New approach to active immunotherapy of Hepatitis C related cancer (LIVE®VAC)

Hepatitis C virus causes hepatocellular carcinomas/HCC and triggers Non-Hodgkin´s B-cell lymphomas/NHL affecting millions of people and presenting a devastating burden to health-care systems all over the world. Directly acting antiviral drugs cure HCV infection, but cannot reliably cure liver cancer, or lymphoid malignancies. Besides, they induce resistance, which would eventually limit their use. Recent clinical trials demonstrated possibility of active cancer immunotherapy. We will develop such therapy against HCC and NHL based on plasmid DNA. DNA-vaccine will target HCV core, and early tumor-associated antigen human telomerase reverse transcriptase/TERT. DNA-vaccine will be reinforced by Toll-Like Receptor 7/8 ligand and check-point inhibitors as PD-1/PD-L1. Their combination will be introduced intratumorally to enhance efficacy and reduce off-side toxicities. Combination will be tested for immunogenicity in two mouse strains. Effector response will be evaluated in the murine models of human cancer responsive and refractory to immunotherapy. Proof of concept will be to demonstrate the capacity of immune response to lyse HCV-, TERT- and HCV/TERT-expressing tumor cells, protect mice from tumor challenge and/or cure animals from HCV/TERT-(co)expressing tumors and their metastases. Project will integrate basic research with R&D of a prototype immunotherapeutical. This novel approach has direct relevance to immunotherapy of cancer caused by other tumorigenic human viruses.

Project output

Publications (2021)

• Isaguliants M, Bayurova E, Avdoshina D, Kondrashova A, Chiodi F, Palefsky JM. Oncogenic Effects of HIV-1 Proteins, Mechanisms Behind. Cancers (Basel). 2021 Jan 15;13(2):305. doi: 10.3390/cancers13020305. PMID: 33467638; PMCID: PMC7830613
• Ljungberg K, Isaguliants M. DNA Vaccine Development at Pre- and Post-Operation Warp Speed. Vaccines (Basel). 2020 Dec 4;8(4):737. doi: 10.3390/vaccines8040737. PMID: 33291723; PMCID: PMC7761981.

Presentations at RSU Research Week 2021

• #919 – Novel mechanism of HIV-1 driven carcinogenicity affecting epithelial cells
  Maria Isaguliants (Issagouliantis), Juris Jansons, Džeina Mežale, Dace Skrastiņa, Ekaterina Bayurova, Darya Avdoshina, Alla Kondrashova
• #886 – Protection of mice against challenge with murine adenocarcinoma cells by naked DNA immunization with reverse transcriptase domain of rat TERT
  Juris Jansons, Ekaterina Bayurova, Dace Skrastiņa, Alisa Kurļanda, Ilya Gordeychuk, Maria Isaguliants (Issagouliantis)

Conclusive Workshop on the LIVE®VAC project of the Latvian Science Fund

The workshop took place on 25 February 2021.

Details

Publications (2019-2020)

 

• Juris Jansons, Ekaterina Bayurova, Dace Skrastina, Alisa Kurlanda, Ilze Fridrihsone, Dmitry Kostyushev, Anastasia Kostyusheva, Alexander Artyuhov, Erdem Dashinimaev, Darya Avdoshina, Alla Kondrashova, Vladimir Valuev-Elliston, Oleg Latyshev, Olesja Eliseeva, Stefan Petkov, Maxim Abakumov, Laura Hippe, Irina Kholodnyuk, Elizaveta Starodubova, Tatiana Gorodnicheva, Alexander Ivanov, Ilya Gordeychuk, Maria Isaguliants. Expression of the Reverse Transcriptase Domain of Telomerase Reverse Transcriptase Induces Lytic Cellular Response in DNA-Immunized Mice and Limits Tumorigenic and Metastatic Potential of Murine Adenocarcinoma 4T1 Cells. Vaccines (Basel). 2020 Jun 18;8(2):E318. doi: 10.3390/vaccines8020318.
• Ekaterina Bayurova, Juris Jansons, Dace Skrastina, Olga Smirnova, Dzeina Mezale, Anastasia Kostyusheva, Dmitry Kostyushev, Stefan Petkov, Philip Podschwadt, Vladimir Valuev-Elliston, Sviataslau Sasinovich, Sergey Korolev, Per Warholm, Anastasia Latanova, Elizaveta Starodubova, Amir Tukhvatulin, Oleg Latyshev, Renat Selimov, Pavel Metalnikov, Alexander Komarov, Olga Ivanova, Tatiana Gorodnicheva, Sergey Kochetkov, Marina Gottikh, Ilze Strumfa, Alexander Ivanov, Ilya Gordeychuk, Maria Isaguliants. HIV-1 Reverse Transcriptase Promotes Tumor Growth and Metastasis Formation via ROS-Dependent Upregulation of Twist. Oxid Med Cell Longev. 2019 Dec2; 2019:6016278. doi:10.1155/2019/6016278. eCollection 2019
• Juris Jansons, Irina Sominskaya, Natalia Petrakova, Elizaveta S Starodubova, Olga A Smirnova, Ekaterina Alekseeva, Ruta Bruvere, Olesja Eliseeva, Dace Skrastina, Elena Kashuba, Marija Mihailova, Sergey N Kochetkov, Alexander V Ivanov, Maria G Isaguliants. The Immunogenicity in Mice of HCV Core Delivered as DNA Is Modulated by Its Capacity to Induce Oxidative Stress and Oxidative Stress Response. Cells 2019 Feb 28;8(3):208 doi: 10.3390/cells8030208.
• Karen K Kyuregyan, Vera S Kichatova, Anastasiya A Karlsen, Olga V Isaeva, Sergei A Solonin, Stefan Petkov, Morten Nielsen,Maria G Isaguliants, Mikhail I Mikhailov. Factors Influencing the Prevalence of Resistance-Associated Substitutions in NS5A Protein in Treatment-Naive Patients With Chronic Hepatitis C. Biomedicines. 2020 Apr 7;8(4):80. doi: 10.3390/biomedicines8040080.

TECHVAC2020 Zoom conference "Perspective technologies of vaccination and immunotherapy"

4th International Conference devoted to vaccines, vaccination and immunotherapy “Perspective technologies of vaccination and immunotherapy” was held online on October 27-29, 2020.

Program and abstract book is on the web site - www.techvac.org 

Workshop Immunotherapy of cancer

Workshop Immunotherapy of Cancer was held on 13 June 2019 in Senate Hall at Rīga Stradiņš University. The seminar is part of the project New approach to active immunotherapy of Hepatitis C related cancer (LZP-2018/2-0308).

One of the world’s leaders in the field of biotechnology research, Professor Edward Rybicki of the University of Cape Town, gave a lecture Therapeutic cancer vaccines made in plants. At the workshop also attended researchers from Sweden, Russia and Latvia with information on the results of recent research in the development of targeted cancer immunotherapy. 

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Agenda and presentations

	Invited lecture Therapeutic cancer vaccines made in plants Ed Rybicki, Molecular & Cell Biology Department, University of Cape Town, South Africa Effective therapeutic vaccines for human cancers would be a highly sought-after solution to often intractable disease problems. While there are presently a number of exciting possibilities in this regard - and specifically, the recent successes with monoclonal antibody therapies - the cost of production of complex biologics limits their application in especially developing countries, where much of the problem resides. The use of plants for the production of such biologics is becoming increasingly feasible and increasingly popular, and could revolutionise the provision of such medicines in the wider world. This presentation will cover plant production of cancer therapeutics in general, with a particular focus on human papillomavirus disease where some signal successes have been obtained. Presentation
	Nonhuman primate models for preclinical testing of cancer vaccines Ilya Gordeychuk, Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products of Russian Academy of Sciences, Moscow, Russia Presentation
	Tumorigenic effects of HIV antigens mediated through the induction of oxidative stress Maria Isaguliants, Riga Stradiņš University, Riga, Latvia, and Karolinska Institutet, Stockholm, Sweden
	Reprogramming of macrophages for immunotherapy of cancer Anna Zajakina, Biomedical Research and Study Centre, Riga, Latvia Presentation
	Multifunctional immune response against tumor associated antigen, telomerase reverse transcriptase (TERT) induced in mice electroporated with TERT DNA Alisa Kurlanda, Riga Stradiņš University, Riga, Latvia
	Optimization of DNA vaccines against hepatitis C virus targeting its nucleocapsid (core) protein Juris Jansons, Riga Stradiņš University, and Biomedical Research and Study Centre, Riga, Latvia Presentation
	University of Lodz Magdalena Kluska, University of Lodz, Lodz, Poland  Presentation

Seminar on the progress of LZP project LIVE®VAC

Seminar took place on 21 November 2019 at RSU, Dzirciema iela 16, Rīga.

Reports discussed

Maria Isaguliants	Eukaryotic expression of synthetic genes for telomerase reverse transcriptase (TERT) and creation of murine adenocarcinoma cell lines expressing TERT and its fragments.
Maria Isaguliants	Prokaryotic expression of fragments of TERT, raising anti-TERT antibodies and characterization of their ability to recognize native TERT in murine and human tissues.
Alisa Kurlanda	Immunogenicity of synthetic TERT DNA in mice.
Juris Jansons	Immunogenicity of HCV core DNA variants in mice, and co-immunization with HCV core and TERT DNA.
Juris Jansons	In vivo growth of murine adenocarcinoma cell lines expressing TERT and its fragments, evidence of immune restriction of tumor growth.
Ilze Fridrihsone	Characterization of tumors and metastasis formed in BALB/C mice after implantation of murine adenocarcinoma cell lines expressing TERT  fragments.
Olga Trofimova	Immune cell infiltration into tumors formed by murine adenocarcinoma cell lines expressing TERT.

Presentations at research meetings

RSU conference Knowledge for Use in Practice 1–3 April 2019

• Maria Isaguliants. MODERN STATE OF VACCINE DEVELOPMENT, DNA VACCINES (oral)
• Dzeina Mezale, Ekaterina Bayurova, Ilze Strumfa, Andrejs Vanags, Ilze Fridrihsone, Stefan Petkov, Ilya Gordeychuk, Juris Jansons, Maria Isaguliants. Expression of HIV reverse transcriptase in implanted murine adenocarcinoma cells increases burden of liver metastasis in BALB/c mice: a pilot study (poster)

Annual Congress of international society for vaccines 27–29 October 2019, Ghent, Belgium

• Jansons Juris, Kurlanda Alica, Skrastina Dace, Petkov Stefan, Latyshev Oleg, Starodubova Elizaveta, Ivanova Olga, Hippe Laura, Kholodnyuk Irina, Ivanov Alexander, Gordeychuk Ilya, Isaguliants Maria. INTRADERMAL DNA IMMUNIZATION OF MICE WITH RAT TELOMERASE REVERSE TRANSCRIPTASE FOLLOWED BY ELECTROPORATION INDUCES MULTIFUNCTIONAL IMMUNE RESPONSE AGAINST ITS REVERSE TRANSCRIPTASE DOMAIN  (poster)
• Olga Trofimova, Juris Jansons, Dace Skrastina, Maria Isaguliants, and Anna Zajakina. SEMLIKI FOREST VIRUS VECTOR PRODUCING IFN-GAMMA INHIBITS INTRATUMORAL INFILTRATION OF MACROPHAGES IN MOUSE MODEL (poster)

VI International Oncology Forum “White Nights” 2020, Sankt-Petersburg, Russia, 25–28 June 2020

• Maria Isaguliants, Jansons Juris, Bayurova Ekaterina, Kurlanda Alisa, Fridrihsone Ilze, Kostyshev Dmitry, Kostysheva Anastasia, Artyuhov Alexander, Dashinimaev Erdem, Avdoshina Darya, Kondrashova Alla, Valuev-Elliston Vladimir, Latyshev Oleg, Eliseeva Olesja, Petkov Stefan, Abakumov Maxim, Hippe Laura, Kholodnyuk Irina, Starodubova Elizaveta, Gorodnicheva Tatiana, Skrastina Dace. EXPRESSION OF THE REVERSE TRANSCRIPTASE DOMAIN OF TELOMERASE REVERSE TRANSCRIPTASE INDUCES LYTIC CELLULAR RESPONSE IN DNA-IMMUNIZED MICE AND LIMITS TUMORIGENIC AND METASTATIC POTENTIAL OF MURINE ADENOCARCINOMA 4T1 CELLS (Oral, Zoom)