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• W2789761490 abstract "As a clinical setting in which local live biological therapy is already well established, non-muscle invasive bladder cancer (NMIBC) presents intriguing opportunities for oncolytic virotherapy. Coxsackievirus A21 (CVA21) is a novel intercellular adhesion molecule-1 (ICAM-1)-targeted immunotherapeutic virus. This study investigated CVA21-induced cytotoxicity in a panel of human bladder cancer cell lines, revealing a range of sensitivities largely correlating with expression of the viral receptor ICAM-1. CVA21 in combination with low doses of mitomycin-C enhanced CVA21 viral replication and oncolysis by increasing surface expression levels of ICAM-1. This was further confirmed using 300-μm precision slices of NMIBC where levels of virus protein expression and induction of apoptosis were enhanced with prior exposure to mitomycin-C. Given the importance of the immunogenicity of dying cancer cells for triggering tumor-specific responses and long-term therapeutic success, the ability of CVA21 to induce immunogenic cell death was investigated. CVA21 induced immunogenic apoptosis in bladder cancer cell lines, as evidenced by expression of the immunogenic cell death (ICD) determinant calreticulin, and HMGB-1 release and the ability to reject MB49 tumors in syngeneic mice after vaccination with MB49 cells undergoing CVA21 induced ICD. Such CVA21 immunotherapy could offer a potentially less toxic, more effective option for the treatment of bladder cancer. As a clinical setting in which local live biological therapy is already well established, non-muscle invasive bladder cancer (NMIBC) presents intriguing opportunities for oncolytic virotherapy. Coxsackievirus A21 (CVA21) is a novel intercellular adhesion molecule-1 (ICAM-1)-targeted immunotherapeutic virus. This study investigated CVA21-induced cytotoxicity in a panel of human bladder cancer cell lines, revealing a range of sensitivities largely correlating with expression of the viral receptor ICAM-1. CVA21 in combination with low doses of mitomycin-C enhanced CVA21 viral replication and oncolysis by increasing surface expression levels of ICAM-1. This was further confirmed using 300-μm precision slices of NMIBC where levels of virus protein expression and induction of apoptosis were enhanced with prior exposure to mitomycin-C. Given the importance of the immunogenicity of dying cancer cells for triggering tumor-specific responses and long-term therapeutic success, the ability of CVA21 to induce immunogenic cell death was investigated. CVA21 induced immunogenic apoptosis in bladder cancer cell lines, as evidenced by expression of the immunogenic cell death (ICD) determinant calreticulin, and HMGB-1 release and the ability to reject MB49 tumors in syngeneic mice after vaccination with MB49 cells undergoing CVA21 induced ICD. Such CVA21 immunotherapy could offer a potentially less toxic, more effective option for the treatment of bladder cancer. Urothelial cancer of the bladder is the seventh most common cancer in the UK, with over 10,000 new cases annually in the UK.1Cancer Research UK (2016). Bladder cancer statistics. http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bladder-cancer.Google Scholar Superficial, non-muscle invasive bladder cancers (NMIBCs) are managed with cystoscopic transurethral resection of all visible lesions followed by intravesical chemotherapy and/or immunotherapy.2Aldousari S. Kassouf W. Update on the management of non-muscle invasive bladder cancer.Can. Urol. Assoc. J. 2010; 4: 56-64Crossref PubMed Scopus (73) Google Scholar The use of Bacillus Calmette-Guerin (BCG) as an immunotherapy for NMIBC and its proven effects of reducing recurrence and progression and improving disease-specific survival revolutionized the treatment of this malignancy in the 1970s. However, the potential for serious side effects of local and systemic BCG infection as well as the fact that there is a significant (30%) group of non-responder patients to BCG highlights the need to develop future immune-based therapies that overcome these problems.3Fuge O. Vasdev N. Allchorne P. Green J.S.A. Immunotherapy for bladder cancer.Res. Rep. Urol. 2015; 7: 65-79PubMed Google Scholar The precise mechanisms underpinning the clinical efficacy of BCG remain unclear. Urothelial cells (including bladder cancer cells themselves) and various components of the immune system both have crucial roles. The possible involvement of bladder cancer cells includes attachment and internalization of BCG, secretion of cytokines and chemokines, and presentation of BCG and/or cancer cell antigens to cells of the immune system. Immune cell subsets that have potential roles in BCG therapy include CD4+ and CD8+ lymphocytes, natural killer cells, granulocytes, macrophages, and dendritic cells. Bladder cancer cells are killed through direct cytotoxicity by these cells; by secretion of soluble factors, such as TRAIL (tumor-necrosis-factor-related apoptosis-inducing ligand); and, to some degree, by the direct action of BCG. New agents are vital, capable of the immunotherapeutic effects of BCG but without the toxicity and need to use a potentially hazardous live agent in the clinic. The accessibility and superficial location of NMIBC allows direct intravesical administration of antitumor agents and is an ideal model for evaluation of new therapies as, through insertion of a conventional urinary catheter, precise modulation of infusion volume, infusion rate, time of retention in the bladder by catheter clamping, as well as frequency of treatments can be precisely undertaken as well as combination with other agents. Alternatives to BCG have been long sought, due to its toxicity and limited efficacy and, also in recent years, the difficulty with its manufacture.4Sanofi Pasteur (2016). Sanofi Pasteur statement on discontinuation of BCG. http://www.sanofipasteur.ca/node/50701.Google Scholar, 5Davies, B. (2016). Sanofi shuts down bladder cancer drug production: inevitable drug shortage to harm patients. https://www.forbes.com/sites/benjamindavies/2016/11/17/sanofi-shuts-down-bladder-cancer-drug-production-inevitable-drug-shortage-to-harm-patients/#27d4a3abc132.Google Scholar Viruses, both non-replication for gene transfer and replication-competent oncolytic viruses (OVs), have been evaluated for the treatment of NMIBC. These viruses infect and selectively lyse tumor cells, leaving non-transformed cells unharmed.6Russell S.J. Peng K.W. Bell J.C. Oncolytic virotherapy.Nat. Biotechnol. 2012; 30: 658-670Crossref PubMed Scopus (963) Google Scholar, 7Patel M.R. Kratzke R.A. Oncolytic virus therapy for cancer: the first wave of translational clinical trials.Transl. Res. 2013; 161: 355-364Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar The roles of the host immune system in contributing to the therapeutic activity of OV through intratumoral and systemic delivery are now well recognized.8Tong A.W. Senzer N. Cerullo V. Templeton N.S. Hemminki A. Nemunaitis J. Oncolytic viruses for induction of anti-tumor immunity.Curr. Pharm. Biotechnol. 2012; 13: 1750-1760Crossref PubMed Scopus (52) Google Scholar, 9Steele L. Errington F. Prestwich R. Ilett E. Harrington K. Pandha H. Coffey M. Selby P. Vile R. Melcher A. Pro-inflammatory cytokine/chemokine production by reovirus treated melanoma cells is PKR/NF-κB mediated and supports innate and adaptive anti-tumour immune priming.Mol. Cancer. 2011; 10: 20Crossref PubMed Scopus (59) Google Scholar, 10Benencia F. Courrèges M.C. Conejo-García J.R. Mohamed-Hadley A. Zhang L. Buckanovich R.J. Carroll R. Fraser N. Coukos G. HSV oncolytic therapy upregulates interferon-inducible chemokines and recruits immune effector cells in ovarian cancer.Mol. Ther. 2005; 12: 789-802Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar Emerging evidence has shown that oncolytic virotherapy induces immunogenic cell death (ICD).11Kroemer G. Galluzzi L. Kepp O. Zitvogel L. Immunogenic cell death in cancer therapy.Annu. Rev. Immunol. 2013; 31: 51-72Crossref PubMed Scopus (1950) Google Scholar, 12Angelova A.L. Grekova S.P. Heller A. Kuhlmann O. Soyka E. Giese T. Aprahamian M. Bour G. Rüffer S. Cziepluch C. et al.Complementary induction of immunogenic cell death by oncolytic parvovirus H-1PV and gemcitabine in pancreatic cancer.J. Virol. 2014; 88: 5263-5276Crossref PubMed Scopus (50) Google Scholar, 13Koks C.A. Garg A.D. Ehrhardt M. Riva M. Vandenberk L. Boon L. De Vleeschouwer S. Agostinis P. Graf N. Van Gool S.W. Newcastle disease virotherapy induces long-term survival and tumor-specific immune memory in orthotopic glioma through the induction of immunogenic cell death.Int. J. Cancer. 2015; 136: E313-E325Crossref PubMed Scopus (146) Google Scholar This is characterized by expression of potent danger signals, such as alterations in the composition of the plasma membrane of dying cells (including surface-exposed calreticulin [ecto-CRT] and heat shock proteins), as well as release of ATP and high-mobility group box 1 protein (HMGB-1). These are thought to be the optimal way to trigger activation of the immune system against cancer, ultimately resulting in long-term success of virotherapy.14Guo Z.S. Liu Z. Bartlett D.L. Oncolytic immunotherapy: dying the right way is a key to eliciting potent antitumor immunity.Front. Oncol. 2014; 4: 74Crossref PubMed Scopus (185) Google Scholar Coxsackievirus A21 (CVA21), a naturally occurring “common cold” intercellular adhesion molecule-1 (ICAM-1)-targeted RNA virus, has exhibited selective oncolytic activity in a range of solid tumors.15Shafren D.R. Au G.G. Nguyen T. Newcombe N.G. Haley E.S. Beagley L. Johansson E.S. Hersey P. Barry R.D. Systemic therapy of malignant human melanoma tumors by a common cold-producing enterovirus, coxsackievirus a21.Clin. Cancer Res. 2004; 10: 53-60Crossref PubMed Scopus (96) Google Scholar, 16Au G.G. Lindberg A.M. Barry R.D. Shafren D.R. Oncolysis of vascular malignant human melanoma tumors by Coxsackievirus A21.Int. J. Oncol. 2005; 26: 1471-1476PubMed Google Scholar, 17Berry L.J. Au G.G. Barry R.D. Shafren D.R. Potent oncolytic activity of human enteroviruses against human prostate cancer.Prostate. 2008; 68: 577-587Crossref PubMed Scopus (36) Google Scholar, 18Skelding K.A. Barry R.D. Shafren D.R. Systemic targeting of metastatic human breast tumor xenografts by Coxsackievirus A21.Breast Cancer Res. Treat. 2009; 113: 21-30Crossref PubMed Scopus (45) Google Scholar, 19Au G.G. Lincz L.F. Enno A. Shafren D.R. Oncolytic coxsackievirus A21 as a novel therapy for multiple myeloma.Br. J. Haematol. 2007; 137: 133-141Crossref PubMed Scopus (65) Google Scholar CAVATAK is a novel bio-selected formulation of CVA21, whose oncolytic and immunotherapeutic capacity has already been clearly demonstrated in in vitro cultures, in vivo melanoma models, and several human trials where CAVATAK has been administered intratumorally alone or in combination with immune checkpoint inhibitors, resulting in significant bystander effects with reduction of distant non-injected metastases.20Andtbacka R. Curti B. Hallmeyer S. Shafren D.R. Abstract CT214: Phase II CALM study: Changes in the tumor microenvironment induced by the immunotherapeutic agent coxsackievirus A21 delivered intratumorally in patients with advanced melanoma.Cancer Res. 2015; 75: CT214Crossref Google Scholar We evaluated CVA21 as a novel oncolytic virus for the treatment of human bladder cancer. Bladder cancer cell lines were assessed for surface expression of the viral receptors ICAM-1 and decay accelerating factor (DAF) by flow cytometry and subsequent susceptibility to viral-induced lytic infection. We hypothesized that lytic infection could be facilitated/enhanced by treatment of bladder cancer cell lines with Mitomycin-C by increasing ICAM-1 expression on the surface of the bladder cancer cells. Furthermore, we investigated the mode of cell death induced by CVA21 and potential immunogenicity in an immunocompetent murine bladder cancer model. Monolayers of each of the ten bladder cancer cell lines were inoculated with CVA21 at MOIs from 0 to 50 and cell viability quantified 72 hr post-infection using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTS) colorimetric cell-viability assay. As shown in Figure 1A, cell viability was significantly decreased in the 253J, VM-UB2, HCV29, T24, TCCSUP, and 5637 cell lines compared to J82, KU19-19, VMCUB1, and RT-112 at MOIs ≥ 1.0. Heat-inactivated CVA21 did not affect the cell viability over the range of MOIs tested, demonstrating that live CVA21 was required for oncolytic potency (Figure S1A). To confirm whether or not CVA21 was entering the least susceptible bladder cancer cell lines, the distribution of CVA21 was examined 24 hr post-infection in the bladder cancer cell lines using immunofluorescence and confocal microscopy. The six most susceptible bladder cancer cell lines, 253J, VM-CUB2, HCV29, T24, 5637, and TCCSUP, all showed CVA21 distributed in the cytoplasm, often with a peri-nuclear localization. Despite the apparent lack of susceptibility to the virus, J82 and KU19-19 cell lines also demonstrated clear infectivity by CVA21 in contrast to VMCUB and RT-112 that remained refractile to infection (Figure 1A). To determine whether the infectivity of the bladder cancer cell lines was due to their viral receptor expression profiles, the surface expression of ICAM-1 and DAF was examined by flow cytometric analysis. Whereas all cancer cell lines expressed a high level of DAF, only the most susceptible cell lines, 253J, VM-CUB2, HCV29, T24, TCCSUP, and 5637, also expressed a high level of ICAM-1, with the exception of J82, which despite expressing ICAM-1 to similar levels still did not succumb to viral infection (Figure 1B). Of note, J82 was the only cell line that showed a significant increase in the antiviral cytokine, interferon (IFN) β, post-CVA21 treatment (Figure S2). A lower level of ICAM-1 was observed on the KU19-19 and VMCUB1 cell lines and minimal to no surface ICAM-1 on the RT-112 cells (Figure 1B). Quantification of the mean absolute number of membrane-bound ICAM-1 molecules per cell using QuantiBRITE PE calibration beads further confirmed this differing viral receptor expression profile for the bladder cancer cell lines (Figure 1C). These results indicated that a threshold of at least 5,000 ICAM-1 molecules per cell was required in order for the virus to exhibit activity. To further demonstrate the importance of ICAM-1 expression for viral infectivity, the KU19-19 cell line that had been shown to display a small subset of ICAM-1-positive cells was sorted into ICAM-1-positive and negative subsets and the susceptibility of these sorted populations to virus assessed as before 72 hr post-infection using the MTS colorimetric cell-viability assay. As shown in Figure 1D, the ICAM-1-negative population showed no susceptibility to the virus, whereas the ICAM-1-positive cells showed enhanced susceptibility compared to the negative population and whole unsorted KU19-19 cells. It has been reported that oncogenic Kras mutations in pancreatic acinar cells induce the expression of ICAM-1.21Liou G.Y. Döppler H. Necela B. Edenfield B. Zhang L. Dawson D.W. Storz P. Mutant KRAS-induced expression of ICAM-1 in pancreatic acinar cells causes attraction of macrophages to expedite the formation of precancerous lesions.Cancer Discov. 2015; 5: 52-63Crossref PubMed Scopus (112) Google Scholar However, in the bladder cancer cell lines we studied, the Sanger COSMIC database22Bamford S. Dawson E. Forbes S. Clements J. Pettett R. Dogan A. Flanagan A. Teague J. Futreal P.A. Stratton M.R. Wooster R. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website.Br. J. Cancer. 2004; 91: 355-358Crossref PubMed Scopus (889) Google Scholar showed no common genomic mutations in one or more of a set of genes (PIK3CA, RB1, RAS, TSC1, CDKN2A, PTEN, and TP53) associated with ICAM-1 expression or the susceptibility of particular bladder cancer cell lines to CVA21 infection. Unpublished work from our group had shown that radiation upregulates expression of the ICAM-1 cell surface receptor on bladder cancer cell lines. However, as radiation is not normally used as a treatment for NMIBC, the commonly used chemotherapy, Mitomycin C, was tested on six bladder cancer cell lines to determine any effects on ICAM-1 receptor expression. Bladder cancer cell lines T24, TCCSUP, and 5637 were treated with increasing doses of Mitomycin-C (0.05–4 μg/mL) for an hour and the mean fluorescence intensity of ICAM-1 expression determined by flow cytometry after incubation in growth media for 24, 48, and 72 hr. Cytotoxic effects of Mitomycin-C were assessed using the live/dead cell discriminator, ViViD. Figure 2A shows that, at low doses of Mitomycin-C (up to 0.5 μg/mL), ICAM-1 surface expression increased in all three cell lines without any significant cytotoxic effects. This increase in Mitomycin-C-induced ICAM-1 expression was further confirmed at the RNA level in the 5637 cell line. RNA was extracted from the 5637 cell line, which had been treated with doses of Mitomycin-C up to 0.8 μg/mL, and qPCR performed. Figure S3 shows upregulated expression of ICAM-1 along with another viral receptor DAF in the 5637 cell line in response to increasing doses of Mitomycin-C treatment. To investigate whether the increased ICAM-1 viral receptor expression induced by Mitomycin-C treatment of bladder cancer cells facilitates CVA21 entry and thus enhanced viral replication, viral titers were measured by standard plaque assays on SKMEL-28 cell monolayers. Three susceptible bladder cancer cell lines (T24, TCCSUP, and 5637) and as a control one refractile cell line (RT-112) were treated with or without 0.5 μg/mL Mitomycin-C for 1 hr before infecting with CVA21 for 5 hr and incubation in growth media for 24, 48, and 72 hr post-infection. Cell supernatant was collected for extracellular virus quantification. The results showed that, in the T24 and TCCSUP cells, there were increased virus yields by 72 hr in the combination-treated cells compared to virus alone. This was true for the 5637 cell line up to 48 hr but then virus yield fell by 72 hr, probably due to significant cell death in this culture. RT-112, which had been shown to be refractile to infection, showed no change in virus yield with either treatment condition (Figure 2B). Similarly, Mitomycin-C treatment of the ICAM-1-negative sorted cells from the cell line KU19-19 also did not induce ICAM-1 expression on these cells, and they remained insensitive to the virus (data not shown). These results suggest that, in ICAM-1-expressing bladder cancer cells, Mitomycin-C treatment can increase further the ICAM-1 surface expression, thus facilitating enhanced CVA21 uptake and subsequent replication. To characterize the cell death pathways involved, the presence of apoptosis markers after treatment with Mitomycin-C, CVA21, or the combination were assessed. Annexin V-7AAD-based fluorescence-activated cell sorting (FACS) analyses showed significant upregulation of annexin V staining at 48 hr and 72 hr after CVA21 infection in all three bladder cancer cell lines tested. This induction of cell death was enhanced when cells had been pre-treated with Mitomycin-C (0.5 μg/mL). In contrast, Mitomycin-C treatment alone showed no significant cytotoxicity over the untreated control cells (Figures 3A and 3B ). Further confirmation of this apoptotic cell death pathway induced by CVA21 was demonstrated by the activation of the effector caspases, caspase-3 and -7, 48 hr after infection (Figure 3C). Furthermore, pre-treatment with the pan-caspase chemical inhibitor zVAD rescued the cells from virus-induced death whereas necrostatin-1 had no effect (Figure 3D). To exclude the involvement of additional interconnected death pathways, western blotting of whole-cell lysates, untreated, Mitomycin-C treated, or CVA21 treated with or without Mitomycin-C, were analyzed using a PARP antibody (apoptosis marker) as well as RIP1 and RIP3 antibodies (necroptosis). The protein levels of RIP1 and RIP3 either decreased or did not change in any of the bladder cancer cell lines exposed to CVA21 and combination treatment whereas, in contrast, the whole PARP was cleaved, yielding an 89-kD PARP fragment (Figure 3E). Altogether, these data indicated that the main mechanism for CVA21-induced cell death in bladder cancer cells was induction of apoptosis. To test the combination treatment of CVA21 and Mitomycin-C in a preclinical model system that represents both tumor architecture, heterogeneity, and the complexity of a tumor in situ, we took advantage of a fresh bladder tumor specimen that came into our lab from which 300-μm precision-cut slices of tumor were prepared. Slices with or without pre-treatment with Mitomycin-C (0.5 μg/mL) for 1 hr were infected with CVA21 (5 × 106 plaque-forming units [PFU]/mL) and cultured for 48 hr. Control slices of the same tumor, which had not been exposed to any treatment but cultured for the same period, were fixed simultaneously and embedded in paraffin for histological analysis. Immunofluorescent staining for the presence of viral protein showed increased viral replication within the combination-treated slices as compared to the CVA21-alone-treated tumor slice (Figure 4A). As expected, there was no evidence of virus within the Mitomycin-C-treated or untreated slices. Furthermore, a significantly higher level of apoptotic activity within the combination-treated tissue slice as compared to CVA21- or Mitomycin-C-alone-treated slices was observed. The control slice had little to no evidence of apoptotic cells, reflecting the situation in the original tumor biopsy (Figure 4B). In order to determine the immunogenic profile of CVA21-infected bladder cancer cell lines, 3 susceptible cell lines (T24, 5637, and TCCSUP) were infected with CVA21 at an MOI of 11.44 for T24, 1.0 for TCCSUP, and 1.8 for 5637 and analyzed for expression of the ICD determinants calreticulin, HSP70, extracellular ATP, and high-mobility group box 1 (HMGB1) at 24, 48, and 72 hr. This treatment induced surface expression of ecto-calreticulin on two out of the three cell lines (T24 and 5637), which was particularly marked by 72 hr in the combination-treated cells (Figure 5A). No significant changes in surface expression of HSP70 were observed in any of the cell lines studied (data not shown). The secreted danger signal, HMGB1, was evident in the culture medium of CVA21 and combination-treated bladder cancer cells at 48 and 72 hr post-treatment (Figure 5B); however, no specific upregulation of extracellular ATP in response to CVA21 infection could be detected. Of note, infection with heat-inactivated virus did not induce upregulation of the ICD markers calreticulin or HMGB1, indicating the need for a productive CVA21 infection to facilitate immunogenic cell death (Figure S1B). As the gold standard approach to evaluate the ability of a specific stimulus to cause bona fide ICD relies on vaccination assays,23Kepp O. Senovilla L. Vitale I. Vacchelli E. Adjemian S. Agostinis P. Apetoh L. Aranda F. Barnaba V. Bloy N. et al.Consensus guidelines for the detection of immunogenic cell death.Oncoimmunology. 2014; 3: e955691Crossref PubMed Scopus (572) Google Scholar a murine cancer model was developed using the mouse urothelial carcinoma cell line MB49 transfected with human ICAM-1 (Figure S4A). The susceptibility of the MB49/ICAM-1 cell line to CVA21 was shown by a significant decrease in cell viability compared to the wild-type MB49 cell line that remained refractile to infection (Figure S4B). Similar to the human bladder cancer cell lines, MB49/ICAM-1 cells exposed to the virus released the ICD determinant HMGB1 (Figure S4C). Thus, C57BL/6 mice were inoculated subcutaneously into the flank with lysates generated from MB49/ICAM-1 cells treated with or without CVA21 (Figure 6A). One week later, viable MB49 cells were introduced into the opposite flank and mice were monitored for the appearance of palpable neoplastic tumors. By day 18, 11 days after re-challenge, 100% of the mice that had initially received lysates from CVA21-treated MB49/ICAM-1 cells had been effectively vaccinated compared to 50% of the mice that had initially received untreated MB49/ICAM-1 cell lysates. As expected, the control mice all developed rapidly growing subcutaneous tumors. In order to evaluate which immune cell population(s) were functionally important in the protection of the vaccinated mice against re-challenge with MB49 tumor cells, depletion was conducted one day prior to initial vaccination using anti-CD8, anti-CD4, or anti-NK monoclonal antibodies (mAbs). Only the mice depleted of CD4 cells showed a rapid outgrowth of tumors upon re-challenge with live MB49 wild-type (WT) cells, with 82% of the animals succumbing to disease by the end of the study period. Mice depleted of CD8+ T cells and natural killer (NK) cells showed comparable antitumor protection to immunoglobulin (Ig) control-treated mice, indicating that these cells do not play an important role in the therapeutic effect (Figure 6B). As expected, the control mice that had been vaccinated with only the MB49 cell lysate showed significant tumor outgrowth compared to the isotype control, CD8-, and NK-depleted groups. Collectively, these data showed for the first time an important role for CD4 cells in the therapeutic response mediated by vaccination with CVA21 MB49/ICAM-1 lysates. Treatment options and their outcomes in NMIBC have not changed significantly in decades. Whereas BCG continues to be the standard of care in patients with high-grade superficial disease, this is at a significant cost in terms of morbidity associated with BCG, the frequency and duration of treatments, and propensity to recur. NMIBC has been the focus of previous studies using an intravesical route of administration for a number of non-replicating viruses and OVs and reviewed recently.24Delwar Z. Zhang K. Rennie P.S. Jia W. Oncolytic virotherapy for urological cancers.Nat. Rev. Urol. 2016; 13: 334-352Crossref PubMed Scopus (15) Google Scholar We have previously shown, using an in vivo orthotopic bladder tumor model, that the use of an oncolytic herpes-simplex virus-1 (Oncovex(GALV/CD)) resulted in enhanced local tumor control by combining oncolysis with the expression of a highly potent pro-drug activating gene and the fusogenic glycoprotein.25Simpson G.R. Horvath A. Annels N.E. Pencavel T. Metcalf S. Seth R. Peschard P. Price T. Coffin R.S. Mostafid H. et al.Combination of a fusogenic glycoprotein, pro-drug activation and oncolytic HSV as an intravesical therapy for superficial bladder cancer.Br. J. Cancer. 2012; 106: 496-507Crossref PubMed Scopus (24) Google Scholar Other viruses have been evaluated, including reovirus26Hanel E.G. Xiao Z. Wong K.K. Lee P.W. Britten R.A. Moore R.B. A novel intravesical therapy for superficial bladder cancer in an orthotopic model: oncolytic reovirus therapy.J. Urol. 2004; 172: 2018-2022Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar and vaccinia.27Potts K.G. Irwin C.R. Favis N.A. Pink D.B. Vincent K.M. Lewis J.D. Moore R.B. Hitt M.M. Evans D.H. Deletion of F4L (ribonucleotide reductase) in vaccinia virus produces a selective oncolytic virus and promotes anti-tumor immunity with superior safety in bladder cancer models.EMBO Mol. Med. 2017; 9: 638-654Crossref PubMed Scopus (26) Google Scholar The most advanced studies in humans involve CG0070, a selectively replicating adenovirus expressing granulocyte macrophage colony-stimulating factor (GM-CSF), in which the human E2F-1 promoter drives expression of the E1A viral gene. CG0070 preferentially replicates in Rb protein-defective bladder cancer cells, resulting in production of GM-CSF that activates the host immune response.28Burke J.M. Lamm D.L. Meng M.V. Nemunaitis J.J. Stephenson J.J. Arseneau J.C. Aimi J. Lerner S. Yeung A.W. Kazarian T. et al.A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer.J. Urol. 2012; 188: 2391-2397Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar The initial study focused on CIS, Ta, and T1 patients with recurrent NMIBC cancer after BCG treatment and led to the current ongoing phase 3 trial for high-grade NMIBC patients who failed BCG therapy and refused cystectomy.29Cold Genesys (2017). Safety and efficacy of CG0070 oncolytic virus regimen for high grade NMIBC after BCG failure (BOND2). https://clinicaltrials.gov/ct2/show/NCT02365818.Google Scholar Following the success of immune checkpoint inhibition in advanced bladder cancer, there are numerous trials evaluating the role of anti-PD-1 agents in NMIBC. Given the limited effect in advanced disease (25% response rate; median duration 12 months; recently reviewed)30Farina M.S. Lundgren K.T. Bellmunt J. Immunotherapy in urothelial cancer: recent results and future perspectives.Drugs. 2017; 77: 1077-1089Crossref PubMed Scopus (57) Google Scholar and the potential toxicities of this form of immunotherapy in an older population, there is still an urgent need for improved, less toxic local agents for long-term tumor control. This study demonstrates the potential of CVA21 as a new oncolytic immunotherapy agent whose anti-cancer activity can now be extended as a novel treatment approach to NMIBC. Whereas the majority of bladder cancer cell lines studied were susceptible to direct oncolysis by CVA21, we hypothesized that increasing the expression of the viral receptor, ICAM-1, would further enhance this oncolysis. Treatment of bladder cancer cell lines with Mitomycin-C, a commonly used chemotherapeutic agent for bladder cancer, upregulated surface expression of ICAM-1, resulting in increased viral replication and oncolysis. This was further" @default.
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• W2789761490 title "Oncolytic Immunotherapy for Bladder Cancer Using Coxsackie A21 Virus" @default.
• W2789761490 cites W1480890018 @default.
• W2789761490 cites W1532789289 @default.
• W2789761490 cites W1910257954 @default.
• W2789761490 cites W1936207051 @default.
• W2789761490 cites W1966766953 @default.
• W2789761490 cites W1967262248 @default.
• W2789761490 cites W1990235635 @default.
• W2789761490 cites W1999896748 @default.
• W2789761490 cites W2008620560 @default.
• W2789761490 cites W2011167174 @default.
• W2789761490 cites W2020158018 @default.
• W2789761490 cites W2022543147 @default.
• W2789761490 cites W2037569123 @default.
• W2789761490 cites W2045179871 @default.
• W2789761490 cites W2046041427 @default.
• W2789761490 cites W2050161362 @default.
• W2789761490 cites W2050899268 @default.
• W2789761490 cites W2052363929 @default.
• W2789761490 cites W2072773155 @default.
• W2789761490 cites W2075489670 @default.
• W2789761490 cites W2091913868 @default.
• W2789761490 cites W2092055002 @default.
• W2789761490 cites W2101268389 @default.
• W2789761490 cites W2102833781 @default.
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• W2789761490 cites W2139397653 @default.
• W2789761490 cites W2142563643 @default.
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• W2789761490 cites W2163252162 @default.
• W2789761490 cites W2165839182 @default.
• W2789761490 cites W2399582291 @default.
• W2789761490 cites W2406148028 @default.
• W2789761490 cites W2597132924 @default.
• W2789761490 cites W2612383893 @default.
• W2789761490 cites W4211238487 @default.
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