly conserved in all poxviruses while the terminal genomic regions are enriched for more unique genes that encode immunomodulatory and host-interactive factors that are involved in subverting the host immune system and other anti-viral responses [20], [24], [25], [26]. A more detailed background on MYXV and its history has been described in recent reviews [21], [27].
MYXV causes a lethal disease called myxomatosis in European rabbits (Oryctolagus cuniculus) but the virus actually co-evolved within lagomorphs of the Sylvilagus genus, such as the Brazilian tapeti [21], [28]. In the tapeti, MYXV replicates robustly and transmits efficiently from host-to-host but causes no overt disease [28]. The basis for the extreme virulence of MYXV in the European rabbit, and absence of pathogenesis in the tapeti, is not well understood but the virus is essentially nonpathogenic for any host outside the lagomorph family [17], [18], [19], [21]. Indeed, the virus fails to replicate to any appreciable extent in any non-rabbit host tested to date, including highly immunodeficient mice [21], [29]. MYXV can successfully replicate in rabbits due to the ability of MYXV to escape multiple diverse host innate and adaptive immune responses [20], [22], [25], [26]. Despite its narrow host range in nature, MYXV has been shown to productively infect various classes of human cancer cells due to several factors, including: (I) the failure of most cancer cells to induce appropriate anti-viral responses, such as the synergistic interferon and tumor necrosis factor pathways that efficiently aborts MYXV replication in normal primary human cells [30], [31] and (II) the constitutive activation of intracellular pathways related to cellular transformation, such as the phosphorylation of Akt, commonly found in many human cancer cells [32]. A detailed study has shown that MYXV-encoded ankyrin-repeat host range factor, M-T5, interacts with Akt and this interaction is required for the enhanced phosphorylation of Akt [32], [33]. Pharmacologic manipulation of Akt activation affects MYXV tropism, indicating a direct correlation between endogenous activated signal transduction pathways and the permissiveness of MYXV to target human cancer cells [34]. Additionally, our laboratory has demonstrated an important role for the IFN signaling in the permissiveness of MYXV to certain specific cell types [35]. Co-treatment of primary human fibroblasts with type I IFN and TNF induces a synergistic antiviral state that aborts MYXV infection [31]. Importantly, a wide spectrum of human cancer cells has been shown to unable to induce the synergistic antiviral state, which may allow for selective/productive MYXV infection in a wide variety of human cancer cells [30].
Attractive features of MYXV as an oncolytic agent include its ability to productively infect various human cancer cells and its consistent safety in all non-rabbit hosts tested, including mice and humans [17], [18], [19], [21], [36]. The work from our laboratory and of others clearly demonstrates that MYXV is an attractive candidate oncolytic virus (reviewed in [22], [37], [38]), and hence, MYXV is currently being developed as a candidate therapeutic for several cancers, including ovarian cancer, glioblastoma, myeloid leukemia, multiple myeloma (MM), melanoma, and pancreatic cancer. This review updates the current status in the oncolytic potential of MYXV for the treatment of these cancers in preclinical animal models (Table 1) and highlights the projected path toward human clinical trials with this virus.
Section snippets
Hematological malignancies: acute myeloid leukemia and multiple myeloma
Hematological malignancies under consideration here include acute myeloid leukemia (AML) and multiple myeloma (MM) that mainly affect adults. Approximately 10% of Americans diagnosed with cancer each year will have one of these blood cancers (National Cancer Institute, Surveillance Epidemiology, and End Results). For high-risk patients with AML, either autologous or allogenic hematopoietic stem cell transplantation has been used to rescue immune function following myeloablative therapy with
Pancreatic cancer
Pancreatic cancer was reported to be the fourth leading cause of cancer related deaths in the US [1]. Surgical resection is the only potentially curative treatment for patients with pancreatic cancer, although many patients are not candidates for resection because of the late stage of disease diagnosis. Current treatment of pancreatic cancer is resection of tumors, if resectable, followed by radiation and/or chemotherapy with gemcitabine (a nucleoside analog) [45], [46], [47]. Unfortunately,
Ovarian cancer
Ovarian cancer is the fifth most prevalent cancer in women [1]. Epithelial ovarian cancer (EOC) constitutes approximately 90% of diagnosed ovarian tumors [52]. Lack of clinical symptoms makes early detection problematic and late diagnosis is a major contributor of the poor survival of most ovarian cancer patients. Current standard treatment includes surgery, followed by chemotherapy. Chemotherapy can be initially effective at inducing regression, but most patients subsequently develop
Brain cancer: glioma, rhabdoid, and medulloblastoma cancers
Malignant gliomas are highly invasive and rapidly growing brain tumors [61]. Current treatment of malignant glioma patients includes surgery, radiation, and/or chemotherapy [62]. But the standard of care treatment is not effective and most patients survive for only 1 year on average [62]. To date, a variety of oncolytic viruses have been tested as therapeutics for glioma, and several clinical trials are ongoing to test efficacy in patients [2], [63], [64], [65]. The oncolytic potential of MYXV
Melanoma
Melanoma is a particularly dangerous type of skin cancer and is the leading cause of death from skin disease [1]. Malignant cutaneous melanoma can further develop into metastatic melanoma brain tumors. Patients with metastasized melanoma currently have very poor prognoses [73]. One current promising method of treating metastatic melanoma is adoptive transfer of tumor-specific T cells [74]. While the treatment is still at the investigational stage, recurrence occurs due to various mechanisms:
Conclusions and future perspectives
MYXV is a relatively new oncolytic virus candidate compared to other viruses being evaluated for oncolytic properties in clinical trials. Based on the literature reviewed here, it is clear that MYXV possesses significant oncolytic potential for many types of cancers, particularly AML, MM, pancreatic cancer, and gliomas, in the pre-clinical models tested to date. Since it is well known that all animal models of cancer suffer various degrees of variance from true human cancers in situ, and the
Conflict of interest
The authors declare no conflict of interest.
Acknowledgements
GM's laboratory is supported by the Bankhead Coley Foundation of Florida, and by NIH Grants R01 AI080607, R01 CA138541 and R21 CA149869.
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2021, Molecular Therapy OncolyticsCitation Excerpt :In nature, this virus is rabbit-specific and does not cause infection or disease in any non-lagomorph, including humans or mice. However, because of idiosyncrasies of carcinogenesis and the selection of progressively malignant phenotypes, most cancer cells invariably lose elements of their innate immune ability to resist infection by many viruses, including MYXV.24–26 Most human or mouse cancer cells behave phenotypically more like permissive rabbit cells, such that MYXV can selectively infect and kill them while leaving normal somatic cells and tissues unharmed.
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