|Year : 2020 | Volume
| Issue : 4 | Page : 708-712
Tanapoxvirus: From discovery towards oncolytic immunovirotherapy
Yogesh R Suryawanshi1, Tiantian Zhang2, Farzad Razi3, Karim Essani4
1 Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN; Department of Biological Sciences, Laboratory of Virology, Western Michigan University, Kalamazoo, MI, USA
2 Department of Biological Sciences, Laboratory of Virology, Western Michigan University, Kalamazoo, MI; Toni Stephenson Lymphoma Center, City of Hope, CA, USA
3 Department of Biology, Kalamazoo College, Kalamazoo, MI, USA
4 Department of Biological Sciences, Laboratory of Virology, Western Michigan University, Kalamazoo, MI, USA
|Date of Submission||14-Mar-2018|
|Date of Acceptance||27-Jun-2018|
|Date of Web Publication||30-Oct-2018|
Department of Biological Sciences, Laboratory of Virology, Western Michigan University, Kalamazoo, MI 49008-5410
Source of Support: None, Conflict of Interest: None
Insufficiency of standard cancer therapeutic agents and a high degree of toxicity associated with chemotherapy and radiotherapy have created a dearth of therapeutic options for metastatic cancers. Oncolytic viruses (OVs) are an emerging therapeutic option for the treatment of various human cancers. Several OVs, including poxviruses, are currently in preclinical and clinical studies and have shown to be effective in treating metastatic cancer types. Tanapoxvirus (TANV), a member of the Poxviridae family, is being developed as an OV for different human cancers due to its desirable safety and efficacy features. TANV causes a mild self-limiting febrile disease in humans, does not spread human to human, and its large genome makes it a relatively safer OV for use in humans. TANV is relatively well characterized at both molecular and clinical levels. Some of the TANV-encoded proteins that are a part of the virus' immune evasion strategy are also characterized. TANV replicates considerably slower than vaccinia virus. TANV has been shown to replicate in different human cancer cells in vitro and regresses human tumors in a nude mouse model. TANV is currently being developed as a therapeutic option for several human cancers including breast cancer, ovarian cancer, colorectal cancer, pancreatic cancer, retinoblastoma, and melanoma. This review provides a comprehensive summary from the discovery to the development of TANV as an OV candidate for a wide array of human cancers.
Keywords: Breast cancer, colorectal cancer, melanoma, oncolytic virus, poxvirus, tanapoxvirus
|How to cite this article:|
Suryawanshi YR, Zhang T, Razi F, Essani K. Tanapoxvirus: From discovery towards oncolytic immunovirotherapy. J Can Res Ther 2020;16:708-12
| > Introduction|| |
Cancer remains a major cause of death and estimated to cause over 600,000 deaths in the United States in 2017. Surgical resection of tumors along with chemotherapy and radiotherapy is still at the core of a standard cancer treatment. The overall survival among cancer patients remains largely unchanged over the past 2 years and has created a need for new treatment modalities that can change the course of disease, quality of life, and the overall survival rate. Oncolytic viruses (OVs) and immunotherapy have emerged as a new treatment option for cancer which is based on the idea of using replication-competent viruses to selectively or preferentially target and kill cancer cells and concomitantly induce an anticancer immune response. T-vec, an oncolytic herpes virus expressing granulocyte monocyte-colony-stimulating factor (GM-CSF), is the first virus that has been approved by the Food and Drug Administration (FDA) for melanoma therapy in the US. Several other viruses, including but not limited to vaccinia virus (VACV), myxoma virus, coxsackievirus, Newcastle disease virus, reovirus, and adenovirus, are being tested in preclinical and clinical studies, where some of them are at the cusp of obtaining an approval for treating cancer. Oncolytic adenovirus is another OV that had been approved by China FDA for treating head-and-neck carcinoma, in 2005. Carefully monitoring antiviral host immune response in patients will be critical for an effective OV therapy, since it may lead to a rapid immune clearance of the OV before it gets a chance to exert a therapeutic effect. In the absence of effective antiviral immune tolerances, the use of antigenically distinct OVs in a serial fashion will be a logical strategy for an effective OV therapy. Hence, availability of a large group of antigenically different OVs will be an advantage.
Cancer cells have shown an enhanced susceptibility to poxviruses due to the defective antiviral response pathways. Nontransformed cells appear to respond quickly to poxvirus infection and arrest the viral replication, but many cancer cells are likely to support viral replication due to their defective antiviral innate defense system. Poxvirus tropism in cancer cells is dependent on the aberrant signaling pathways within cells and not at the entry level. Poxviruses are capable of entering all animal cells. Recently, poxviruses have received considerable attention as OVs and have shown favorable results in several preclinical and clinical studies.,,
Tanapoxvirus (TANV), a member of family Poxviridae, is a suitable OV candidate as it is antigenically distinct from other poxviruses, including VACV, and most of the global human population is immunologically naïve to TANV as it is endemic only in equatorial Africa. Large genome size (>144 kilo base pairs [bps]) of TANV, like other poxviruses, allows insertion and stable expression of multiple therapeutic transgenes that can further enhance the therapeutic effectiveness of the virus. Safety is an important factor and OVs are being engineered to decrease their virulence to make them safer to be used in humans. For example, deletion of thymidine kinase (TK) encoding gene not only increases the onco-specificity of VACV, but also decreases its virulence. TANV does not spread directly from human to human and causes only a mild self-limiting febrile illness in humans, and hence relatively safer to be used in cancer patients. TANV is a brick-shaped, large DNA virus with a diameter of about 250 nm and length of about 350 nm and is structurally indistinguishable from VACV. Genomes of two isolates of TANV, namely TANV-Kenya and TANV-Republic of Congo (ROC), isolated from different geographical regions in Africa, almost 50 years apart, have been sequenced. Genome of TANV-Kenya showed 99.98% identity with the genome of TANV-ROC and differed by only 35 nucleotide bps. TANV Kenya strain genome encodes for 151 Open reading frames (ORFs). Some of these ORFs encode for immune-modulatory proteins, host range/ankyrin proteins, and yatapoxvirus-specific proteins. Human tumor necrosis factor (TNF)-binding protein (encoded by 2 L ORF), chemokine inhibitor (encoded by 7 L ORF), interleukin (IL)-18-binding protein (encoded by 14 L ORF), IL-24-like protein (encoded by 134R ORF), and Type-I interferon (IFN) receptor (encoded by 136R ORF) are some of the major immune-modulatory proteins, encoded by TANV. Moreover, deletion of TANV genes such as 15 L that encodes for a neuregulin (NRG) mimetic protein has been shown to enhance the antitumor effect of the virus through abolishing the tumor growth promotion mediated through ErbB2/3 receptor activation in human melanoma in the nude mouse model. TANV can be developed as an OV for the treatment of a wide range of human cancers, and the effect of specific TANV gene deletion on the virus' oncolytic potential is being explored further.
| > Discovery and Early Studies|| |
TANV was first isolated during epidemics in 1957 and then in 1962, in the flooding planes of Tana River Valley in Kenya and hence named “tanapox.” Several cases of TANV infection were also reported from the ROC between 1979 and 1983. Geographically, TANV is limited to equatorial Africa. Five genera of nonhuman primates are found to be potential reservoirs for the virus. The identity of a new poxvirus genus, Yatapoxvirus and its three members: TANV, Yaba-like disease virus (YLDV), and Yaba monkey tumor virus (YMTV), was established in 1989. Restriction endonuclease analyses of TANV-Kenya and YLDV genomes using Bam HI, MIu I, and Pst I showed that these two viruses are two strains of TANV. So far, only two cases of TANV infections outside Africa have been reported, but in both cases, the patients had a travel history to Africa., Clinical features of TANV infection in humans have been described earlier, but the exact incubation period of the disease is unknown. TANV causes a self-limiting, mild febrile illness in humans that may be associated with headache, backache, and generalized weakness with one or two skin lesions. Skin lesions begin as a papular lesion and change into the vesicular form during the febrile phase of infection.
An outbreak of TANV infection in monkeys in the primate centers in North America has been reported in the past, which supports the notion that TANV is likely to be a zoonotic virus, where African monkeys are serving as the primary source of the infection. The ability of TANV to infect only monkeys among all experimental animals further supports the notion that monkeys are likely to be the reservoirs for TANV. A definitive mode of transmission of TANV is yet to be established and no human-to-human transmission has been reported. However, several studies support the idea that mosquitoes may play an important role in the transmission of TANV. These included: (a) many humans who were infected with TANV in Africa were living in close proximity with animals and they reported of being bitten by mosquitoes, (b) seasonal outbreaks of TANV in the ROC coincided with the abundance of mosquitoes, and (c) serological analyses of inhabitants in the Tana River Valley, in 1971, showed a similarity in the incidence and distribution of antibodies against TANV and West Nile virus (known to be transmitted through mosquitoes) in the same serum samples.
The replication cycle of TANV is significantly longer as compared to that of VACV. TANV replicates well at both 33° C and 37°C. A single-step replication curve showed the eclipse phase of 24–48 h postinfection (hpi) and a latent phase of 36–48 hpi, in TANV. An earlier study demonstrated that the host range of TANV is limited to humans and monkeys. TANV isolated from skin lesions of infected humans was tested for its ability to infect a wide range of hosts including calf, lamb, pig, goat, and monkeys, among which TANV was only able to infect monkeys as demonstrated by the development of skin lesions and neutralizing antiviral antibodies in infected monkeys. TANV has also been shown to be antigenically distinct from other poxviruses, including YMTV, VACV, and variola virus.
VACV showed a strong bias toward the infection of blood cells such as monocytes, followed by B-lymphocytes and natural killer cells, indicating that poxviruses spread through hematogenous route to manifest the clinical disease. The ability of TANV to infect primary human dermal fibroblasts (pHDFs) and peripheral blood mononuclear cells (PBMCs) was tested, as both these cells are the major targets of poxviruses. TANV replicated well in pHDFs when the cells were in an exponential growth phase, while the viral replication was significantly lowered in quiescent pHDFs, invitro. Among the PBMCs, TANV showed a robust replication in monocytes (CD14+ cells), while it failed to infect other PBMCs with a low level of CD14 expression, invitro. Although the freshly isolated monocytes supported TANV replication, the virus failed to replicate after monocytes differentiated into macrophages. TANV also showed poor infectivity in peripheral blood lymphocytes, irrespective of their state of activation. Only a small proportion of T-lymphocytes (CD3+ cells) was infected with TANV, but the virus failed to replicate in these cells. An inability of TANV to cause a productive infection in most of the PBMCs except monocytes has been suggested to be the underlying cause of the self-limiting pathogenesis of TANV, in humans.
| > Immune Evasion|| |
Many viruses have evolved strategies to evade the innate and adaptive antiviral immune responses for their survival in hosts. These strategies usually involve secreted viral immunomodulators, also referred as virokines and viroceptors., A wide array of immunomodulatory strategies have been identified in poxviruses, including the TNF inhibition, the inactivation of IFN, and molecules mimicking epidermal growth factors.,, TANV-encoded virokines and viroceptors include TANV-2 L, TANV-15 L, TANV-136R, and TANV-142R gene products. TANV also induces selective inhibition of cell adhesion molecule expression. The viral protein responsible for this phenomenon was identified and originally termed gp38. Later, the viral gene encoding this protein was identified as 2 L. Moreover, it has been shown that the TANV-2 L gene product exhibited inhibitory properties for human TNF (hTNF) and blocked the hTNF from binding to its receptors including TNFRI and TNFRII., Further studies revealed the ability of TANV-2 L to interact with human beta2-microglobulin, in a similar manner as the major histocompatibility complex-I heavy chain. Similarly, TANV-15 L gene product was characterized as a mimetic of human NRG-1 and was capable of binding to the NRG receptor ErbB2/3. Recombinant TANV with 15 L gene deletion exhibited a reduced replication as compared to the wild type (wt) TANV, in human umbilical vein endothelial cells expressing NRG receptors, suggesting a stimulatory role of TANV-15 L protein in virus replication and production in some human cell types. Overexpression of ErbB3/4 has been associated with therapeutic resistance of many cancer types including breast cancer, prostate cancer, and melanoma, and elevated NRG has been shown to contribute to the melanoma progression.,, We have demonstrated that the purified TANV-15 L protein elevated the melanoma cell proliferation as effectively as NRG. TANV-136R encodes a Type I IFN-binding receptor, which shares more than 99% identity as YLDV-136R gene product. YLDV-136R protein has been shown to not only neutralize Type I IFNs, but also block the activity of Type III IFNs. Further studies are needed to confirm the biological activities of TANV-136R gene product in the pathogenesis and replication of TANV. Moreover, TANV-142R encodes a protein that is orthologous to the B1R protein expressed by VACV. This protein was demonstrated to possess the ability of phosphorylating p53, which induces cell apoptosis in viral infection and tumorigenesis.
| > Immuno-Oncolytics|| |
Although standard cancer treatments such as surgical tumor resection, chemotherapy, and radiotherapy can improve the survival rate, many human cancers are still difficult to treat. OVs offer an attractive treatment option which can selectively or preferentially kill cancer cells through both direct cell lysis and induction ofin vivo antitumor immunity. Poxviruses have drawn significant attention as OVs and are currently being investigated in several clinical studies.,, The susceptibility of a spectrum of human cancer cells to the TANV infection has been evaluated for its ability to replicate in human cancer cell lines. The cancer cells in our studies include those of breast cancer, glioblastoma, melanoma, osteosarcoma, retinoblastoma, ovarian cancer, renal cancer, colorectal cancer, and prostate cancer. Among all the cell lines tested, efficient TANV replication has been observed in melanoma cell line SK-MEL-3; breast cancer cell lines MDA-MB-231, MDA-MB-436, and MDA-MB-157; glioblastoma cell lines U-373 and U-118; colorectal cancer cell line HCT-116; and renal cancer cell lines ACHN and Caki-1.,,, Thesein vitro cell susceptibility experiments served as theoretical foundation for the subsequentin vivo experiments, where human xenograft tumors were induced in animal models and treated with oncolytic TANVs. Recent studies have shown that TANV is capable of significantly regressing a spectrum of human tumors, including colorectal cancer, melanoma, breast cancer, and retinoblastoma in a nude mouse model [Table 1].,, A variety of strategies have been devised in engineering oncolytic TANV variants for preferential targeting of tumor cells, virus-induced cancer cell lysis, and induction of antitumor immune responses. For instance, high quantities of TK are present in cancer cells in comparison to normal cells. Based on the functional similarity between the cellular and viral TK, ablation of viral TK from virus genome has been widely used for enhancing the tumor selectivity of OVs. We have deleted 66R gene-encoding viral TK from recombinant viruses to attain increased tumor selectivity.,
Moreover, immunomodulators encoded by TANV have also been manipulated to attain enhanced oncolysis. We have reported that TANV-15 L gene product mimicking the function of NRG elevates the melanoma cell proliferation. Therefore, we generated the recombinant TANV with 15 L gene deleted (TANVΔ15 L), which showed a more remarkable melanoma tumor regression compared to wt TANV., Since TANV-2 L gene product possesses functional TNF-binding activity, we hypothesized that the ablation of 2 L would increase the local concentration of TNF in the virus-infected tumors and that the inflammatory immune responses elicited by TNF would assist the tumor clearance. Hence, we deleted 2 L gene from TANV and generated TANVΔ2 L, which demonstrated a significant tumor reduction in colorectal tumors burdened in animal models. Our unpublished data also showed that TANVΔ136R significantly regressed melanoma tumors xenografted in nude mice, which might be due to the increase of local concentration of Type I IFN that possesses the antiproliferative activity.
A variety of cytokines and chemokines including IL-2, GM-CSF, bacterial flagellin C (FliC), and monocyte chemoattractant protein-1 have been incorporated into TANV for increasing the antitumor immune responses. For example, TANVΔ66R/mIL-2 was generated via replacing 66R gene with mouse IL-2 ORF. TANVΔ66R/mIL-2 has been shown to regress the human breast tumors established in nude mice, where mIL-2 expression has been shown to increase the accumulation of macrophages and monocytes in the tumors, contributing to more extensive tumor cell degradation. TANVΔ66R/mIL-2 has also demonstrated an ability to reduce the human melanoma tumor xenografts in nude mouse model (unpublished data). TANVΔ66R/mCCL2, expressing mCCL2, was also able to suppress the growth of human breast tumor xenografts in nude mice significantly.
| > Summary and Future Perspectives|| |
Our work has clearly demonstrated that TANV can serve as an efficient oncolytic agent for a variety of human cancers, including breast, melanoma, and colorectal cancers in the nude mouse model.,, More importantly, we have shown that the therapeutic potential of TANV can be significantly enhanced by engineering the virus to express immune modulatory cytokines and chemokines as it recruits the immune system in regressing cancer., Further understanding the functions of immunomodulators of TANV in the context of cancer initiation and progression would be valuable in optimizing the oncolytic capabilities of TANV. One example would be the TANV-15 L protein which mimics the function of NRG and enhances melanoma cell proliferation. Deletion of TANV-15 L was then applied for enhancing the melanoma regression ability of TANV. Moreover, instead of using TANV as a monotherapy, properly designed strategies for combining with other therapies are highly desired. While we have incorporated transgenes expressing mouse IL-2, mouse GM-CSF, mouse CCL2, and FliC in TANV for immune enhancement, other immunostimulatory proteins such as CD40 ligand (CD40 L), IL-12, and IL-18 are also of great immune activation potential to be included in TANV. In addition, combination of TANV with other immunotherapies, radiotherapy, and chemotherapy will be included in our future studies. Similarly, experiments are now in progress to demonstrate the effectiveness of TANV recombinants in an immunocompetent model.
Although the genome sequence of TANV has been reported, many gene products which are potentially immunomodulators have not been fully explored and remain of great interest. For example, TANV-10 L gene product is closely related to the serine proteinase inhibitor, which is widely known for its function in the suppression of toll-like receptor-mediated antiviral immune response and inflammation. TANV-134R protein showed a similarity to melanoma differentiation antigen mda-7, which possesses an antiproliferative activity for melanoma. More studies are needed to elucidate the immunomodulatory and immunostimulatory mechanisms of these gene products which can guide the engineering of improved oncolytic TANV.
Financial support and sponsorship
Michigan Kickstart Grant to KE.
Conflicts of interest
There are no conflicts of interest.
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