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  • Tumor Colonization and Therapy by Escherichia coli Nissle 1917 Strain in Syngeneic Tumor-Bearing Mice Is Strongly Affected by the Gut Microbiome. Cancers Gentschev, I., Petrov, I., Ye, M., Kafuri Cifuentes, L., Toews, R., Cecil, A., Oelschaeger, T. A., Szalay, A. A. 2022; 14 (24)


    In the past, different bacterial species have been tested for cancer therapy in preclinical and clinical studies. The success of bacterial cancer therapy is mainly dependent on the ability of the utilized bacteria to overcome the host immune defense system to colonize the tumors and to initiate tumor-specific immunity. In recent years, several groups have demonstrated that the gut microbiome plays an important role of modulation of the host immune response and has an impact on therapeutic responses in murine models and in cohorts of human cancer patients. Here we analyzed the impact of the gut microbiome on tumor colonization and tumor therapy by the Escherichia coli Nissle 1917 (EcN) strain. This EcN strain is a promising cancer therapy candidate with probiotic properties. In our study, we observed significantly better tumor colonization by EcN after antibiotic-induced temporal depletion of the gut microbiome and after two intranasal applications of the EcN derivate (EcN/pMUT-gfp Knr) in 4T1 tumor-bearing syngeneic BALB/c mice. In addition, we demonstrated significant reduction in tumor growth and extended survival of the EcN-treated mice in contrast to phosphate-buffered saline (PBS)-treated tumor-bearing control animals. Multispectral imaging of immune cells revealed that depletion of the gut microbiome led to significantly lower infiltration of cytotoxic and helper T cells (CD4 and CD8 cells) in PBS tumors of mice pretreated with antibiotics in comparison with antibiotic untreated PBS-or EcN treated mice. These findings may help in the future advancement of cancer treatment strategies using E. coli Nissle 1917.

    View details for DOI 10.3390/cancers14246033

    View details for PubMedID 36551519

  • Canine Adipose-Derived Mesenchymal Stem Cells (cAdMSCs) as a "Trojan Horse" in Vaccinia Virus Mediated Oncolytic Therapy against Canine Soft Tissue Sarcomas VIRUSES-BASEL Petrov, I., Gentschev, I., Vyalkova, A., Elashry, M. I., Klymiuk, M. C., Arnhold, S., Szalay, A. A. 2020; 12 (7)


    Several oncolytic viruses (OVs) including various human and canine adenoviruses, canine distemper virus, herpes-simplex virus, reovirus, and members of the poxvirus family, such as vaccinia virus and myxoma virus, have been successfully tested for canine cancer therapy in preclinical and clinical settings. The success of the cancer virotherapy is dependent on the ability of oncolytic viruses to overcome the attacks of the host immune system, to preferentially infect and lyse cancer cells, and to initiate tumor-specific immunity. To date, several different strategies have been developed to overcome the antiviral host defense barriers. In our study, we used canine adipose-derived mesenchymal stem cells (cAdMSCs) as a "Trojan horse" for the delivery of oncolytic vaccinia virus Copenhagen strain to achieve maximum oncolysis against canine soft tissue sarcoma (CSTS) tumors. A single systemic administration of vaccinia virus-loaded cAdMSCs was found to be safe and led to the significant reduction and substantial inhibition of tumor growth in a CSTS xenograft mouse model. This is the first example that vaccinia virus-loaded cAdMSCs could serve as a therapeutic agent against CSTS tumors.

    View details for DOI 10.3390/v12070750

    View details for Web of Science ID 000558450300001

    View details for PubMedID 32664672

    View details for PubMedCentralID PMC7411685

  • Delivery of oncolytic vaccinia virus by matched allogeneic stem cells overcomes critical innate and adaptive immune barriers JOURNAL OF TRANSLATIONAL MEDICINE Draganov, D. D., Santidrian, A. F., Minev, I., Duong Nguyen, Kilinc, M., Petrov, I., Vyalkova, A., Lander, E., Berman, M., Minev, B., Szalay, A. A. 2019; 17: 100


    Previous studies have identified IFNγ as an important early barrier to oncolytic viruses including vaccinia. The existing innate and adaptive immune barriers restricting oncolytic virotherapy, however, can be overcome using autologous or allogeneic mesenchymal stem cells as carrier cells with unique immunosuppressive properties.To test the ability of mesenchymal stem cells to overcome innate and adaptive immune barriers and to successfully deliver oncolytic vaccinia virus to tumor cells, we performed flow cytometry and virus plaque assay analysis of ex vivo co-cultures of stem cells infected with vaccinia virus in the presence of peripheral blood mononuclear cells from healthy donors. Comparative analysis was performed to establish statistically significant correlations and to evaluate the effect of stem cells on the activity of key immune cell populations.Here, we demonstrate that adipose-derived stem cells (ADSCs) have the potential to eradicate resistant tumor cells through a combination of potent virus amplification and sensitization of the tumor cells to virus infection. Moreover, the ADSCs demonstrate ability to function as a virus-amplifying Trojan horse in the presence of both autologous and allogeneic human PBMCs, which can be linked to the intrinsic immunosuppressive properties of stem cells and their unique potential to overcome innate and adaptive immune barriers. The clinical application of ready-to-use ex vivo expanded allogeneic stem cell lines, however, appears significantly restricted by patient-specific allogeneic differences associated with the induction of potent anti-stem cell cytotoxic and IFNγ responses. These allogeneic responses originate from both innate (NK)- and adaptive (T)- immune cells and might compromise therapeutic efficacy through direct elimination of the stem cells or the induction of an anti-viral state, which can block the potential of the Trojan horse to amplify and deliver vaccinia virus to the tumor.Overall, our findings and data indicate the feasibility to establish simple and informative assays that capture critically important patient-specific differences in the immune responses to the virus and stem cells, which allows for proper patient-stem cell matching and enables the effective use of off-the-shelf allogeneic cell-based delivery platforms, thus providing a more practical and commercially viable alternative to the autologous stem cell approach.

    View details for DOI 10.1186/s12967-019-1829-z

    View details for Web of Science ID 000462925100002

    View details for PubMedID 30917829

    View details for PubMedCentralID PMC6437877

  • Oncolytic virus efficiency inhibited growth of tumour cells with multiple drug resistant phenotype in vivo and in vitro JOURNAL OF TRANSLATIONAL MEDICINE Goncharova, E. P., Ruzhenkova, J. S., Petrov, I. S., Shchelkunov, S. N., Zenkova, M. A. 2016; 14: 241


    Tumour resistance to a wide range of drugs (multiple drug resistant, MDR) acquired after intensive chemotherapy is considered to be the main obstacle of the curative treatment of cancer patients. Recent work has shown that oncolytic viruses demonstrated prominent potential for effective treatment of diverse cancers. Here, we evaluated whether genetically modified vaccinia virus (LIVP-GFP) may be effective in treatment of cancers displaying MDR phenotype.LIVP-GFP replication, transgene expression and cytopathic effects were analysed in human cervical carcinomas KB-3-1 (MDR-), KB-8-5 (MDR+) and in murine melanoma B-16 (MDR-), murine lymphosarcomas RLS and RLS-40 (MDR+). To investigate the efficacy of this therapy in vivo, we treated immunocompetent mice bearing murine lymphosarcoma RLS-40 (MDR+) (6- to 8-week-old female CBA mice; n = 10/group) or melanoma B-16 (MDR-) (6- to 8-week-old female C57Bl mice; n = 6/group) with LIVP-GFP (5 × 10(7) PFU of virus in 0.1 mL of IMDM immediately and 4 days after tumour implantation).We demonstrated that LIVP-GFP replication was effective in human cervical carcinomas KB-3-1 (MDR-) and KB-8-5 (MDR+) and in murine melanoma B-16 (MDR-), whereas active viral production was not detected in murine lymphosarcomas RLS and RLS-40 (MDR+). Additionally, it was found that in tumour models in immunocompetent mice under the optimized regimen intratumoural injections of LIVP-GFP significantly inhibited melanoma B16 (33 % of mice were with complete response after 90 days) and RLS-40 tumour growth (fourfold increase in tumour doubling time) as well as metastasis.The anti-tumour activity of LIVP-GFP is a result of direct oncolysis of tumour cells in case of melanoma B-16 because the virus effectively replicates and destroys these cells, and virus-mediated activation of the host immune system followed by immunologically mediated destruction of of tumour cells in case of lymphosarcoma RLS-40. Thus, the recombinant vaccinia virus LIVP-GFP is able to inhibit the growth of malignant cells with the MDR phenotype and tumour metastasis when administered in the early stages of tumour development.

    View details for DOI 10.1186/s12967-016-1002-x

    View details for Web of Science ID 000382292800001

    View details for PubMedID 27538520

    View details for PubMedCentralID PMC4989492

  • Oncolytic Virotherapy of Canine and Feline Cancer VIRUSES-BASEL Gentschev, I., Patil, S. S., Petrov, I., Cappello, J., Adelfinger, M., Szalay, A. A. 2014; 6 (5): 2122-2137


    Cancer is the leading cause of disease-related death in companion animals such as dogs and cats. Despite recent progress in the diagnosis and treatment of advanced canine and feline cancer, overall patient treatment outcome has not been substantially improved. Virotherapy using oncolytic viruses is one promising new strategy for cancer therapy. Oncolytic viruses (OVs) preferentially infect and lyse cancer cells, without causing excessive damage to surrounding healthy tissue, and initiate tumor-specific immunity. The current review describes the use of different oncolytic viruses for cancer therapy and their application to canine and feline cancer.

    View details for DOI 10.3390/v6052122

    View details for Web of Science ID 000337160900013

    View details for PubMedID 24841386

    View details for PubMedCentralID PMC4036544

  • Antitumor effect of the LIVP-GFP recombinant vaccinia virus. Doklady biological sciences : proceedings of the Academy of Sciences of the USSR, Biological sciences sections Petrov, I. S., Goncharova, E. P., Kolosova, I. V., Pozdnyakov, S. G., Shchelkunov, S. N., Zenkova, M. A., Vlasov, V. V. 2013; 451: 248-52

    View details for DOI 10.1134/S0012496613040133

    View details for PubMedID 23975469