Triple-Negative Breast Cancer: Basic Biology and Immuno-Oncolytic Viruses.

1. Introduction

1.1. Triple-Negative Breast Cancer (TNBC)

Breast cancer (BC) is the most diagnosed cancer in the United States for women, and is also the number two killer among cancers in women [ 1 , 2 ]. The biggest challenge with BC treatment lies in the heterogeneity of the tumors. There are three different receptors that define different BC subtypes: estrogen receptors (ERs, inside cells), progesterone receptors (PRs, inside cells), and human epidermal growth factor receptor 2 (HER-2, also named CD340, a cell surface receptor) [ 3 , 4 ]. Of all of the new cases of BC each year, approximately 10–20% are negative for all 3 receptors and are categorized as TNBC [ 5 , 6 ]; however, within TNBC itself, there are several different subtypes based on differential gene expression. These types are as follows: basal-like (BL1 and BL2), mesenchymal (M), mesenchymal-stem-cell-like (MSL), immunomodulatory (IM), and luminal androgen receptor (LAR) [ 7 , 8 , 9 , 10 ].

The BL1 and BL2 subtypes differ in that BL1 has elevated gene expression for DNA damage response, proliferation signaling, and cell cycle checkpoint loss, whereas BL2 has elevated growth factor (GF) signaling, glycolysis/gluconeogenesis signaling, and myoepithelial surface receptors. This suggests that cells of the BL1/2 subtypes may be of basal or myoepithelial origin. The M subtype has elevated expression of cell motility pathways, receptor interaction with the extracellular matrix (ECM), and cell differentiation pathways. The MSL subtype shares expression with the M subtype, but it also uniquely expresses pathways related to GF signaling (inositol phosphate metabolism, platelet-derived growth factor (PDGF), epidermal growth factor receptor (EGFR), calcium (Ca 2+ ), G-protein-coupled receptor (GPCR), and extracellular-related kinase (ERK 1 and 2)), epithelial–mesenchymal transition (EMT), and Wnt/β-catenin. The MSL subtype also has a reduced expression of genes for cell proliferation. The IM subtype has an elevated expression of pathways involving immune cell signaling, cytokine signaling, antigen processing/presentation, and immune signal transduction. Finally, the LAR subtype has a heavily elevated expression of pathways related to hormone regulation, particularly with androgen receptor signaling (which can be approximately nine times as much as that of other TNBC subtypes) [ 8 ]. These extremely diverse genetic regulation conditions define tumor heterogeneity within TNBC, which helps to explain why TNBC is extremely difficult to treat in comparison with other BCs [ 8 , 11 ].

1.2. Development of Heterogeneity in TNBC

There have been a few theories to describe how heterogeneity in TNBC is established and maintained. The two main concepts are the cancer stem cell (CSC) hypothesis and the clonal evolution model (CEM). Other concepts, such as the deregulation of adult mammary stem cells (aMSCs), are described as contributing to developing TNBC in its initial stages [ 12 , 13 , 14 , 15 ].

The division of aMSCs gives rise to progenitors that further differentiate into basal or luminal progenitor cells. Under normal conditions, if basal or luminal progenitor cells are made, they further develop into mature basal or luminal cells; however, when the development of luminal progenitors is disrupted, cancer cells may develop. This is believed to occur via the improper regulation of Wnt/β-catenin pathways, transcription factors (TFs), such as Snail, and embryonic stem cell (ESC) markers (Sox2, Nanog, and Oct4). Combinations of genetic alterations to these pathways can make the progenitor cells de-differentiate and return to a proliferative state, which, when combined with other mutations, may result in TNBC [ 15 ].

The CSC model proposes that there is a hierarchy within cancers of tumorigenic cancer cells and their non-tumorigenic progeny. Within these subpopulations, the CSCs are hypothesized to be the driving forces behind the growth of a tumor, its progression, resistance to certain treatments, and metastasis [ 12 , 16 , 17 , 18 , 19 ]. This model does not address how to account for the massive variability in tumor heterogeneity between cancers of the same type in different individuals. Early characterizations of tumorigenic CSCs in BCs were via the expression of CD44 and not CD24 (including the opposite expression pattern); however, these characterizations have not held because many subtypes do not follow these marker patterns [ 12 ]. Moreover, the alteration of aldehyde dehydrogenase 1 (ALDH1) expression has also been independently reported to have tumorigenic potential in BCs [ 20 ].

The CEM presumes that there is one original clone that becomes cancerous, which then divides and, as carcinogenesis progresses, the cell as well as its subsequent progeny accumulate mutations in each cycle of clonal expansion, which results in the heterogeneity of the tumor. This model also assumes that there is no hierarchy among the cells and that, instead, natural selection determines which clones are successful and continue to divide. The cells that cannot undergo division are maintained as part of the tumor or will senesce, eventually being eliminated via necrosis [ 13 , 14 ]. Tumor heterogeneity may originate via some combination of the two models and several additional variables, including environmental factors, genetic background, and immune status. Hence, additional studies are needed to define the role of these contributing factors in individual cancers in order to formulate a more comprehensive model in the future.

1.3. TNBC Pathogenesis

Among the approximately 268,600 new cases of BC in the United States in 2019, about 10–20% of these were TNBC [ 21 ]. Estimates for 2022 suggested 287,850 new cases of BC in women of the United States, resulting in approximately 43,250 deaths [ 1 ]. TNBC, as a whole, is more aggressive, has more p53 mutations, has higher mitotic indices, has less defined nuclear pleomorphisms, has a higher average grade, and demonstrates higher rates of proliferation than typical BCs [ 22 ]. In addition to the above, TNBC has a high risk for relapsing in a patient following therapy, which factors into its high mortality compared to other BCs [ 23 ].

In the development and progression of carcinogenesis, epithelial–mesenchymal transition (EMT) has been repeatedly shown to be important in changing cell profile, metastasis, and even tumor recurrence [ 24 , 25 , 26 ]. Two genes, SLUG (a transcriptional repressor and regulator) and SOX10 (a TF), have been shown to have increased and preferential expression within TNBC. It has been shown that, when ALDH1 is simultaneously expressed with SLUG, there is an association with shorter disease-free survival rates and the conversion from EMT into mesenchymal–epithelial transition (MET) in metastatic sites. MET is the reverse of EMT, and it is denoted by the reacquisition of epithelial characteristics [ 27 , 28 ]. Of the TNBC subtypes, M and MSL have been linked to metaplastic BCs expressing some of these characteristics [ 29 ].

Another factor that contributes to the difficulty in treating TNBCs is the high degree of variance among the mutations acquired. The most common mutations are to p53 (up to 80%), followed by phosphatase and tensin homolog (PTEN) (35%) as well as inositol-polyphosphate-4-phosphatase type 2 (INPP4B, 30%) [ 30 , 31 , 32 ]. So far, none of the mutations described in TNBCs have been determined to be the “driver” of carcinogenesis [ 33 ]. The BRCA1 and BRCA2 genes have been shown to contribute to carcinogenesis particularly in BCs with a familial linkage (15–20%) or in those who are already carriers of one mutation in breast tissue [ 34 , 35 , 36 ]. Other risk factors are numerous, and lifestyle habits, such as diet and obesity, can increase the likelihood of developing TNBC [ 37 ]. During metastasis, TNBC has been documented to go to the lungs, liver, and brain more often than bone, which is the typical site for other BCs [ 38 ]. In a separate study, it was observed that, of 116 patients diagnosed with TNBC between 2000 and 2006 at the Dana–Farber Cancer Institute, 46% of the patients were diagnosed with metastases to parts of the central nervous system (CNS), and the median survival rate following prognosis was 4.6 months [ 39 ].

1.4. TNBC Ecology

Neoplastic cells must compete for resources with nearby healthy cells; however, these neoplastic clones also often compete amongst themselves. This is because different mutations acquired in these neoplasms impact replication and resource acquisition rates. It has been shown that neoplastic TNBC cell clones injected into opposite flanks of mice and rats can inhibit the growth of one another or that one set of clones can completely inhibit the other [ 40 , 41 ]. Neoplastic cells have also been described as parasites working towards establishing independence [ 14 ]. It has been suggested that the stimulation of fibroblasts and macrophages towards angiogenesis and the release of growth factors could aid TNBC clones in establishing tumors. The release of elastases and matrix metalloproteinases (MMPs) by macrophages for ECM degradation has also been suggested to be a contributing factor in establishing tumor beds and metastasis [ 42 , 43 ]. Additionally, it has been suggested that neoplastic TNBC clones participate in a commensal interaction with nearby non-metastatic clones where diffusible factors are absorbed, allowing them to take up a metastatic phenotype without needing to accumulate genetic mutations first [ 40 , 44 , 45 , 46 ].

Furthermore, data acquired from studying cocultures of different BC cell lines in vitro show that certain interactions between cells can impact growth, both positively and negatively. MDA-MB-231 cells coincubated with supernatants of MCF-7 cells increased proliferation over time, whereas coincubation with BT-474 cells or simply other MDA-MB-231 cells hampered growth [ 47 ]. Potential explanations for these observations were hypothesized as distant cell interactions where cell culture medium differences created competitively favorable environmental conditions or that ER − /PR − cells can utilize auto and paracrine self-regulation pathways to synthesize their own GFs more frequently than BC cells that express ER and/or PR [ 48 ]. Therefore, these cells could independently sustain their growth without an autocrine loop. Neoplasms also have important interactions with the TME in supporting the growth of a developing tumor. These interactions are complex as differing TME conditions have varied impacts on carcinogenesis; normal epithelial cells can become carcinomas [ 49 ] and teratocarcinomas can have their phenotype suppressed [ 50 ] or even potentially reverted [ 51 ] based on conditions present in the TME.

1.5. Current Standard Therapies for TNBC

Due to the extreme heterogeneity of TNBC, chemotherapy with anthracyclines or taxanes remains the standard for the treatment of TNBC. There are a few mechanistic targets for therapy such as DNA repair, cell proliferation, and p53 [ 52 ]. Patients with TNBC have been documented to receive significant benefit from and even respond better to chemotherapy than other BC types do, despite the more aggressive phenotypes [ 53 , 54 , 55 ]. Ultimately, if a patient’s TNBC becomes metastatic, particularly during a recurrence, survival falls to 0%; even combinatorial therapies that trade increased toxicity for potentially elevated responses result in no benefit to survival rates [ 56 , 57 ].

However, in March 2019, the US FDA granted accelerated approval for an immunotherapy regimen for patients with BC. The treatment includes the use of atezolizumab (Tecentriq ® ) combined with nanoparticle albumin-bound paclitaxel (Abraxane ® , nab-paclitaxel) in patients with metastatic TNBC where ≥1% of the tumor area is positive for immune cells expressing programmed cell death-ligand 1 (PD-L1) [ 58 , 59 ]. Atezolizumab is a humanized IgG1 monoclonal antibody that binds directly to PD-L1 and blocks a receptor’s interaction with PD-1 as well as the costimulatory protein B7-1 [ 60 ]. Nab-paclitaxel is a microtubule inhibitor that, when bound to nanoparticle albumin, increases solubility, minimizes hypersensitivity reactions, has better transport across endothelial tissue, greater tissue penetration, and a slower elimination time as compared to unbound paclitaxel [ 61 , 62 , 63 , 64 , 65 , 66 ]. Results from a double-blind, randomized, and placebo phase III clinical trial lead to this regimen’s accelerated approval [ 60 ]. When the combination of atezolizumab and nab-paclitaxel was compared with the placebo plus nab-paclitaxel for the primary treatment group, patients had an average increased progression-free survival (PFS) of 1.7 months and a 20% reduction in risk for disease progression and/or death. In the PD-L1-positive subgroup, the PFS increased further to 2.5 months as well as further decreased the risk for disease progression and/or death to 38% [ 60 ]. Even though this new therapy shows promise to increase the lifespan of patients slightly, this may merely delay the inevitable in most cases; therefore, new targeted therapies are still needed for TNBC.

2. Oncolytic and Immuno-Oncolytic Viruses (OVs)

These are a class of viruses that have either been selected as unmodified wild-type ( wt ) viruses or genetically engineered via the deletion of viral genes and/or the addition of immuno-modulatory genes for use as therapeutics against cancer. These viruses enter a tumor and ultimately lyse the cancer cells in a targeted manner, aiming to leave non-cancerous cells alone. Some OVs bear genetic inserts that induce changes within a cell, to the TME, or to immune cells within a host. Many of these viruses may also be modified via deletions to accomplish things such as decreased pathogenicity or increased tumor preference/selectivity [ 67 ]. As of now, there are 157 studies across the world that are using OVs in the treatment of various cancers in human trials, with 10 having TNBC as the host disease [ 68 ]; however, there are many more virus platforms “in the pipelines” for BC/TNBC. Some of these viruses are as follows: adenovirus [ 69 , 70 ], vaccinia virus [ 71 , 72 ], tanapoxvirus [ 73 ], parapoxvirus [ 74 ], marabavirus [ 75 ], poliovirus [ 76 ], measles virus [ 77 ], herpes simplex virus [ 78 ], and Newcastle disease virus [ 79 ].

2.1. History of Viruses in Cancer Therapy

Even though the term “oncolytic virus” did not immediately appear in the field of oncology, the first clinician credited for observing a virus inducing spontaneous tumor regression dates back to De Pace in 1912 [ 80 ]; he administered a rabies vaccine after a female patient was bitten by a dog, and her gynecological tumor began shrinking. There were also case reports from before De Pace, where a tumor would begin regressing alongside the incidence of a natural infection. In these reports, many of the patients had malignancies such as lymphomas or leukemia, both of which create significant immunosuppressive environments [ 81 , 82 , 83 ]. George Dock’s case has been widely referenced because there was a woman with leukemia who went into remission after being infected with influenza; her enlarged spleen and liver reduced in size almost back to normal, and she had a 70-fold reduction in leukocytes. The original report was made in 1896 and published in 1904, before De Pace, and nearly 40 years prior to influenza being categorized as a viral infection in 1933 [ 84 ].

Throughout the 1920s, Levaditi and Nicolau from the Pasteur Institute experimented on tumors transplanted into animals, mostly rabbits. They showed evidence that multiple “naturally occurring” viruses could induce the remission of implanted tumors, including complete regressions [ 85 ]. Newcastle disease virus (NDV) emerged as a virus of interest, originally isolated from poultry, by Levaditi and Haber, who more extensively described its oncolytic activity in 1936 [ 86 ]. In the late 1940s–50s, clinical trials commenced in the United States with naturally occurring viruses, such as dengue virus, West Nile virus, mumps virus, and NDV. These trials were abandoned, as most patients either suffered from viral disease in addition to their cancer or oncolytic effects were short-lived upon the development of antiviral antibodies [ 87 ].

Separately in 1949, there were two patients with Hodgkin’s lymphoma that experienced brief incidents of remission after becoming infected with hepatitis B virus. This generated a clinical trial where 22 patients with Hodgkin’s lymphomas were treated with impure samples of sera or tissue from individuals infected with “the hepatitis” virus [ 88 ]. Of the 22 patients, the first died directly from the virus and 13 others developed disease from hepatitis B; however, 7 of those who showed signs of viral disease had noticeable improvement in their cancer for at least 30 days, and 4 in that group even had tumor regressions. However, the trials with hepatitis viruses were stopped due to unacceptable toxicities.

One set of human trials with the mumps virus in Japan garnered much interest in the field. It was observed that host antiviral immunity enhanced the oncolytic activity seen in patients with ovarian cancer and glioblastomas [ 89 , 90 ]. Although the initial human trials had numerous issues, such as the selection of patients with pre-existing antiviral immunity and inconsistent sourcing for viral treatments, the results reported were promising; there were 90 patients treated, and 37 of them showed significant and even total tumor regression. Furthermore, 90% of the patients had some degree of response to the therapy, despite the presence of antiviral immunity in the majority of the enrolled patients [ 89 ]. Unfortunately, subsequent trials did not show similar levels of success, leading to the eventual halting of the pursuit of its use as a cancer therapeutic, until recently [ 90 , 91 , 92 ].

The expansion of chemotherapeutics, radiotherapy, and surgery, alongside a lack of funding, caused reluctance to continue clinical research on OVs in the U.S.A. With the U.S. president Nixon’s declared “war on cancer” in 1971, funding in the field was expanded for research on various cancer therapeutics, though for OVs funding was tighter than for other experimental therapies [ 85 ]. For progress to be made in the field, research had to be focused on developing better in vitro and in vivo animal models in order to provide evidence that oncolytic virotherapy was viable and, most importantly, safe in humans.

Attempts to address this issue had been developing since the mid-1940s by establishing animal models in order to test OVs. Initial reports showed that the newly available cell line mouse sarcoma 180 could be lysed by OVs in animals [ 93 ]. Russian Far East encephalitis virus (EEV) (known now as tick-borne encephalitis virus) [ 94 ] was used to treat transplantable mouse tumor cells, and observed tumors were completely eliminated with elevated doses in some cases. In 1951, another study described complete responses in experiments with five other mouse tumor lines [ 95 ]; it was observed that, after the tumors were infected and removed from one animal, the transplant would fail in another animal. A significant downside to EEV was that its neurotropism caused death for the treated mice. Regardless, these experiments set the precedent for using animal models in testing as a proof of concept prior to clinical trials in human subjects [ 96 ].

These experiments helped generate the hypothesis that viruses of non-human origin could be used in an oncolytic capacity without causing disease in non-adapted hosts. This would circumvent the obstacle of pre-existing antiviral immunity and pathogenicity [ 96 ]. Support for this idea came from work showing that the reverse was true; human viruses could be used to treat animal cancers [ 93 , 95 ], and work performed with NDV in Europe supported the idea that viruses from non-human natural hosts could be used as OVs in humans [ 86 , 97 , 98 ]. To increase efficiency and adapt viruses to human cells, repeated selective passaging was carried out in cancer cells. Data from EEV showed that it could increase oncolytic efficacy when passaged 20–30× in a tumor cell line as compared to the non-passaged parental strain [ 99 ]. It was also hypothesized that passaging in purified cancer cells would decrease tropism for healthy cells or avoid it altogether [ 100 , 101 ]. Another study was conducted where 24 candidate viruses were tested for replicative ability in human tumor cell lines; 6 viruses were identified with the capacity to do so in vitro [ 100 ]. Of those six, infectious bovine rhinotracheitis virus and equine rhinopneumonitis virus showed oncolytic activity in vivo in Syrian hamster models against HeLa cells and KB cells, respectively, further confirming the potential for viruses not endemic to humans to be candidates for development as OVs [ 101 ].

Other animal viruses were also explored, such as the avian plague virus (AVP), which was tested due to the belief that it would be less pathogenic to humans than many of the viruses used in the past were. A common side effect was strong neurotropism that would inevitably kill the host, even after destroying transplanted tumor cells [ 102 ]. The hypothesis that AVP was a safer and equally effective OV was tested in mice bearing sarcoma-97 tumors; the tumors were initially regressed and even caused some remissions, but AVP quickly spread to the brain of these mice and ultimately killed them [ 96 ]. Unfortunately, these data supported numerous other observations that every OV tested so far had some degree of neurotropism [ 99 , 103 , 104 , 105 ]. As described by Cassel and Garrett in a 1965 study, “When one considers the viruses that might be studied to derive a type which is oncolytic, non-neurotropic and has no major drawback, it is apparent that the list of candidate viruses is impressively small. A practical compromise would be to settle for an oncolytic virus with the lowest degree of neurotropism obtainable” [ 106 ]. NDV was selected as a potential OV for this study, where it was inoculated into mice with Ehrlich ascites carcinomas (EAC). Within 8 days, 97% of tumor cells were lysed. Considering that this was carried out with a very small inoculation of NDV (1 × 10 4 EID 50 ), and that there were no observable neurotropic effects, the results provided strong evidence that viruses were capable of cancer treatment. Further work still needed to be performed with potential OVs in order for them to become viable anticancer agents, as it was clear that many viruses were not suitable for therapeutic use in their natural forms.

2.2. Genome Manipulation and Genetically Engineered Viruses

Pathogenicity and neurotropism concerns with most OVs led the field to focus on decreasing tropism for non-cancerous tissues. An early review addressed the future of OV development [ 107 ]. One question was whether OVs could be manipulated in the lab to increase their oncolytic efficacy. The problem was that no technology was available for identifying genes of interest in the viruses, let alone modify them. Instead, it was suggested that tropisms for other tissues could be interfered with by other viruses or chemicals. It was well-known that viruses could interfere with the replication of one another [ 108 ], so experiments were carried out to see if NDV could reduce the neurotropism of viruses that showed great oncolytic potential, but later killed the mice due to encephalitis; most importantly, doing so while still retaining oncolytic efficacy at the tumor [ 109 ]. The investigation showed that the protection provided by viral interference was related to how quickly encephalitis took place. If encephalitis occurred rapidly, the protection was minimal from NDV; however, if the neurotropic process was slower, the protection was greater, but not complete. For Egypt 101 (West Nile virus), not only did NDV fail to prevent death from encephalitis, it also became less effective against the EAC tumors that it was supposed to treat. Alternatively, Bunyamwera virus encephalitis was prevented by NDV, but it failed to have therapeutic efficacy and the tumors killed the mice.

It took almost 30 years to see genetic engineering used for OVs, even though the principle was being used for gene editing therapies in other diseases [ 110 , 111 ]. The proof of concept for genetic engineering in viruses had been accomplished in the 1960s via the insertion of nucleotides to express polylysine in the tobacco mosaic virus [ 112 ]. It took until 1991 for genetic engineering to be used for OVs, with the deletion of viral thymidine kinase (TK) in herpes simplex virus-1 (HSV) for the treatment of glioma [ 113 ]. It was observed that TK-negative mutants of HSV were replicatively attenuated in normal, non-dividing cells, but could still replicate in cells that divided regularly, such as in cancer. Mice bearing U87 human gliomas were injected directly into their brains with the mutant HSV (dlsptk). Not only did the virus prolong survival, but it was capable of complete tumor elimination. This virus, although attenuated for neurovirulence, still had evidence of encephalitis in some mice. Despite this, more than 25% of the mice survived the cancer and OV injection [ 113 ].

Since then, the field of oncolytic virology has rapidly expanded, with the advent of genome sequencing to specifically target and remove pathogenicity genes [ 114 ], add in genes with immunomodulatory characteristics [ 73 ], and even modify viral surface proteins to allow the specific replication of an OV into tumor cells with corresponding receptors [ 77 ]. Genetic manipulation allowed for the attenuation of pathogenicity without crippling oncolytic efficacy, potentially even enhancing it. The threat of non-human OVs undergoing evolutionary pressure to switch host tropism exists, but modern screening techniques allow for the selection of viruses with lower mutational rates and higher genome stability.

3. Preclinical OVs for TNBC

Much research is being carried out in order to study several different OV platforms for the potential treatment of TNBC. OVs being studied in BCs not classified as TNBC will not be described here, though recent reviews of these viruses are available [ 115 , 116 ]. Below, currently described viruses tested against TNBC preclinically in vitro and in vivo, as well as those currently in human clinical trials, are summarized.

3.1. Adenovirus

Adenoviruses (ADV) are non-enveloped dsDNA viruses in the genus Mastadenovirus and the family Adenoviridae . At this moment in time, the largest number of OV recombinants from any viral classification that have been tested against TNBC are adenovirus strains. A type 5 adenovirus expressing green fluorescent protein (GFP) and the human telomerase reverse transcriptase gene (hTERT), OBP-401, was tested for infectivity in specialized MDA-MB-231 cells that had shown higher metastatic potential than their parental lines [ 117 , 118 ]. In vitro testing displayed increased GFP expression in the highly metastatic cells, which translated into lower percent cell viability in the highly metastatic cells than the parental cells [ 117 ]. It was also demonstrated that, following three treatments of OBP-401 in vivo, xenografted cells could be eliminated completely with no lymph node metastasis and very few lung metastatic cells in comparison to the vast metastasis seen in the control animals.

Another adenovirus, P55-HTERT-HRE-TRAIL, expresses TNF-related apoptosis-inducing ligand (TRAIL) with expression specificity to tumor cells driven by hTERT and hypoxia response element (HRE) promoters [ 69 ]. In vitro, the virus infected MDA-MB-231 cells preferentially over control MCF-10A cells in a significant manner, while also expressing TRAIL at elevated levels. When tested in vivo, the TRAIL expressing ADV inhibited orthotopic tumor growth, with increased efficacy at a higher dose (4 × 10 8 ) and significantly prolonged survival in a metastatic tumor model, while also reducing metastases compared to control animals.

Combinatorial therapies and new approaches to the modulation of gene expression within infected tumors are also being tested in ADV platforms against TNBC. An oncolytic ADV was tested with an adjuvant therapeutic temozolomide, which is converted into an alkylating agent under physiological conditions. The combination was shown to enhance viral replication and oncolytic effect in TNBC cells in vitro [ 119 ]. Long non-coding RNAs have also been inserted into an ADV recombinant to disrupt metastatic cell signaling and oncogenic miRNAs that can help cancerous cells undergo EMT [ 120 ]. The resulting recombinant AdSVP-lncRNAi9 was effective at reducing tumor growth in mice and blocking the activity of multiple miRNAs that drive oncogenesis. Furthermore, a recombinant ADV expressing granulocyte-macrophage colony-stimulating factor (GMCSF) in combination with immune checkpoint inhibitors (ICIs) was able to control tumor growth in vivo and promote increased survival compared to control-treated animals [ 121 ]. Pairing histone deacetylase inhibitors (HDACis) with a recombinant ADV expressing an αvβ6-integrin-binding peptide from foot and mouth disease virus demonstrated effective tumor reduction and increased viral replication in a SUM159 xenograft mouse model [ 122 ].

Finally, a chimeric ADV has also been constructed to be tested as an oncolytic against TNBC. A chimeric virus between type 5 ADV and type 11b ADV was produced and the cytokine Rantes (regulated upon activation, normal T cells expressed and presumably secreted, also known as CCL5) was inserted into the E3 region of the viral genome [ 123 ]. The chimeric and recombinant Ad5F11bSP-Rantes was tested against a panel of TNBC cell lines in vitro and then trialed in an NCG mouse xenograft model bearing MDA-MB-231 tumors. The results from this study showed that the chimeric ADV efficiently reduced tumor size and that the expression levels of Rantes were elevated in the blood of mice treated with Ad5F11bSP-Rantes compared to a control and an eGFP expressing ADV. Added to this were significantly elevated levels of CD3 + T cells infiltrating tumors treated with the chimeric ADV, demonstrating that Rantes expression was helping to direct the chemotaxis of immune cells towards the tumor.

3.2. Herpes Simplex Virus

Herpes simplex virus (HSV) is a dsDNA virus from the genus Simplexvirus , family Alphaherpesvirinae . Canerpaturev (C-REV) is an oncolytic mutant of HSV that alone has antitumor efficacy against TNBC. It has also shown a promising oncolytic effect when combined with 5-fluorouracil (5-FU) and S-1 (a combination of gimeracil, oteracil, and tegafur) against TNBC in vivo in a bilateral 4T1 tumor model [ 124 ]. S-1 metabolizes into 5-FU and includes protective effects to increase the bioavailability of 5-FU within treated tissues [ 125 ]. The antitumor effect of C-REV is augmented by 5-FU via the latter enhancing the inhibition of growth factors, increasing the number of CD8 + T cells and their interferons, and decreasing the number of myeloid-derived suppressor cells (MDSCs). Reduced MDSC numbers are important as these cells suppress T cell activation, which would directly inhibit the antitumor effects driven by the immune response [ 126 , 127 , 128 , 129 , 130 ]. The study suggested that MDSCs should therefore be a cellular target when treating TNBC.

Talimogene laherparepvec (T-vec, Imlygic) is another HSV-1 mutant that has GMCSF inserted and deletes viral ICP34.5 as well as ICP47. The deletion of ICP34.5 is to decrease pathogenicity and make the virus tumor-selective [ 131 ]. ICP47 is deleted to prevent T-vec from replicating within cytotoxic T cells [ 132 ]. The deletion increases the expression of US11 within the virus, which increases its replication in tumor cells without compromising tumor selectivity [ 114 ]. Its mode of action is two-fold: the direct lysis of cancer cells, leading to the release of tumor-specific antigens (TSAs), and then the attraction of dendritic cells as well as macrophages to the TME from the release of GMCSF. The addition of the ICI paclitaxel as an adjuvant therapy stabilizes tubulin within microtubules and prevents depolymerization. This leads to mitotic arrest during the metaphase as spindle fibers cannot function properly [ 133 ]. When used together, they have been demonstrated to be a potent antitumor combination. Not coincidentally, T-vec is in clinical trials for many cancers and has been approved as the only oncolytic virus in the United States for the treatment of advanced-stage melanomas [ 114 , 134 ]. Though T-vec is currently in human trials for TNBC, no preclinical data on this cancer are available.

3.3. Chimeric Poxvirus

The original study detailing a chimeric Orthopoxvirus (dsDNA virus), CF33, describes the genome of this OV derived from nine different parental poxviruses: cowpox virus (Brighton strain), raccoonpox virus (Herman strain), rabbitpox virus (Utrecht strain), and six different vaccinia virus (VV) strains (WR, IHD, Elstree, CL, AS, and Lederle-Chorioallantoic) [ 135 ]. These viruses were coinfected into CV-1 cells, plaque-purified, and the isolates were then high-throughput screened for the highest tumorigenic properties against the cancer cell lines present in the NCI-60 lineup; CF33 was chosen from this screening. In vitro testing demonstrated potent cytotoxicity and viral replication in TNBC cell lines where endogenous phospho-Akt activity was present (BT-549, Hs578T, and MDA-MB-468). This activity results from mutations to the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. The cell lines that demonstrated this activity allowed for better CF33 replication than in the MDA-MB-231 cell line, which has wtPI3K/Akt and PTEN pathways. When CF33 was tested in vivo in an MDA-MB-468 xenograft model, low titers of virus (10 3 and 10 4 ) demonstrated a significant reduction in tumor volume when compared to mock treated control tumors.

These results prompted another preclinical study where CF33 was modified to CF33-hNIS-anti-PD-L1 [ 136 ]. CF33-hNIS-anti-PD-L1 expressed two genes: sodium iodide symporter (hNIS) and a single-chain variable fragment of the PD-L1 binding ligand. CF33-hNIS-anti-PD-L1 also showed efficacy against MDA-MB-468 cells when tested in a xenograft model and did not show any dose-related toxicity. This included an intracranial injection at ten times the lethal dose of the Western Reserve (WR) strain. There was a lower degree of efficacy in syngeneic TNBC models 4T1 and E0771, but previous work had shown that the murine tumor cells were less susceptible to infection by CF33 [ 137 ]. Of note, the anti-PD-L1 antibody encoded by the virus was shown to be nearly as effective at competitive binding as the FDA-approved atezolizumab, with expression and functionality confirmed.

Another chimeric poxvirus has been developed and studied against TNBC. This chimeric virus, CF189, was created using a coinfection of cow kidney epithelial cells with orf virus strain NZ2 and the TJS strain of pseudocowpox virus [ 74 ]. CF189 caused lytic infection in numerous TNBC cell lines in vitro. MDA-MB-468 xenografts on mice were significantly reduced compared to the negative control with doses as low as 1 × 10 3 PFU of CF189. Contralateral tumor sites on these mice were also controlled, even when the virus was not injected directly into those tumors, indicating the virus can travel to distal sites and exert antitumor effects.

3.4. Tanapoxvirus

Tanapoxvirus is a dsDNA virus from the genus Yatapoxvirus and family Poxviridae . It is of similar genomic and particle size to VV (144 kbp and ~65 nm, respectively), and causes mild febrile illness that is limited to humans and monkeys [ 138 , 139 , 140 ]. Preclinically, two virus recombinants have been tested in vivo against an MDA-MB-231 xenograft model in athymic nude mice, demonstrating significant tumor growth reduction: TPV/Δ66R/mIL-2 and TPV/Δ66R/mCCL2 [ 73 ]. The first recombinant carries inserted mouse interleukin-2 (IL-2), which serves primarily as the T cell and natural killer (NK) cell growth factor but also helps in T cell maturation as well as the activation of antitumor macrophages [ 141 , 142 ]; the second recombinant carries inserted mouse chemoattractant protein 1 (CCL2/ MCP1), which is an activator of monocytes, mast cells, dendritic cells, NK cells, and T cells in the inflammatory response [ 143 , 144 , 145 ]. Both viruses carry deletions of viral thymidine kinase (TK, ORF 66R), as is the case in many other poxviruses, to provide preferential replication in tumor cells. When tested in an athymic nude mouse model, both viruses showed significant differences in tumor volume compared to control mice and demonstrated increased immune cell infiltration into tumor sites as well as a reduced tumor mitotic index within the tumors compared to the control-treated tumors [ 73 ].

3.5. Vaccinia Virus

VV is a dsDNA Orthopoxvirus in the family Poxviridae . It is a prominent poxvirus in many cancer studies due to its large genome, which can handle many genetic inserts simultaneously, the fact that it replicates quickly, and due to it having a known safety profile. GLV-1h153 is an oncolytic VV that expresses hNIS. The natural expression of hNIS exists in tissues outside of the thyroid, including breast tissues; therefore, its overexpression in some cancers serves as a potential target, including in TNBC [ 71 , 146 ]. This treatment was paired with single-photon emission computed tomography (SPECT) imaging to track the uptake of radioactive iodine into tissues where the virus replicated. The radioactive iodine was also used as an adjuvant therapy for GLV-1h153, increasing its efficacy when used in combination in MDA-MB-231-xenografted mice compared to either treatment alone [ 71 ]. A similar virus, GLV-1h164, which encodes for GLAF-2 (an antibody against vascular endothelial growth factor, VEGF), was also tested in TNBC. Similar to the results with GLV-1h153, GLV-1h164 also showed efficacy in vivo in terms of treating MDA-MB-231 xenografts compared to a negative control and the parent virus (GLV-1h100). This virus also decreased blood flow to the infected tumors compared to parent-virus-infected tumors, demonstrating the effective targeting of VEGF [ 72 ]. DNA-based oncolytic viruses and genetic modifications employed therein, which have been tested preclinically in TNBC, are summarized in Table 1 .

3.6. Alphavirus M1

M1 is a strain of the Getah-like alphavirus that was derived initially from mosquitos and is non-pathogenic in normal mice or rat tissues. It also has no known disease-causing capability in humans. It is a positive-sense RNA virus from the family Togaviridae . Initial studies showed that this virus had the ability to selectively kill cells lacking the antiviral zinc finger protein (ZAP) in human cancers. Oncolytic activity was reported to be mediated through stress to the endoplasmic reticulum leading to apoptosis [ 147 ]. Later, this virus was tested against varying types of BC, including TNBC [ 148 ]. In this study, M1 did not initiate anticancer activity as previously shown, but instead activated necroptosis. Though some pathways are shared between necroptosis and apoptosis, the inhibition of caspases and activation via tumor necrosis factor is required for necroptosis to occur [ 149 ]. This study also revealed that doxorubicin (a topoisomerase II inhibitor) activates the GAS6/AXL pathway of M1, enhancing replication and increasing oncolytic efficacy [ 148 ].

3.7. Coxsackievirus B3

Coxsackieviruses are positive-sense RNA viruses from the genus Enterovirus in the family Picornaviridae . A coxsackievirus B3 (CVB3) platform was used to generate a recombinant virus that expressed multiple targeting sequences (TSs) of microRNAs (miRNAs) to reduce off-target toxicities when used in vivo. The initial TSs selected were mouse miR-145 and miR-143 as they are significantly downregulated in tumor cells to assist in proliferation and cell division. Multiple copies of each were inserted into the 5′UTR of the CVB3 genome. Initial testing showed safety concerns by day 12 following intraperitoneal (IP) injections of recombinant miR-CVB3 [ 150 ]. Further modifications were then made to add additional tissue-specific TSs of miRNAs for muscle-specific miR-1 and pancreas-selective miR-216; the former is highly expressed in the heart of mice and the latter is highly expressed in the pancreas. Both have been reported to be downregulated in numerous cancer types, including breast cancers [ 151 ]. The new recombinant, miR-CVB3-1.1, demonstrated significantly better safety results and significantly less viral capsid protein detected in the target organs of the heart and pancreas than wtCVB3. When tested in a syngeneic murine TNBC tumor model bearing 4T1 tumors, miR-CVB3-1.1 showed a significant reduction in tumor volume when injected IT at a titer of 1 × 10 6 when compared to an untreated control. The recombinant virus also significantly increased survival after 28 days compared to both untreated and wtCVB3 groups; however, intravenous (IV) administration failed to yield similar results to IT administration [ 150 ].

3.8. Maraba Virus

The oncolytic Maraba virus, MG1, is a genetically modified rhabdovirus (negative-sense RNA) originating from the vesicular stomatitis virus serogroup in the genus Vesiculovirus . Mutations were made to amino acid L123W in the M protein and Q242R in the G protein for attenuation in normal cells, while improving replication in cancer cells. This virus was also altered to include GFP [ 152 ]. After showing considerable efficacy in a mouse colorectal cancer model (CT26), with 100 percent survival and complete regression by day 35, the virus was tested in different BC lines, including patient-derived xenograft (PDX) models of TNBC [ 75 ]. MG1 showed variable infectivity in vitro of various BC lines but was greatly enhanced with paclitaxel treatment prior to infection. When the treatment was applied to a syngeneic mouse model bearing TNBC tumors, MG1 combined with paclitaxel significantly improved survival and reduced tumor volume in all three cell lines tested (EMT6, 4T1, and EO771) compared to a control, and in two cases when compared to MG1 alone [ 75 ]. Furthermore, when investigating metastases developed from TNBC in the same mouse models as before, MG1 was able to significantly reduce the number of metastases to the lungs. A combination with an ICI (anti-PD-L1 antibody) had the most promising results; the results showed that the combinatorial treatment had the smallest tumor loads and highest percent survivals when compared with any of their previous syngeneic TNBC mouse model experiments [ 153 ].

3.9. Measles Virus

Measles virus (MV) is a negative-sense RNA virus from the genus Morbillivirus in the family Paramyxoviridae . One oncolytic measles virus recombinant has been modified to include the proapoptotic gene BNiP3 in humans, rMV-BNiP3, which can act on BCL-2 family proteins and E1B 19 kDa proteins from adenoviruses [ 154 ]. This virus demonstrated a significant reduction in cell viability against MCF-7 and MDA-MB-231 cells in vitro when combined with paclitaxel and separately with a synthetic hydrazone derivative, H2, which is similar in structure to tamoxifen (estrogen modulator). Both H2 and paclitaxel, when combined with the oncolytic MV, significantly enhanced caspase 3 activity and apoptosis induction in MDA-MB-231 cells.

Another set of measles viruses was generated in order to target the urokinase cell surface receptor (uPAR), which is overexpressed in both mouse and human cancers [ 77 ]. One virus targets the human uPAR protein (MV-h-uPA) and the other targets the mouse homologous protein (MV-m-uPA). This occurs via the insertion of the corresponding amino terminal fragments of either human or mouse uPAR into the C-terminus of the mutated viral H glycoprotein [ 155 ]. Both virus recombinants were tested in NOD/SCID mice bearing MDA-MB-231 xenografts. The mice were injected three times, every other measurement period, and both viruses demonstrated the ability to individually regress the xenografts significantly when compared to a control. Furthermore, when both viruses were combined together in one treatment, an even greater synergistic effect was observed as the combinatorial treatment significantly reduced tumor volumes when compared to MV-h-uPA alone. The authors mention how MV-m-uPA cannot bind to the human uPAR present on the xenografted tumors but can bind to the mouse stromal cells and other mouse immune cells [ 156 , 157 ] that may have been recruited to the tumor [ 77 ].

3.10. Mumps Virus

Mumps virus is an enveloped, negative-sense RNA virus from the genus Orthorubulavirus in the family Paramyxoviridae . Samples of mumps virus used in the clinical trials described earlier in this review were obtained with the goal of continuing its development as an OV [ 158 ]. Since it was known that the original source material was not composed of purified viruses, the sample obtained from Japan was designated as MuV-U-Japan, and the subtypes within were isolated and studied for their oncolytic potential. Two of these isolates, named MuV-UA and MuV-UC, demonstrated potent oncolytic activity in vitro against stock TNBC cell lines and in vivo against an MDA-MB-231 xenograft model. The MuV-UC virus showed great potential in both tumor control and increasing survival when administered both IT and IV. In fact, multiple isolates alone, combinations of MuV-UA and MuV-UC, and even the MuV-U-Japan stock viruses showed significantly enhanced survival when delivered IV at 2 × 10 7 median tissue culture infectious doses (TCID 50 ), both as single-dose and multi-dose administrations. Conclusions drawn from this study support the idea of using MuV-UC for translation into clinical studies in the future.

3.11. Newcastle Disease Virus

NDV is a negative-sense RNA strain of Avian orthoavulavirus 1 from the Avulavirinae subfamily and the Paramyoviridae family. A lentogenic strain of NDV, called LaSota, was used to determine the oncolytic nature and efficacy of this virus in combination with doxorubicin in TNBC. The in vitro results showed that this NDV strain could replicate in and cause the cytolysis of 4T1 cancer cells in a dose-dependent manner [ 159 ]. When tested in a 4T1 syngeneic mouse model, the virus was administered at various hemagglutination unit (HAU) doses from 32 to 128, with one group featuring a combination with doxorubicin at 64 HAUs. This combinatorial experimental group demonstrated the greatest tumor reduction by eliminating treated tumors by day 10. The further evaluation of visceral organs showed no toxicity from viral administration and no reported long-term effects 1 year post-treatment.

3.12. Reovirus

Reoviruses are segmented dsRNA viruses in the Orthoreovirus genus, subfamily Spinareovirinae . A reassortant r2Reovirus was genetically engineered to include nine segments from the T1L strain (serotype 1 Lang) and one segment from the T3D strain (serotype 3 Dearing) of reoviruses [ 160 ]. The r2Reovirus has shown the capability to infect BC cell lines with variable efficacy, with most efforts concentrated on MDA-MB-231 cells. With the addition of multiple topoisomerase inhibitors, including doxorubicin, r2Reovirus infectivity increased and infected cell viability decreased compared to a control treatment [ 161 ]. The r2Reovirus demonstrated that IFN III mRNA and protein were produced in infected MDA-MB-231 cells as opposed to type I IFN, with a combinatorial treatment with topoisomerase inhibitors having no effect on viral replication. Caspase activity is also activated as a result of reovirus infection, but not in the typical manner; in some cases caspase 9 is activated, but not caspases 3 and 7, to induce programmed cell death [ 160 ]. In a different study, doxorubicin was conjugated to the r2Reovirus in order to enhance cytotoxicity and investigate in vivo applications of this combination against TNBC in a syngeneic 4T1 mouse model [ 162 ]. Both r2Reovirus alone and r2Reovirus conjugated with doxorubicin significantly reduced tumor growth when compared to a buffer-treated control or doxorubicin alone. This model also produces metastases to the lungs of tumor-bearing mice, and, though not statistically significant, treatment with r2Reovirus alone or when combined with doxorubicin reduced metastatic 4T1 cells in the lungs compared to an untreated control. All of the listed RNA OVs and their genetic modifications are outlined in Table 2 .

4. OVs in the Clinical Stage for TNBC

Oncolytic viruses that have reached human clinical trials for patients with TNBC are described below. A number of different approaches are being tested, including viruses being used as a monotherapy or combined with adjuvant chemotherapies, radiotherapy, or immunotherapies. A recent review of all available human trials involving OVs as of 2020 summarized the results and discussed the conclusions drawn from these studies [ 163 ]. Many trial studies have chosen combinatorial approaches with other commercial anticancer agents to be tested against each treatment individually, as some therapeutic regiments have seen improved clinical responses when compared to their components as monotherapies in other non-TNBC trials [ 164 , 165 ].

4.1. Adenovirus

ADV/HSV-tk is being tested in a phase II trial, with the objective being to test the efficacy as well as safety of stereotactic body radiation therapy (SBRT) together with the administration of ADV/HSV-tk and valacyclovir prior to treatment with pembrolizumab (Keytruda ® ) ( NCT03004183 ). ADV/HSV-tk + valacyclovir has shown an increased antitumor activity of NK cells, the stimulation of T-cells, and promoted lymphocyte infiltration into treated tumors in a previous human trial for patients with recurrent ovarian cancer [ 166 ]. The addition of valacyclovir is used to inhibit viral DNA replication. This, in addition to SBRT, induces the “abscopal effect”, where antitumor immune responses are enhanced from the radiation, allowing localized treatment to have an impact on metastatic tumor sites [ 167 ]. Pembrolizumab binds to the PD-1 receptor and allows for the activation of self-reactive Th17 clones. Some preliminary results are available, but have not yet been analyzed fully.

A different adenovirus, MEM-288, is being tested in a phase I dose escalation study as a monotherapy against numerous solid tumors, including TNBC. MEM-288 carries human interferon beta and recombinant, chimeric CD40 (MEM40). The overall goal of this study is to determine the maximum tolerated dose within a 3-week period and its safety in patients. The secondary objectives include the determination of the recommended dosage for a phase II trial (where MEM-288 will be combined with an ICI), efficacy, progression-free survival, response duration, and the presence as well as nature of the antitumor responses elicited. Dosages in the preliminary trial will reach as high as 1 × 10 11 adenovirus particles ( NCT05076760 ).

4.2. Herpes Simplex Virus (T-vec)

T-vec has entered a phase I clinical trial ( NCT04185311 ) for patients with TNBC, where the goal of the trial is to study the OV together with iplilmumab (an anti-CTLA-4 antibody) and nivolumab (an anti PD-1 antibody) prior to an attempted surgical resection. T-vec is to be injected intratumorally (IT) on three separate days (1, 22, and 36) with four nivolumab treatments as well as two ipilimumab treatments over the course of the study. In a different phase II study with T-vec, it was administered IT and combined with paclitaxel, followed by doxorubicin, cyclophosphamide, and surgery in patients with stage 2–3 TNBC. This study has been completed, with an analysis having been carried out of 37 of the 40 enrolled patients’ biopsies and trial outcome results ( NCT02779855 ) [ 168 ]. The primary end point of the trial was met as 45.9% of patients having a grade 0 residual cancer burden index (RCB) and the RCB0-1 (minimal residual disease) rate being 65%, totaling 24 of 37 analyzed patients. In all of the enrolled patients, 4 had distant recurrence after 30 months with 1 death because of the cancer, though none of these recurrence events were from patients in the RCB0-1 group. Six weeks post-therapy, there was a significant increase in effector T cell and memory T cell populations compared to pretreatment, with 76% of patients also having an increase in CD8 + tumor-infiltrating T cells. This increased CD8 + cell population was significantly higher in RCB0-1 patients than RCB2-3 patients. Responses for patients with >1% PD-L1 + cells were positively correlated with treatment outcome, though not significant. A key conclusion from this study was that immunotherapy agents should be administered as closely as possible to the adjuvant chemotherapeutic to help take advantage of the activation of immune cells rather than waiting for residual disease or planning for sequential administrations after the chemotherapy regimen.

Additionally, another HSV-1, called ONCR-177, is being tested in a phase I trial against a multitude of cancers, including TNBC ( NCT04348916 ). ONCR-177 expresses five different transgenes: interleukin 12 (IL-12), C-C motif chemokine 4 (CCL4, previously known as macrophage inflammatory protein), FMS-like tyrosine kinase 3 ligand extracellular domain (FLT3LG ECD), and anti-PD-1 as well as anti-CTLA-4 antibodies. It also does not have γ34.5 deleted, as is the case in most other HSV recombinant OVs. Previous work used miRNA silencing to allow the functional copy of ICP34.5 to exist in the viral genome and be inactivated at discretion; however, in cases where the interferon response may still function properly within a cancer cell, ONCR-177 would not be attenuated in these cells [ 169 ]. The goal of the clinical trial is to determine MTD and evaluate preliminary efficacy when ONCR-177 is injected IT either alone or when combined with pembrolizumab. Early data from this trial have led to the determination that the phase II dosage will be 4 × 10 8 plaque-forming units (PFU)/4 mL every 2 weeks, for up to 10 total doses. No dose-limiting toxicity was observed, and the side effects were deemed to be mild, grade 1–2 [ 170 ].

4.3. Reovirus (Pelareorep)

Pelareorep (Reolysin) is a naturally occurring Dearing strain of reovirus serotype 3, and is currently in two different clinical trials for humans. The first is an early phase I clinical trial that includes the use of three other drugs, in addition to the oncolytic, in patients with various types of BC. In addition to pelareoreop, atezolizumab will also be used for patients with TNBC, administered on day 3 of treatment. The goal of this study is to determine the safety profile and elicitation of antitumor responses by the OV in early stage BC ( NCT04102618 ). The second is a phase II clinical trial combining pelareorep with an ICI monoclonal antibody (retifanlimab) in late-stage TNBC (including metastatic TNBC) and other BCs ( NCT04445844 ). The goal is to test the efficacy and safety of the treatment regimen, as well as whether the PD-L1 expression levels pre-, during, and post-treatment are indicators of treatment outcomes. In both cases, the OV is delivered IV, and the virus will be administered a total of four times in the planned 28-day increments (repeated cyclically as long as quality of life remains acceptable and disease progression does not occur in the phase II trial).

4.4. Vaccinia Virus

A phase I/IIa multicenter trial using BT-001, an oncolytic vaccinia virus encoding recombinant human anti-CTLA-4 and GMCSF, is being tested both alone and in combination with pembrolizumab. The phase Ia trial is exploring the dose escalation for BT-001 via repeated IT injections in many different advanced solid tumors with or without metastases as a monotherapy. Phase Ib will have BT-001 administered IV in combination with pembrolizumab in the same types of tumors. Finally, in the phase IIa trial, BT-001 will be administered IT while pembrolizumab is used IV ( NCT04725331 ).

4.5. Measles Virus

A measles virus expressing hNIS (MV-NIS) is currently in a phase I clinical trial treating a variety of cancer types from squamous cell head and neck cancer to metastatic TNBC ( NCT01846091 ). The primary objective of the trial is to determine how well the virus is tolerated in these patients and to assess the safety profile of the virus when administered IT. The study also aims to look for efficacy in treating the target cancers as well as tracking the expression of NIS throughout cancerous tissues using SPECT imaging [ 171 ]. MV-NIS displays selective oncolytic activity via CD46. CD46 serves as a membrane regulator of complement activation that is overexpressed in many types of human cancers [ 172 , 173 , 174 ]. CD46 is bound to the virus using the hemagglutinin protein, and infection causes syncytia to form, leading to lysis [ 175 , 176 ]. CD46 also functions as a cofactor for the inactivation of C3b and C4b of the complement cascade via Factor-I, which can protect the cell from apoptosis [ 177 , 178 ]. The virus was tested and shown to be effective in human patients when delivered IV with titers as high as 1 × 10 11 capable of being tolerated in the treatment of multiple myeloma as long as the viral uptake was relatively slow [ 179 ]. MV-NIS is also genomically stable, with a low risk of reversion from its attenuated form into the pathogenic form [ 180 ].

Another phase I trial using a different recombinant, MV-s-NAP, is recruiting patients with metastatic breast cancers ( NCT04521764 ). The primary objectives of this trial are to determine the overall safety profile, MTD, and cumulative immune responses to the virus and tumor following IT injection of the virus. Virus administration is set to occur up to three additional times following the initial injection, provided that there are no signs of unacceptable toxicities or disease progression. This virus recombinant expresses neutrophil-activating protein (NAP) from Helicobacter pylori and was tested for safety in mice prior to clinical assessment [ 181 ]. MV-s-NAP showed, when administered IT or IV, that mice sensitive to measles infection tolerated the injections well, having no signs of negative effects on body weight, liver function, or circulating proinflammatory cytokines. Though viruses were detected in multiple organs via quantitative real-time reverse transcription PCR, mice did not succumb to disease and continued growing as normal throughout the study period. OVs and the current status of their clinical trials in humans are summarized in Table 3 .

5. Conclusions

This review summarizes the cellular biology of TNBC and the unique challenges that it presents to treatment. A brief history of OVs and their current studies in the pursuit of treating TNBC were also described. The combination of engineered tumor selectivity or replication preference, safety, low toxicity, and efficacy in vivo against a cancer type that makes conventional treatment extremely difficult would deem OVs as logical choices for further and continued investigation. Due to the extreme heterogeneity of TNBCs, many standard therapies have fallen short of achieving similar treatment success as compared to other BCs; all types except TNBC have seen increased 5-year survival rates over the past 20 years. The use of OVs with or without combinatorial drugs or radiotherapy has been taken to the clinic as a potential future treatment modality for TNBC and many other cancer types. Combinatorial regimens, such as the use of HDACis to enhance oncolytic HSV entry and replication within tumor cells [ 182 ], show that new pairings of already-existing therapies with OVs can lead to promising outcomes that can be translated quickly into human trials. Immuno-oncolytic viruses and other immunotherapies reflect a shift from a chemical to biological approach in the treatment of cancers. With T-vec being approved already in the United States for melanoma, other OVs will have the chance to gain approvals as well.

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Author Contributions

Conceptualization, M.L.M. and K.E.; methodology, M.L.M. and K.E.; validation, K.E.; formal analysis, M.L.M., O.A.I. and K.E.; investigation, M.L.M. and O.A.I.; writing—original draft preparation, M.L.M. and O.A.I.; writing—review and editing, M.L.M., O.A.I. and K.E.; visualization, M.L.M.; supervision, K.E.; project administration, K.E. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

References

1. Giaquinto A.N. Sung H. Miller K.D. Kramer J.L. Newman L.A. Minihan A. Jemal A. Siegel R.L. Breast Cancer Statistics, 2022 CA Cancer J. Clin. 2022 72 524 541 10.3322/caac.21754 36190501

2. American Cancer Society Cancer Facts and Figures 2022 American Cancer Society Atlanta, GA, USA 2022

3. Polyak K. Review series introduction Heterogeneity in breast cancer J. Clin. Investig. 2011 121 2011 2013 10.1172/JCI60534 21965334 PMC3195489

4. Neophytou C. Boutsikos P. Papageorgis P. Molecular Mechanisms and Emerging Therapeutic Targets of Triple-Negative Breast Cancer Metastasis Front. Oncol. 2018 8 31 10.3389/fonc.2018.00031 29520340 PMC5827095

5. Slamon D.J. Leyland-Jones B. Shak S. Fuchs H. Paton V. Bajamonde A. Fleming T. Eiermann W. Wolter J. Pegram M. Use of Chemotherapy plus a Monoclonal Antibody against HER2 for Metastatic Breast Cancer That Overexpresses HER2 N. Engl. J. Med. 2001 344 783 792 10.1056/NEJM200103153441101 11248153

6. Anders C.K. Carey L. A Biology, Metastatic Patterns and Treatment of Patients with Triple-Negtive Breast Cancer Clin. Breast Cancer 2010 9 S73 S81 10.3816/CBC.2009.s.008 PMC2919761 19596646

7. Lehmann B.D. Jovanović B. Chen X. Estrada M.V. Johnson K.N. Shyr Y. Moses H.L. Sanders M.E. Pietenpol J.A. Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection PLoS ONE 2016 11 e0157368 10.1371/journal.pone.0157368 27310713 PMC4911051

8. Lehmann B.D. Bauer J.A. Chen X. Sanders M.E. Chakravarthy A.B. Shyr Y. Pietenpol J.A. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies J. Clin. 2011 121 2750 10.1172/JCI45014 PMC3127435 21633166

9. Chen X. Li J. Gray W.H. Lehmann B.D. Bauer J.A. Shyr Y. Pietenpol J.A. TNBC type: A subtyping tool for triple-negative breast cancer Cancer Inform. 2012 11 147 156 10.4137/CIN.S9983 22872785 PMC3412597

10. Hatzis C. A Genomic Predictor of Response and Survival Following Taxane-Anthracycline Chemotherapy for Invasive Breast Cancer JAMA 2011 305 1873 10.1001/jama.2011.593 21558518 PMC5638042

11. Bertucci F. Finetti P. Cervera N. Charafe-Jauffret E. Mamessier E. Adélaïde J. Debono S. Houvenaeghel G. Maraninchi D. Viens P. Gene expression profiling shows medullary breast cancer is a subgroup of basal breast cancers Cancer Res. 2006 66 4636 4644 10.1158/0008-5472.CAN-06-0031 16651414

12. Corbin M. Morrison S. Tumor heterogeneity and cancer cell plasticity Nature 2013 501 328 337 24048065 10.1038/nature12624 PMC4521623

13. Marusyk A. Polyak K. Tumor heterogeneity: Causes and consequences Biochim. Biophys. Acta 2011 1805 105 117 10.1016/j.bbcan.2009.11.002 PMC2814927 19931353

14. Merlo L.M.F. Pepper J.W. Reid B.J. Maley C.C. Cancer as an evolutionary and ecological process Nat. Rev. Cancer 2006 6 924 935 10.1038/nrc2013 17109012

15. Rangel M.C. Bertolette D. Castro N.P. Klauzinska M. Cuttitta F. Salomon D.S. Developmental signaling pathways regulating mammary stem cells and contributing to the etiology of triple-negative breast cancer Breast Cancer Res. Treat. 2016 156 211 226 10.1007/s10549-016-3746-7 26968398 PMC4819564

16. Bao S. Wu Q. McLendon R.E. Hao Y. Shi Q. Hjelmeland A.B. Dewhirst M.W. Bigner D.D. Rich J.N. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response Nature 2006 444 756 760 10.1038/nature05236 17051156

17. Diehn M. Cho R.W. Lobo N.A. Kalisky T. Jo M. Kulp A.N. Qian D. Lam J.S. Ailles L.E. Wong M. Association of Reactive Oxygen Species Levels and Radioresistance in Cancer Stem Cells Nature 2009 458 780 783 10.1038/nature07733 19194462 PMC2778612

18. Mani S.A. Guo W. Liao M.J. Eaton E.N. Ayyanan A. Zhou A.Y. Brooks M. Reinhard F. Zhang C.C. Shipitsin M. The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells Cell 2008 133 704 715 10.1016/j.cell.2008.03.027 18485877 PMC2728032

19. Balic M. Lin H. Young L. Hawes D. Giuliano A. McNamara G. Datar R.H. Cote R.J. Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype Clin. Cancer Res. 2006 12 5615 5621 10.1158/1078-0432.CCR-06-0169 17020963

20. Ginestier C. Hur M.H. Charafe-Jauffret E. Monville F. Dutcher J. Brown M. Jacquemier J. Viens P. Kleer C.G. Liu S. ALDH1 Is a Marker of Normal and Malignant Human Mammary Stem Cells and a Predictor of Poor Clinical Outcome Cell Stem Cell 2007 1 555 567 10.1016/j.stem.2007.08.014 18371393 PMC2423808

21. American Cancer Society Breast Cancer Facts and Figure 2019 and Figure 2020 American Cancer Society Atlanta, GA, USA 2019 1 44

22. Eberlein T.J. Race, Breast Cancer Subtypes, and Survival in the Carolina Breast Cancer Study Yearb. Surg. 2007 2007 304 305 10.1016/S0090-3671(08)70227-1

23. Bauer K.R. Brown M. Cress R.D. Parise C.A. Caggiano V. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: A population-based study from the California Cancer Registry Cancer 2007 109 1721 1728 10.1002/cncr.22618 17387718

24. Arias A.M. Epithelial mesenchymal interactions in cancer and development Cell 2001 105 425 431 10.1016/S0092-8674(01)00365-8 11371340

25. Soady K. Smalley M.J. Slugging their way to immortality: Driving mammary epithelial cells into a stem cell-like state Breast Cancer Res. 2012 14 319 10.1186/bcr3188 22971267 PMC4053093

26. Guo W. Keckesova Z. Donaher J.L. Shibue T. Tischler V. Reinhardt F. Itzkovitz S. Noske A. Zürrer-Härdi U. Bell G. Slug and Sox9 cooperatively determine the mammary stem cell state Cell 2012 148 1015 1028 10.1016/j.cell.2012.02.008 22385965 PMC3305806

27. Pomp V. Leo C. Mauracher A. Korol D. Guo W. Varga Z. Differential expression of epithelial–mesenchymal transition and stem cell markers in intrinsic subtypes of breast cancer Breast Cancer Res. Treat. 2015 154 45 55 10.1007/s10549-015-3598-6 26467042

28. Ito M. Shien T. Omori M. Mizoo T. Evaluation of aldehyde dehydrogenase 1 and transcription factors in both primary breast cancer and axillary lymph node metastases as a prognostic factor Breast Cancer 2015 23 2 5 10.1007/s12282-015-0583-1 25599843

29. Zhou S. Sun X. Yu L. Zhou R. Li A. Li M. Yang W. Differential expression and clinical significance of epithelial-mesenchymal transition markers among different histological types of triple-negative breast cancer J. Cancer 2018 9 604 613 10.7150/jca.19190 29483966 PMC5820928

30. Shah Sohrab P. Roth Andrew G. Rodrigo O. Arusha H.G. Zhao Y. Turashvili G. Ding J. Tse K. Haffari G. Bashashati A. The clonal and mutational evolution spectrum of primary triple negative breast cancers Nature 2013 486 395 399 10.1038/nature10933 PMC3863681 22495314

31. Curtis C. Shah S.P. Chin S.-F. Turashvili G. Rueda O.M. Dunning M.J. Speed D. Lynch A.G. Samarajiwa S. Yuan Y. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups Nature 2012 486 346 352 10.1038/nature10983 22522925 PMC3440846

32. Kalimutho M. Parsons K. Mittal D. López J.A. Srihari S. Khanna K.K. Targeted Therapies for Triple-Negative Breast Cancer: Combating a Stubborn Disease Elsevier Current Trends Amsterdam, The Netherlands 2015 Volume 36 822 846 10.1016/j.tips.2015.08.009 26538316

33. Munzone E. Gray K.P. Fumagalli C. Guerini-Rocco E. Láng I. Ruhstaller T. Gianni L. Kammler R. Viale G.L. Leo A.D. Mutational analysis of triple-negative breast cancers within the International Breast Cancer Study Group (IBCSG) Trial 22-00 Breast Cancer Res. Treat. 2018 170 351 360 10.1007/s10549-018-4767-1 29589138

34. Tung N. Lin N.U. Kidd J. Allen B.A. Singh N. Wenstrup R.J. Hartman A.R. Winer E.P. Garber J.E. Frequency of germline mutations in 25 cancer susceptibility genes in a sequential series of patients with breast cancer J. Clin. Oncol. 2016 34 1460 1468 10.1200/JCO.2015.65.0747 26976419 PMC4872307

35. Turnbull C. Rahman N. Genetic Predisposition to Breast Cancer: Past, Present, and Future Annu. Rev. Genom. Hum. Genet. 2008 9 321 345 10.1146/annurev.genom.9.081307.164339 18544032

36. Kuchenbaecker K.B. Hopper J.L. Barnes D.R. Phillips K.-A. Mooij T.M. Roos-Blom M.-J. Jervis S. van Leeuwen F.E. Milne R.L. Andrieu N. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers JAMA 2017 317 2402 10.1001/jama.2017.7112 28632866

37. American Cancer Society Cancer Facts & Figures 2017 2017 Available online: https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2017.html (accessed on 15 April 2018)

38. Heitz F. Harter P. Traut A. Lueck H.J. Beutel B. du Bois A. Cerebral metastases (CM) in breast cancer (BC) with focus on triple-negative tumors J. Clin. Oncol. 2008 26 1010 10.1200/jco.2008.26.15_suppl.1010

39. Lin N.U. Claus E. Sohl J. Razzak A.R. Arnaout A. Winer E.P. Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer Cancer 2008 113 2638 2645 10.1002/cncr.23930 18833576 PMC2835546

40. Miller B.E. Miller F.R. Leith J. Heppner G.H. Growth Interaction in Vivo between Tumor Subpopulations Derived from a Single Mouse Mammary Tumor Growth Interaction in Vivo between Tumor Subpopulations Derived from a Single Mouse Mammary Tumor1 Cancer Res. 1980 40 3977 3981 7471048

41. Caignard A. Martin M.S. Michel M.F. Martin F. Interaction between two cellular subpopulations of a rat colonic carcinoma when inoculated to the syngeneic host Int. J. Cancer 1985 36 273 279 10.1002/ijc.2910360221 4018914

42. Rundhaug J.E. Matrix metalloproteinases and angiogenesis J. Cell Mol. Med. 2007 9 267 285 10.1111/j.1582-4934.2005.tb00355.x PMC6740080 15963249

43. Nagy J.D. Competition and natural selection in a mathematical model of cancer Bull. Math. Biol. 2004 66 663 687 10.1016/j.bulm.2003.10.001 15210312

44. Jouanneau J. Moens G. Bourgeois Y. Poupon M.F. Thiery J.P. A minority of carcinoma cells producing acidic fibroblast growth factor induces a community effect for tumor progression Proc. Natl. Acad. Sci. USA 1994 91 286 290 10.1073/pnas.91.1.286 7506417 PMC42932

45. Axelrod R. Axelrod D.E. Pienta K.J. Evolution of cooperation among tumor cells Proc. Natl. Acad. Sci. USA 2006 103 13474 13479 10.1073/pnas.0606053103 16938860 PMC1557388

46. Heppner G.H. Miller F.R. The Cellular Basis of Tumor Progression International Review of Cytology Jeon K.W. International Review of Cytology; Academic Press Cambridge, MA, USA 1997 Volume 177 1 56 10.1016/s0074-7696(08)62230-5 9378615

47. Bychkov V.A. Pevzner A.M. Nebova J.A. Ermakova N.N. Ibragimova M.K. Tsyganov M.M. Lyapunova L.S. Litviakov N.V. In vitro modeling of tumor interclonal interactions using breast cancer cell lines Exp. Oncol. 2021 43 118 124 10.32471/exp-oncology.2312-8852.vol-43-no-2.16142 34190521

48. Ethier S.P. Growth factor synthesis and human breast cancer progression J. Natl. Cancer Inst. 1995 87 964 973 10.1093/jnci/87.13.964 7629883

49. Kuperwasser C. Chavarria T. Wu M. Magrane G. Gray J.W. Carey L. Richardson A. Weinberg R.A. Reconstruction of functionally normal and malignant human breast tissues in mice Proc. Natl. Acad. Sci. USA 2004 101 4966 4971 10.1073/pnas.0401064101 15051869 PMC387357

50. Mintz B. Illmensee K. Normal genetically mosaic mice produced from malignant teratocarcinoma cells Proc. Natl. Acad. Sci. USA 1975 72 3585 3589 10.1073/pnas.72.9.3585 1059147 PMC433040

51. Kenny P.A. Bissell M.J. Tumor reversion: Correction of malignant behavior by microenvironmental cues Int. J. Cancer 2003 107 688 695 10.1002/ijc.11491 14566816 PMC2933180

52. Wahba H.A. El-hadaad H.A. Current approaches in treatment of triple-negative breast cancer Treatment modalities of TNBC Cancer Biol. Med. 2015 12 106 116 10.7497/j.issn.2095-3941.2015.0030 26175926 PMC4493381

53. Albain K. Anderson S. Arriagada R. Barlow W. Bergh J. Bliss J. Wood W. Comparisons between different polychemotherapy regimens for early breast cancer: Meta-analyses of long-term outcome among 100 000 women in 123 randomised trials Lancet 2012 379 432 444 10.1016/S0140-6736(11)61625-5 22152853 PMC3273723

54. Cortazar P. Zhang L. Untch M. Mehta K. Costantino J.P. Wolmark N. Bonnefoi H. Cameron D. Gianni L. Valagussa P. Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis Lancet 2014 384 164 172 10.1016/S0140-6736(13)62422-8 24529560

55. Carey L.A. Dees E.C. Sawyer L. Gatti L. Moore D.T. Collichio F. Ollila D.W. Sartor C.I. Graham M.L. Perou C.M. The triple negative paradox: Primary tumor chemosensitivity of breast cancer subtypes Clin. Cancer Res. 2007 13 2329 2334 10.1158/1078-0432.CCR-06-1109 17438091

56. Bonotto M. Gerratana L. Poletto E. Driol P. Giangreco M. Russo S. Minisini A.M. Andreetta C. Mansutti M. Pisa F.E. Measures of Outcome in Metastatic Breast Cancer: Insights from a Real-World Scenario Oncologist 2014 19 608 615 10.1634/theoncologist.2014-0002 24794159 PMC4041678

57. Conlin A.K. Seidman A.D. Taxanes in Breast Cancer: An Update Corresponding author Curr. Oncol. Rep. 2007 9 22 30 10.1007/BF02951422 17164044

58. US FDA Website FDA Approves Atezolizumab for PD-L1 Positive Unresectable Locally Advanced or Metastatic Triple-Negative Breast Cancer Available online: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-pd-l1-positive-unresectable-locally-advanced-or-metastatic-triple-negative (accessed on 12 December 2022)

59. Kang C. Syed Y.Y. Atezolizumab (in Combination with Nab-Paclitaxel): A Review in Advanced Triple-Negative Breast Cancer Drugs 2020 80 601 607 10.1007/s40265-020-01295-y 32248356

60. Schmid P. Adams S. Rugo H.S. Schneeweiss A. Barrios C.H. Iwata H. Dieras V. Hegg R. Im S.A. Shaw Wright G. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer N. Engl. J. Med. 2018 379 2108 2121 10.1056/NEJMoa1809615 30345906

61. Ibrahim N.K. Desai N. Legha S. Soon-Shiong P. Theriault R.L. Rivera E. Esmaeli B. Ring S.E. Bedikian A. Hortobagyi G.N. Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel Clin. Cancer Res. 2002 8 1038 1044 12006516

62. Gradishar W.J. Tjulandin S. Davidson N. Shaw H. Desai N. Bhar P. Hawkins M. O’Shaughnessy J. Phase III Trial of Nanoparticle Albumin-Bound Paclitaxel Compared with Polyethylated Castor Oil–Based Paclitaxel in Women With Breast Cancer J. Clin. Oncol. 2005 23 7794 7803 10.1200/JCO.2005.04.937 16172456

63. Desai N. Trieu V. Yao Z. Louie L. Ci S. Yang A. Tao C. De T. Beals B. Dykes D. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel Clin. Cancer Res. 2006 12 1317 1324 10.1158/1078-0432.CCR-05-1634 16489089

64. Chen N. Li Y. Ye Y. Palmisano M. Chopra R. Zhou S. Pharmacokinetics and pharmacodynamics of nab-paclitaxel in patients with solid tumors: Disposition kinetics and pharmacology distinct from solvent-based paclitaxel J. Clin. Pharmacol. 2014 54 1097 1107 10.1002/jcph.304 24719309 PMC4302229

65. Gardner E.R. Dahut W.L. Scripture C.D. Jones J. Aragon-Ching J.B. Desai N. Hawkins M.J. Sparreboom A. Figg W.D. Randomized crossover pharmacokinetic study of solvent-based paclitaxel and nab-paclitaxel Clin. Cancer Res. 2008 14 4200 4205 10.1158/1078-0432.CCR-07-4592 18594000 PMC2661025

66. Brufsky A. Nab-Paclitaxel for the treatment of breast cancer: An update across treatment settings Exp. Hematol. Oncol. 2017 6 7 10.1186/s40164-017-0066-5 28344858 PMC5361712

67. Suryawanshi Y.R. Zhang T. Essani K. Oncolytic viruses: Emerging options for the treatment of breast cancer Med. Oncol. 2017 34 43 10.1007/s12032-017-0899-0 28185165

68. U.S. National Library of Medicine Clinicaltrials.gov Available online: https://clinicaltrials.gov/ (accessed on 24 March 2023)

69. Zhu W. Zhang H. Shi Y. Song M. Zhu B. Wei L. Oncolytic adenovirus encoding tumor necrosis factor-related apoptosis inducing ligand (TRAIL) inhibits the growth and metastasis of triple-negative breast cancer Cancer Biol. Ther. 2013 14 1016 1023 10.4161/cbt.26043 24025362 PMC3925656

70. Bramante S. Koski A. Liikanen I. Vassilev L. Oksanen M. Siurala M. Heiskanen R. Hakonen T. Joensuu T. Kanerva A. Oncolytic virotherapy for treatment of breast cancer, including triple-negative breast cancer Oncoimmunology 2016 5 e1078057 10.1080/2162402X.2015.1078057 27057453 PMC4801445

71. Gholami S. Chen C.-H. Lou E. Belin L.J. Fujisawa S. Longo V.A. Chen N.G. Gönen M. Zanzonico P.B. Szalay A.A. Vaccinia virus GLV-1h153 in combination with 131I shows increased efficiency in treating triple-negative breast cancer FASEB J. 2014 28 676 682 10.1096/fj.13-237222 24186964 PMC4005795

72. Gholami S. Marano A. Chen N.G. Aguilar R.J. Frentzen A. Chen C.-H. Lou E. Fujisawa S. Eveno C. Belin L. A novel vaccinia virus with dual oncolytic and anti-angiogenic therapeutic effects against triple-negative breast cancer Breast Cancer Res. Treat. 2014 148 489 499 Erratum in Breast Cancer Res. Treat. 2016 , 156 , 607–608 10.1007/s10549-014-3180-7 25391896 PMC5724036

73. Suryawanashi Y.R. Zhang T. Woyczesczyk H.M. Christie J. Byers E. Kohler S. Eversole R. Mackenzie C. Essani K. T-independent response mediated by oncolytic tanapoxvirus recombinants expressing interleukin-2 and monocyte chemoattractant protein-1 suppresses human triple negative breast tumors Med. Oncol. 2017 34 112 10.1007/s12032-017-0973-7 28466296

74. Choi A.H. O′Leary M.P. Chaurasiya S. Lu J. Kim S.I. Fong Y. Chen N.G. Novel chimeric parapoxvirus CF189 as an oncolytic immunotherapy in triple-negative breast cancer Surgery 2017 163 336 342 10.1016/j.surg.2017.09.030 29174433 PMC5780196

75. Bourgeois-Daigneault M.C. St-Germain L.E. Roy D.G. Pelin A. Aitken A.S. Arulanandam R. Falls T. Garcia V. Diallo J.S. Bell J.C. Combination of Paclitaxel and MG1 oncolytic virus as a successful strategy for breast cancer treatment Breast Cancer Res. 2016 18 83 10.1186/s13058-016-0744-y 27503504 PMC4977613

76. Gromeier M. Nair S.K. Recombinant Poliovirus for Cancer Immunotherapy Annu. Rev. Med. 2018 69 289 299 10.1146/annurev-med-050715-104655 29414253 PMC6013836

77. Jing Y. Chavez V. Ban Y. Acquavella N. El-Ashry D. Pronin A. Chen X. Merchan J.R. Molecular effects of stromal-selective targeting by uPAR-retargeted oncolytic virus in breast cancer Mol. Cancer Res. 2017 15 1410 1420 10.1158/1541-7786.MCR-17-0016 28679779 PMC5682105

78. Cody J.J. Markert J.M. Hurst D.R. Histone deacetylase inhibitors improve the replication of oncolytic herpes simplex virus in breast cancer cells PLoS ONE 2014 9 e92919 10.1371/journal.pone.0092919 24651853 PMC3961437

79. Laurie S.A. Bell J.C. Atkins H.L. Roach J. Bamat M.K. O’Neil J.D. Roberts M.S. Groene W.S. Lorence R.M. A phase 1 clinical study of intravenous administration of PV701, an oncolytic virus, using two-step desensitization Clin. Cancer Res. 2006 12 2555 2562 10.1158/1078-0432.CCR-05-2038 16638865

80. DePace N. Sulla Scomparsa di un enorme cancro vegetante del callo dell’utero senza cura chirurgica Ginecologia 1912 9 82 89

81. Dock G. The influence of complicating diseases upon leukemia Am. J. Med. Sci. 1904 127 563 592 10.1097/00000441-190412740-00001

82. Pelner L. Fowler G.A. Nauts H.C. Effects of concurrent infections and their toxins on the course of leukemia Acta Med. Scand. Suppl. 1958 338 1 47 10.1111/j.0954-6820.1958.tb17327.x 13605619

83. Bierman H.R. Crile D.M. Dod K.S. Kelly K.H. Petrakis N.L. White L.P. Shimkin M.B. Remissions in leukemia of childhood following acute infectious disease: Staphyloccous and streptococcus, varicella, and feline panleukopenia Cancer 1953 6 591 605 10.1002/1097-0142(195305)6:3<591::AID-CNCR2820060317>3.0.CO;2-M 13042782

84. Smith W. Andrewes C.H. Laidlaw P.P. A Virus Obtained from Influenza Patients Lancet 1933 222 66 68 10.1016/S0140-6736(00)78541-2

85. Sinkovics J.G. Horvath J.C. Natural and genetically engineered viral agents for oncolysis and gene therapy of human cancers Arch. Immunol. Ther. Exp. 2008 56 178 216 10.1007/s00005-008-0047-9 19104757

86. Sinkovics J.G. Horvath J.C. Newcastle disease virus (NDV): Brief history of its oncolytic strains J. Clin. Virol. 2000 16 1 15 10.1016/S1386-6532(99)00072-4 10680736

87. Newman W. Southam C.M. Virus treatment in advanced cancer. A pathological study of fifty-seven cases Cancer 1954 7 106 118 10.1002/1097-0142(195401)7:1<106::AID-CNCR2820070112>3.0.CO;2-L 13126905

88. Hoster H.A. Zanes R.P. Jr. Haam E.V. Studies in Hodgkin’s Syndrome IX. The Association of “Viral” Hepatitis and Hodgkin’s Disease (A Preliminary Report) Cancer Res. 1949 9 473 480 18134519

89. Asada T. Treatment of human cancer with mumps virus Cancer 1974 34 1907 1928 10.1002/1097-0142(197412)34:6<1907::AID-CNCR2820340609>3.0.CO;2-4 4611607

90. Shimizu Y. Hasumi K. Okadaira Y. Yaminishi K. Takahashi M. Immunotherapy of advanced gynecologic cancer patients utilizing mumps virus Cancer Detect. 1988 12 487 495 2972361

91. Okuno Y. Asada T. Yamanishi K. Otsuka T. Takahashi M. Tanioka T. Aoyama H. Fukui O. Matsumoto K. Uemura F. Studies on the use of mumps virus for treatment of human cancer Biken J. 1978 21 37 49 749908

92. Sato M. Urade M. Sakuda M. Shirasuna K. Yoshida H. Maeda N. Yanagawa T. Morimoto M. Yura Y. Miyazaki T. Attenuated mumps virus therapy of carcinoma of the maxillary sinus Int. J. Oral. Surg. 1979 8 205 211 10.1016/S0300-9785(79)80020-4 118126

93. Moore A.E. The destructive effects of the virus of Russian Far East encephalitis on the transplantable mouse sarcoma 180 Cancer 1949 2 525 534 10.1002/1097-0142(194905)2:3<525::AID-CNCR2820020317>3.0.CO;2-O 18131412

94. Mansfield K.L. Johnson N. Phipps L.P. Stephenson J.R. Fooks A.R. Solomon T. Tick-borne encephalitis virus—A review of an emerging zoonosis J. Gen. Virol. 2009 90 1781 1794 10.1099/vir.0.011437-0 19420159

95. Moore A.E. Inhibition of growth of five transplantable mouse tumours by the virus of Russian far east encephalitis Cancer 1951 4 375 382 10.1002/1097-0142(195103)4:2<375::AID-CNCR2820040227>3.0.CO;2-A 14821935

96. Kelly E. Russell S.J. History of oncolytic viruses: Genesis to genetic engineering Mol. Ther. 2007 15 651 659 10.1038/sj.mt.6300108 17299401

97. Sinkovics J.G. Enhancement of carcinostatic activity of Newcastle Disease Virus (NDV) associated with adaptation fo suckling mouse brain Bact. Proc 1957 96 M108

98. Sinkovics J.G. Interactions of the Newcastle Disease Virus with mouse tissues Arch. Ges. Virusforsch. 1960 10 103 125 10.1007/BF01258769 14447143

99. Moore A.E. Viruses with oncolytic properties and their adaptation in tumours Ann. N. Y. Acad. Sci. 1952 54 945 952 10.1111/j.1749-6632.1952.tb39969.x 12976996

100. Hammon W.M. Yohn D.S. Casto B.C. Atchison R.W. Oncolytic potentials of nonhuman viruses for human cancer. I. Effects of twenty-four viruses on human cancer cell lines J. Natl. Cancer Inst. 1963 31 329 345 14046628

101. Yohn D.S. Hammon W.M. Atchison R.W. Casto B.C. Oncolytic potentials of nonhuman viruses for human cancer. II. Effects of five viruses on heterotransplantable human tumors J. Natl. Cancer Inst. 1968 41 523 529 4299541

102. Southam C.M. Moore A.E. West Nile, Ilheus, and Bunyamwera virus infections in man Am. J. Trop. Med. Hyg. 1951 31 724 741 10.4269/ajtmh.1951.s1-31.724 14894758

103. Ginder D.R. Tumor-destroying effects of viruses. Antimetabolites and Cancer Am. Assn. Adv. Sci. 1955 243 251

104. Southam C.M. Moore A.E. Clinical studies of viruses as antineoplastic agents, with particular reference to Egypt 101 virus Cancer 1952 5 1025 1034 10.1002/1097-0142(195209)5:5<1025::AID-CNCR2820050518>3.0.CO;2-Q 12988191

105. Moore A.E. Effects of viruses on tumors Annu. Rev. Microbiol. 1954 8 393 410 10.1146/annurev.mi.08.100154.002141 13198114

106. Cassel W.A. Garrett R.E. Newcastle disease virus as an antineoplastic agent Cancer 1965 18 863 868 10.1002/1097-0142(196507)18:7<863::AID-CNCR2820180714>3.0.CO;2-V 14308233

107. Southam C.M. Present status of oncolytic virus studies Trans. N. Y. Acad. Sci. 1960 22 657 673 10.1111/j.2164-0947.1960.tb00739.x 13833074

108. Hoskins M. A protective action of neurotropic against viscerotropic yellow fever virus in Macaccus rhesus Am. J. Trop. Med. 1935 15 675 680 10.4269/ajtmh.1935.s1-15.675

109. Speir R.W. Southam C.M. Interference of Newcastle disease virus with neuropathogenicity of oncolytic viruses in mice Ann. N. Y. Acad. Sci. 1960 83 551 563 10.1111/j.1749-6632.1960.tb40929.x 13833221

110. Anderson W.F. Prospects for human gene therapy Science 1984 226 401 409 10.1126/science.6093246 6093246

111. Anderson W.F. Human gene therapy Science 1992 256 808 813 10.1126/science.256.5058.808 1589762

112. Rogers S. Use of viruses as carriers of added genetic information Nature 1968 219 749 751 10.1038/219749a0 5667075

113. Martuza R.L. Malick A. Markert J.M. Ruffner K.L. Coen D.M. Experimental therapy of human glioma by means of a genetically engineered virus mutant Science 1991 252 854 856 10.1126/science.1851332 1851332

114. Ott P.A. Hodi F.S. Talimogene laherparepvec for the treatment of advanced melanoma Clin. Cancer Res. 2016 22 3127 3131 10.1158/1078-0432.CCR-15-2709 27146699

115. Kwan A. Winder N. Muthana M. Oncolytic virotherapy treatment of breast cancer: Barriers and recent advances Viruses 2021 13 1128 10.3390/v13061128 34208264 PMC8230950

116. Cejalvo J.M. Falato C. Villanueva L. Tolosa P. González X. Pascal M. Canes J. Gavilá J. Manso L. Pascual T. Oncolytic viruses: A new immunotherapeutic approach for breast cancer treatment? Cancer Treat. Rev. 2022 106 102392 10.1016/j.ctrv.2022.102392 35436729

117. Yano S. Takehara K. Kishimoto H. Tazawa H. Urata Y. Kagawa S. Bouvet M. Fujiwara T. Hoffman R.M. OBP-401-GFP telomerase-dependent adenovirus illuminates and kills high-metastatic more effectively than low-metastatic triple-negative breast cancer in vitro Cancer Gene Ther. 2017 24 45 47 10.1038/cgt.2016.67 28106046

118. Yano S. Takehara K. Kishimoto H. Tazawa H. Urata Y. Kagawa S. Bouvet M. Fujiwara T. High-metastatic triple-negative breast-cancer variants selected in vivo become chemoresistant in vitro Vitr. Cell Dev. Biol. Anim. 2017 53 285 287 10.1007/s11626-016-0117-y 28127701

119. Garza-Morales R. Gonzalez-Ramos R. Chiba A. De Oca-Luna R.M. McNally L.R. McMasters K.M. Gomez-Gutierrez J.G. Temozolomide enhances triple-negative breast cancer virotherapy in vitro Cancers 2018 10 144 10.3390/cancers10050144 29772755 PMC5977117

120. Ang L. Guo L. Wang J. Huang J. Lou X. Zhao M. Oncolytic virotherapy armed with an engineered interfering lncRNA exhibits antitumor activity by blocking the epithelial mesenchymal transition in triple-negative breast cancer Cancer Lett. 2020 479 42 53 10.1016/j.canlet.2020.03.012 32200038

121. Zhang H. Xie W. Zhang Y. Dong X. Liu C. Yi J. Zhang S. Wen C. Zheng L. Wang H. Oncolytic adenoviruses synergistically enhance anti-PD-L1 and anti-CTLA-4 immunotherapy by modulating the tumour microenvironment in a 4T1 orthotopic mouse model Cancer Gene Ther. 2022 29 456 465 10.1038/s41417-021-00389-3 34561555 PMC9113929

122. Rodríguez M.D.C.R. Rodríguez I.G. Nattress C. Qureshi A. Halldén G. HDAC Inhibitors Enhance Efficacy of the Oncolytic Adenoviruses Ad∆∆ and Ad-3∆-A20T in Pancreatic and Triple-Negative Breast Cancer Models Viruses 2022 14 1006 10.3390/v14051006 35632748 PMC9143155

123. Ang L. Li J. Dong H. Wang C. Huang J. Li M. Zhao M. Su C. Wu Q. Chimeric Oncolytic Adenovirus Armed Chemokine Rantes for Treatment of Breast Cancer Bioengineering 2022 9 342 10.3390/bioengineering9080342 35892755 PMC9332706

124. Miyajima N. Eissa I.R. Abdelmoneim M. Naoe Y. Ichinose T. Matsumura S. Bustos-Villalobos I. Mukoyama N. Morimoto D. Shibata M. S-1 facilitates canerpaturev (C-REV)-induced antitumor efficacy in a triple-negative breast cancer model Nagoya J. Med. Sci. 2021 83 683 696 10.18999/nagjms.83.4.683 34916713 PMC8648537

125. El Sayed Y.M. Sadée W. Metabolic activation of R,S-1-(tetrahydro-2-furanyl)-5-fluorouracil (ftorafur) to 5-fluorouracil by soluble enzymes Cancer Res. 1983 43 4039 4044 6409396

126. Filipazzi P. Valenti R. Huber V. Pilla L. Canese P. Iero M. Castelli C. Mariani L. Parmiani G. Rivoltini L. Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine J. Clin. Oncol. 2007 25 2546 2553 10.1200/JCO.2006.08.5829 17577033

127. Bronte V. Serafini P. Mazzoni A. Segal D.M. Zanovello P. L-arginine metabolism in myeloid cells controls T-lymphocyte functions Trends Immunol. 2003 24 301 305 10.1016/S1471-4906(03)00132-7 12810105

128. Rodriguez P.C. Hernandez C.P. Quiceno D. Dubinett S.M. Zabaleta J. Ochoa J.B. Gilbert J. Ochoa A.C. Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma J. Exp. Med. 2005 202 931 939 10.1084/jem.20050715 16186186 PMC2213169

129. Nagaraj S. Gupta K. Pisarev V. Kinarsky L. Sherman S. Kang L. Herber D.L. Schneck J. Gabrilovich D.I. Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer Nat. Med. 2007 13 828 835 10.1038/nm1609 17603493 PMC2135607

130. Kusmartsev S. Gabrilovich D.I. Inhibition of myeloid cell differentiation in cancer: The role of reactive oxygen species J. Leukoc. Biol. 2003 74 186 196 10.1189/jlb.0103010 12885935

131. Brown S.M. MacLean A.R. McKie E.A. Harland J. The herpes simplex virus virulence factor ICP34.5 and the cellular protein MyD116 complex with proliferating cell nuclear antigen through the 63-amino-acid domain conserved in ICP34.5, MyD116, and GADD34 J. Virol. 1997 71 9442 9449 10.1128/jvi.71.12.9442-9449.1997 9371605 PMC230249

132. Raafat N. Sadowski-Cron C. Mengus C. Heberer M. Spagnoli G.C. Zajac P. Preventing vaccinia virus class-I epitopes presentation by HSV-ICP47 enhances the immunogenicity of a TAP-independent cancer vaccine epitope Int. J. Cancer 2011 131 E659 E669 10.1002/ijc.27362 22116674

133. Weaver B.A. How Taxol/paclitaxel kills cancer cells Mol. Biol. Cell 2014 25 2677 2681 10.1091/mbc.e14-04-0916 25213191 PMC4161504

134. Pol J. Kroemer G. Galluzzi L. First oncolytic virus approved for melanoma immunotherapy Oncoimmunology 2016 5 e1115641 10.1080/2162402X.2015.1115641 26942095 PMC4760283

135. O′Leary M.P. Warner S.G. Kim S.I. Chaurasiya S. Lu J. Choi A.H. Park A.K. Woo Y. Fong Y. Chen N.G. A Novel Oncolytic Chimeric Orthopoxvirus Encoding Luciferase Enables Real-Time View of Colorectal Cancer Cell Infection Mol. Ther. Oncolytics 2018 9 13 21 10.1016/j.omto.2018.03.001 29988502 PMC6026443

136. Chaurasiya S. Yang A. Zhang Z. Lu J. Valencia H. Kim S.I. Woo Y. Warner S.G. Olafsen T. Zhao Y. A comprehensive preclinical study supporting clinical trial of oncolytic chimeric poxvirus CF33-hNIS-anti-PD-L1 to treat breast cancer Mol. Ther. Methods Clin. Dev. 2022 24 102 116 10.1016/j.omtm.2021.12.002 35024377 PMC8718831

137. Chaurasiya S. Chen N.G. Lu J. Martin N. Shen Y. Kim S.-I. Warner S.G. Woo Y. Fong Y. A chimeric poxvirus with J2R (thymidine kinase) deletion shows safety and anti-tumor activity in lung cancer models Cancer Gene Ther. 2020 27 125 135 10.1038/s41417-019-0114-x 31209267 PMC7170804

138. Downie A.W. Taylor-Robinson C.H. Caunt A.E. Nelson G.S. Manson-Bahr P.E. Matthews T.C. Tanapox: A new disease caused by a pox virus Br. Med. J. 1971 1 363 368 10.1136/bmj.1.5745.363 5541925 PMC1795031

139. Jezek Z. Arita I. Szczeniowski M. Paluku K.M. Ruti K. Nakano J.H. Human tanapox in Zaire: Clinical and epidemiological observations on cases confirmed by laboratory studies Bull. World Health Organ. 1985 63 1027 1035 3011301 PMC2536461

140. Nazarian S.H. Barrett J.W. Stanford M.M. Johnston J.B. Essani K. McFadden G. Tropism of Tanapox virus infection in primary human cells Virology 2007 368 32 40 10.1016/j.virol.2007.06.019 17632198

141. Henney C.S. Kuribayashi K. Kern D.E. Gillis S. Interleukin-2 augments natural killer cell activity Nature 1981 291 335 338 10.1038/291335a0 6164929

142. Han X. Wilbanks G.D. Devaja O. Ruperelia V. Raju K.S. IL-2 Enhances Standard IFNγ/LPS Activation of Macrophage Cytotoxicity to Human Ovarian Carcinoma in Vitro: A Potential for Adoptive Cellular Immunotherapy Gynecol. Oncol. 1999 75 198 210 10.1006/gyno.1999.5557 10525372

143. Carr M.W. Roth S.J. Luther E. Rose S.S. Springer T.A. Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant Proc. Natl. Acad. Sci. USA 1994 91 3652 3656 10.1073/pnas.91.9.3652 8170963 PMC43639

144. Xu L.L. Warren M.K. Rose W.L. Gong W. Wang J.M. Human recombinant monocyte chemotactic protein and other c-c chemokines bind and induce directional migration of dendritic cells in vitro J. Leukoc. Biol. 1996 60 365 371 10.1002/jlb.60.3.365 8830793

145. Collington S.J. Hallgren J. Pease J.E. Jones T.G. Rollins B.J. Westwick J. Austen K.F. Williams T.J. Gurish M.F. Weller C.L. The role of the CCL2/CCR2 axis in mouse mast cell migration in vitro and in vivo J. Immunol. 2010 184 6114 6123 10.4049/jimmunol.0904177 20427772 PMC2956277

146. Gholami S. Chen C.-H. Lou E. De Brot M. Fujisawa S. Chen N.G. Szalay A.A. Fong Y. Vaccinia Virus GLV-1h153 Is Effective in Treating and Preventing Metastatic Triple-Negative Breast Cancer Ann. Surg. 2012 256 437 445 10.1097/SLA.0b013e3182654572 22868370

147. Lin Y. Zhang H. Liang J. Li K. Zhu W. Fu L. Wang F. Zheng X. Shi H. Wu S. Identification and characterization of alphavirus M1 as a selective oncolytic virus targeting ZAP-defective human cancers Proc. Natl. Acad. Sci. USA 2014 111 E4504 E4512 10.1073/pnas.1408759111 25288727 PMC4210284

148. Zhang J. Liu Y. Tan J. Zhang Y. Wong C.W. Lin Z. Liu X. Sander M. Yang X. Liang L. Necroptotic virotherapy of oncolytic alphavirus M1 cooperated with Doxorubicin displays promising therapeutic efficacy in TNBC Oncogene 2021 40 4783 4795 10.1038/s41388-021-01869-4 34155344

149. Fritsch M. Günther S.D. Schwarzer R. Albert M.C. Schorn F. Werthenbach J.P. Schiffmann L.M. Stair N. Stocks H. Seeger J.M. Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis Nature 2019 575 683 687 10.1038/s41586-019-1770-6 31748744

150. Bahreyni A. Liu H. Mohamud Y. Xue Y.C. Zhang J. Luo H. A new miRNA-Modified coxsackievirus B3 inhibits triple negative breast cancer growth with improved safety profile in immunocompetent mice Cancer Lett. 2022 548 215849 10.1016/j.canlet.2022.215849 35995138

151. Nohata N. Hanazawa T. Enokida H. Seki N. MicroRNA-1/133a and microRNA-206/133b clusters: Dysregulation and functional roles in human cancers Oncotarget 2012 3 9 21 10.18632/oncotarget.424 22308266 PMC3292888

152. Brun J. McManus D. Lefebvre C. Hu K. Falls T. Atkins H. Bell J.C. McCart J.A. Mahoney D. Stojdl D.F. Identification of genetically modified maraba virus as an oncolytic rhabdovirus Mol. Ther. 2010 18 1440 1449 10.1038/mt.2010.103 20551913 PMC2927055

153. Bourgeois-Daigneault M.C. Roy D.G. Aitken A.S. El Sayes N. Martin N.T. Varette O. Falls T. St-germain L.E. Pelin A. Lichty B.D. Neoadjuvant oncolytic virotherapy before surgery sensitizes triple-negative breast cancer to immune checkpoint therapy Sci. Transl. Med. 2018 10 eaao1641 10.1126/scitranslmed.aao1641 29298865

154. Lal G. Rajala M.S. Combination of oncolytic measles virus armed with BNiP3, a pro-apoptotic gene and paclitaxel induces breast cancer cell death Front. Oncol. 2019 9 676 10.3389/fonc.2018.00676 30697531 PMC6340943

155. Jing Y. Tong C. Zhang J. Nakamura T. Iankov I. Russell S.J. Merchan J.R. Tumor and vascular targeting of a novel oncolytic measles virus retargeted against the urokinase receptor Cancer Res. 2009 69 1459 1468 10.1158/0008-5472.CAN-08-2628 19208845 PMC2739455

156. Xu Y. Hagege J. Doublet J.D. Callard P. Sraer J.D. Rønne E. Rondeau E. Endothelial and macrophage upregulation of urokinase receptor expression in human renal cell carcinoma Hum. Pathol. 1997 28 206 213 10.1016/S0046-8177(97)90108-8 9023404

157. Hildenbrand R. Schaaf A. The urokinase-system in tumor tissue stroma of the breast and breast cancer cell invasion Int. J. Oncol. 2009 34 15 23 10.3892/ijo_00000124 19082473

158. Behrens M.D. Stiles R.J. Pike G.M. Sikkink L.A. Zhuang Y. Yu J. Wang L. Boughey J.C. Goetz M.P. Federspiel M.J. Oncolytic Urabe mumps virus: A promising virotherapy for triple-negative breast cancer Mol. Ther. Oncolytics 2022 27 239 255 10.1016/j.omto.2022.11.002 36458203 PMC9703006

159. Faranoush P. Jahandideh A. Nekouian R. Mortazavi P. Evaluation of the in vitro and in vivo effect of liposomal doxorubicin along with oncolytic Newcastle disease virus on 4T1 cell line: Animal preclinical research Vet. Med. Sci. 2023 1 12 10.1002/vms3.1109 PMC10188073 36920334

160. Rodriguez S. Roxana M. Raghuram V. Berry J.T.L. Joshi G.N. Mainou B.A. Noncanonical Cell Death Induction by Reassortant Reovirus J. Virol. 2020 94 e01613-20 32847857 10.1128/JVI.01613-20 PMC7592226

161. Stewart R.M.R. Berry J.T.L. Berger A.K. Yoon B. Hirsch A.L. Enhanced Killing of Triple-Negative Breast Cancer Cells by Reassortant Reovirus and Topoisomerase Inhibitors J. Virol. 2019 93 e01411-19 31511390 10.1128/JVI.01411-19 PMC6854488

162. Berry J.T.L. Muñoz L.E. Rodríguez Stewart R.M. Selvaraj P. Mainou B.A. Doxorubicin Conjugation to Reovirus Improves Oncolytic Efficacy in Triple-Negative Breast Cancer Mol. Ther. Oncolytics 2020 18 556 572 10.1016/j.omto.2020.08.008 32995480 PMC7493048

163. Cook M. Chauhan A. Clinical application of oncolytic viruses: A systematic review Int. J. Mol. Sci. 2020 21 7505 10.3390/ijms21207505 33053757 PMC7589713

164. Puzanov I. Milhem M.M. Minor D. Hamid O. Li A. Chen L. Chastain M. Gorski K.S. Anderson A. Chou J. Talimogene laherparepvec in combination with ipilimumab in previously untreated, unresectable stage IIIB-IV melanoma J. Clin. Oncol. 2016 34 2619 2626 10.1200/JCO.2016.67.1529 27298410 PMC7189507

165. Ribas A. Dummer R. Puzanov I. VanderWalde A. Andtbacka R.H.I. Michielin O. Olszanski A.J. Malvehy J. Cebon J. Fernandez E. Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy Cell 2017 170 1109 1119.e10 10.1016/j.cell.2017.08.027 28886381 PMC8034392

166. Hasenburg A. Tong X.W. Rojas-Martinez A. Nyberg-Hoffman C. Kieback C.C. Kaplan A. Kaufman R.H. Ramzy I. Aguilar-Cordova E. Kieback D.G. Thymidine kinase gene therapy with concomitant topotecan chemotherapy for recurrent ovarian cancer Cancer Gene Ther. 2000 7 839 844 10.1038/sj.cgt.7700192 10880013

167. Bernicker E.H. Teh B.S. Butler B. Chang J.C. Abstract CT064: Trial of SBRT and in-situ gene therapy followed by nivolumab in metastatic non-small cell lung carcinoma (ENSIGN) Cancer Res. 2017 77 CT064 10.1158/1538-7445.AM2017-CT064

168. Soliman H. Hogue D. Han H. Mooney B. Costa R. Lee M.C. Niell B. Williams A. Chau A. Falcon S. Oncolytic T-VEC virotherapy plus neoadjuvant chemotherapy in nonmetastatic triple-negative breast cancer: A phase 2 trial Nat. Med. 2023 29 450 457 10.1038/s41591-023-02210-0 36759673

169. Haines B.B. Denslow A. Grzesik P. Lee J.S. Farkaly T. Hewett J. Wambua D. Kong L. Behera P. Jacques J. ONCR-177, an oncolytic HSV-1 designed to potently activate systemic antitumor immunity Cancer Immunol. Res. 2021 9 291 308 10.1158/2326-6066.CIR-20-0609 33355229

170. Park J.C. Soliman H. Falchook G. Owonikoko T. Spreafico A. Massarelli E. McKean M. Chow L. Ott P. Wesolowski R. 511 Initial results of a phase 1 study of intratumoral ONCR-177, an oncolytic herpes-simplex virus-1 expressing five immunomodulatory transgenes, in subjects with advanced injectable tumors J. Immunother. Cancer 2021 9 A542 10.1136/jitc-2021-SITC2021.511

171. Penheiter A.R. Wegman T.R. Classic K.L. Dingli D. Bender C.E. Russell S.J. Carlson S.K. Sodium iodide symporter (NIS)-mediated radiovirotherapy for pancreatic cancer Am. J. Roentgenol. 2010 195 341 349 10.2214/AJR.09.3672 20651188 PMC3117397

172. Myers R.M. Greiner S.M. Harvey M.E. Griesmann G. Kuffel M.J. Buhrow S.A. Federspiel M. Ames M.M. Dingli D. Schweikart K. Preclinical Pharmacology and Toxicology of Intravenous MV-NIS, an Oncolytic Measles Virus Administered With or Without Cyclophosphamide Clin. Pharmacol. Ther. 2009 82 700 710 10.1038/sj.clpt.6100409 PMC2769566 17971816

173. Liszewski M.K. Post T.W. Atkinson J.P. Membrane Cofactor Protein (MCP or CD46): Newest Member of the Regulators of Complement Activation Gene Cluster Annu. Rev. Immunol 1991 9 431 455 10.1146/annurev.iy.09.040191.002243 1910685

174. Jurianz K. Ziegler S. Garcia-Schüler H. Kraus S. Bohana-Kashtan O. Fishelson Z. Kirschfink M. Complement resistance of tumor cells: Basal and induced mechanisms Mol. Immunol. 1999 36 929 939 10.1016/S0161-5890(99)00115-7 10698347

175. Dörig R.E. Marcil A. Chopra A. Richardson C.D. The human CD46 molecule is a receptor for measles virus (Edmonston strain) Cell 1993 75 295 305 10.1016/0092-8674(93)80071-L 8402913

176. Anderson B.D. Nakamura T. Russell S.J. Peng K.W. High CD46 receptor density determines preferential killing of tumor cells by oncolytic measles virus Cancer Res. 2004 64 4919 4926 10.1158/0008-5472.CAN-04-0884 15256464

177. Oglesby T.J. White D. Tedja I. Liszewski K. Wright L. Van den Bogarde J. Atkinson P. Protection of mammalian cells from complement-mediated lysis by transfection of human membrane cofactor protein and decay-accelerating factor Trans. Assoc. Am. Physicians 1991 104 164 172 1726964

178. Adams E.M. Brown M.C. Nunge M. Krych M. Atkinson J.P. Contribution of the repeating domains of membrane cofactor protein (CD46) of the complement system to ligand binding and cofactor activity J. Immunol. 1991 147 3005 3011 10.4049/jimmunol.147.9.3005 1717583

179. Cimermancic P. Weinkam P. Rettenmaier T.J. Bichmann L. Keedy D.A. Woldeyes R.A. Schneidman-duhovny D. Omar N. Mitchell J.C. Wells J.A. Phase I Trial of Systemic Administration of Edmonston Strain of Measles Virus, Genetically Engineered to Express the Sodium Iodide Symporter in Patients with Recurrent or Refractory Multiple Myeloma Leukemia 2017 428 709 719 10.1016/j.jmb.2016.01.029.CryptoSite PMC5656536 28439108

180. Aref S. Bailey K. Fielding A. Measles to the rescue: A review of oncolytic measles virus Viruses 2016 8 294 10.3390/v8100294 27782084 PMC5086626

181. Viker K.B. Steele M.B. Iankov I.D. Concilio S.C. Ammayappan A. Bolon B. Jenks N.J. Goetz M.P. Panagioti E. Federspiel M.J. Preclinical safety assessment of MV-s-NAP, a novel oncolytic measles virus strain armed with an H. pylori immunostimulatory bacterial transgene Mol. Ther. Methods Clin. Dev. 2022 26 532 546 10.1016/j.omtm.2022.07.014 36092362 PMC9437807

182. Kawamura Y. Hua L. Gurtner A. Wong E. Kiyokawa J. Shah N. Gorham J. Wakimoto H.H. Rabkin S.D. Martuza R.L. Histone deacetylase inhibitors enhance oncolytic herpes simplex virus therapy for malignant meningioma Biomed. Pharmacother. 2022 155 113843 10.1016/j.biopha.2022.113843 36271587 PMC9590235