Development and investigation of the oncolytic activity of genetically engineered vaccinia virus strains expressing immunomodulatory agents/Разработка и исследование рекомбинантных онколитических штаммов осповакцины, экспрессирующих иммуномодулирующие агенты тема диссертации и автореферата по ВАК РФ 00.00.00, кандидат наук Шакиба Йасмин

• Шакиба Йасмин
• кандидат наук
• 2023

Оглавление диссертации кандидат наук Шакиба Йасмин

TABLE OF CONTENTS

Introduction

CHAPTER 1. LITERATURE REVIEW

1.1 General information about oncolytic viruses and oncolytic viral immunotherapy

1.2 Biology of vaccinia virus

1.2.1 Genome structure, replication, and transcription

1.2.2 Phylogenetic analysis of the virus

1.2.3 Vaccinia virus life cycle

1.2.4 Spread

1.3 Vaccinia virus oncolytic properties

1.3.1 Cancer-selective oncolytic vaccinia viruses

1.3.2 Armed oncolytic vaccinia viruses

1.3.3 Arming vaccinia virus with interleukin15 and its receptor

1.3.4 Arming vaccinia virus with bacterial flagellin as an immunostimulatory molecule

1.4 Preclinical data on oncolytic vaccinia virus

1.5 Clinical data on oncolytic vaccinia virus

1.5.1 Clinical data on wild-type vaccinia virus

1.5.2 Clinical data on recombinant oncolytic vaccinia viruses

1.6 Oncolysates

1.6.1 Clinical data about oncolysates

1.7 Cell carriers for oncolytic vaccinia virus

1.8 Oncolytic vaccinia virus in combination with other therapies

1.8.1 Vaccinia virus in combination with chemotherapy

1.8.2 Vaccinia virus in combination with radiotherapy

1.8.3 Vaccinia virus in combination with other oncolytic viruses

1.8.4 Vaccinia virus in combination with hyperthermia

1.9 Safety concerns

CHAPTER 2. MATERIALS AND METHODS

2.1 Materials and reagents used in the work

2.1.1 Reagents:

2.1.2 Buffer solutions:

2.1.3 Oligonucleotide primers:

2.1.4 Bacterial culture media:

2.1.5 Strain of Escherichia coli and plasmids used in this work:

2.2 Cell culture

2.3 Cell freezing

2.4 Preparations and construction of the recombinant vaccinia virus strains used in this work

2.4.1 Production of DNA plasmid in Escherichia Coli strain 10 beta

2.4.2 DNA cutting with restriction endonucleases

2.4.3 Fractionation of DNA plasmid by agarose gel electrophoresis

2.4.4 Elution of DNA fragments from agarose gel

2.4.5 Obtaining the insertions

2.4.6 PCR

2.4.7 Ligation of the vector plasmid with DNA fragments

2.4.8 Isolation of plasmid DNA

2.4.9 Transfection of the plasmid DNA, optimizing TK-deficient strains, and

obtaining pure recombinant virus clones

2.5 Western blotting

2.6 Sequencing/ Isolation of genomic DNA

2.7 Production of recombinant viruses and sucrose purification

2.8 Virus titration

2.9 Determination of the sensitivity of tumor cell lines to the recombinant strains of vaccinia virus by MTT-assay

2.10 Determining the viral infection efficacy in the tumor cell lines by titration using the Reed and Muench method

2.11 Viral kinetics by the Flow cytometry

2.12 Bioluminescence assay in vitro

2.13 Evaluation of LIVP-FlaB-RFP induced cytotoxicity in the presence of macrophages in vitro

2.14 Obtaining allografts of tumor models in immunocompetent mice

2.15 Introduction of vaccinia virus recombinant strains into the body of immunocompetent mice to induce viral oncolysis

2.16 Cytokine analysis

2.17 Real-time quantitative PCR

2.18 Analysis of the tumor infiltrating lymphocytes

2.19 Enzyme-linked Immunosorbent Assay

2.20 Statistical analysis

CHAPTER 3. RESULTS

3.1 A comparative study of the oncolytic activities of two strains of vaccinia virus

3.1.1 Cytotoxicity assessment of the LIVP-RFP and MVA-RFP

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3.1.2 Flow cytometric assessment of the viral kinetics

3.1.3 Oncolytic efficacy of the recombinant vaccinia viruses in vivo

3.2 Oncolytic activity of the LIVP-FlaB-RFP

3.2.1 Construction of the recombinant viruses and confirmation of the transgene expression

3.2.2 Assessment of the recombinant virus's replication efficiency, kinetics, and cytotoxicity

3.2.3 Flagellin expression increases macrophage's cytolytic activity in vitro

3.2.4 The administration of the LIVP results in significant viral deposition within the tumor but not in normal organs

3.2.5 Flagellin expression augments the oncolytic activity of the LIVP in the murine melanoma models

3.2.6. Vaccinia virus expressing flagellin modulates the tumor microenvironment

3.3 Experiment with LIVP-IL15-RFP and LIVP-IL15Ra-RFP

3.3.1 Construction and characteristics of the recombinant viruses

3.3.2 Recombinant strains efficiently replicate and lyse tumor cells in vitro

3.3.3 Detection of IL15/IL15Receptor alpha complex in vitro

3.3.4 The combination of the LIVP-IL15-RFP and LIVP-IL 15Ra-RFP strains cause a synergetic oncolytic effect in vivo

3.3.5 Recombinant strains modulate the tumor microenvironment

3.3.6 Cytokine analysis of the Sera and tumor tissue

Chapter 4. DISCUSSION

4.1 LIVP strain has an excellent oncolytic property compared with MVA

4.2 Recombinant strain LIVP-FlaB-RFP elicits significant tumor regression in melanoma models

4.3. Simultaneous injection of LIVP-IL15-RFP with LIVP-IL15Ra-RFP exhibits

significant oncolytic activity in breast cancer models

Conclusion

Findings and outlook

Ethics

List of abbreviations

Acknowledgment

References

Введение диссертации (часть автореферата) на тему «Development and investigation of the oncolytic activity of genetically engineered vaccinia virus strains expressing immunomodulatory agents/Разработка и исследование рекомбинантных онколитических штаммов осповакцины, экспрессирующих иммуномодулирующие агенты»

Introduction

Metastatic cancer still remains an incurable disease. When cancer cells begin to spread in the form of metastases, it is necessary to provide systemic therapy that selectively kills malignant cells. Unfortunately, for over a half of century, the primary agents for systemic cancer therapy have been chemotherapy drugs which are often accompanied by numerous adverse side effects that worsen patient's quality of life, suppress natural antitumor immunity, promote therapy-resistant variants of tumor cells, and has a low contribution to 5-years survival of the patients [1, 2]. Thus, prerequisites have emerged for developing targeted biotherapy approaches based on modulating the natural mechanisms of rejection and destruction of malignant cells to treat cancer [3, 4]. This includes various immunotherapeutic strategies that use the host's innate and adaptive antitumor immunity or the creation of recombinant vectors carrying specific features directed explicitly against tumor cells [5]. Amongst all methods, live oncolytic viruses for cancer therapy have recently gained enormous attention [6].

Oncolytic viruses can predominantly replicate in tumor cells causing their death. In addition to the direct cytolytic effect, viruses can significantly enhance antitumor immunity. They attract immune system components to recognize and destroy cancer cells [7, 8]. Several clinical trials have demonstrated the high efficiency of these methods, especially when applied to metastatic cancer. Unlike chemotherapy, such virotherapy has minimal adverse side effects [9, 10].

Vaccinia Virus (VV) has been shown to hold promising oncolytic properties. Since the 1980s, VV strains have been used as vectors for active immunization of cancer and infectious disease [11]. Several advantages make VV a promising agent for oncolytic therapy. First, VV was used as a live vaccine in the World Health Organization (WHO) smallpox eradication program in which over 200 million people were vaccinated, this makes VV an exceptionally safe oncolytic agent and gene vector [12], even in case of emergency related to VV infection vaccinia immunoglobulins,

and antiviral medications are widely available [13]. Second, VV has a large genome of approximately 190 kb making it suitable for genetic manipulation. It enables large amounts of foreign DNA to be inserted into its genome without severely reducing the virus replication efficiency [14]. Third, replication of the virus within the cytoplasm minimizes the chance of integration of viral DNA into the host's genome, and its DNA-based genome makes it more stable than RNA viruses [15]. Finally, VV naturally has a tropism to infect tumor cells while it can evade the host's antiviral immune responses [7]. Numerous genetic engineering approaches have been employed to develop VV recombinant strains with enhanced oncolytic activities; for instance, recombinant VV with the deletion of the thymidine kinase (TK) gene, that is involved in the viral genome synthesis, improves tumor selectivity of the VV by limiting replication to nucleotide rich fast-proliferating cancerous tissues [16], or expression of immune-modulatory molecules such as cytokines or chemokines by VV drastically fortifies its oncolytic properties [17].

Interleukin (IL)-15 is a pleiotropic cytokine that plays an essential role in the development, activation, and survival of T, natural killer (NK), and NK-T cells [18]. IL-15 receptor subunit alpha (IL-15Ra) is one of the primary receptors required to mediate the IL-15 signaling pathway. It can bind to IL-15 independently from other subunits with high affinity forming an IL-15/IL-15Ra complex on the surface of the activated monocytes. This complex promotes the survival of T cells [19]. IL-15 and IL-15Ra are actively being tested in Phase I and II clinical trials with evidence of immune modulation in cancer patients [20-22].

Another interesting immunostimulatory molecule is bacterial flagellin. Flagellin is a ligand for the toll-like receptor- 5 (TLR-5). TLR-5 activation has been shown to effectively increases necrosis and causes tumor regression [23, 24]. In addition, bacterial flagellins strongly stimulate the innate immune response in mammalian cells. Exposure to flagellin promotes virus attachment to epithelial cells, increasing virus entry via TLR5-dependent activation of NF-kB (Nuclear factor kappa-light-chain) [25].

The current study used the vaccinia virus Lister strain from the Institute of Virus Preparations, Moscow, Russia (LIVP) to develop genetically engineered strains. This strain is an attenuated variant that has not been extensively studied yet, but there have been reports that it holds promising oncolytic properties [26-28]. First, we compared the oncolytic activity of this strain with the modified vaccinia Ankara (MVA) strain, a well-established oncolytic strain. Results indicated excellent oncolytic activity of LIVP with fewer inflammatory reactions. Then, to enhance the oncolytic property of LIVP recombinant strains which express interleukin-15 or interleukin-15 receptor subunit alpha or bacterial flagellin subunit B were developed. Also, all developed strains have TK gene deletion to enhance tumor selectivity. Afterward, we assessed these strain's oncolytic potential in vitro and in vivo in different tumor cell line models, including 4T1breast carcinoma, B16 melanoma, and CT26 colon carcinoma. Moreover, for in vivo imaging, we constructed LIVP expressing firefly luciferase to detect the biodistribution of the virus after administration to the tumor-bearing mice models. After treatment, analysis of tumor-infiltrated lymphocytes and cytokines were conducted. Our results revealed that simultaneous injection of viruses expressing IL-15 with the strain expresses IL-15-receptor alpha can form IL15/IL15Ra complex, which is the bioactive form of IL-15, and has a promising anti-tumor potential in 4T1 breast cancer models leading to regression of tumors up to 80%. Analysis indicated tumor regression in this group is associated with enhanced level of CD8+cells at the tumor. LIVP strain expressing bacterial flagellin has shown excellent anti-tumor activity in B16 melanoma models with tumor regression rate of 50%, and treatment enhanced recruitment of the macrophages at the tumor. Besides, in both groups significant elevation of the cytokines TNF-a and GM-CSF were detected at tumor microenvironment. Moreover, by in vivo imaging it has been revealed that recombinant viruses have favorable onco-selectivity and biodistribution in the tumor foci.

PURPOSE OF THE WORK AND TASKS

The primary goal of this study was to develop recombinant strains of VV expressing immunomodulatory agents for the treatment of various malignant neoplasm, and evaluate the safety and impact of viral therapy on the immune system. According to the goal of the study, we set the following objectives:

- Compare the efficacy of two VV strains, LIVP and MVA deficient in TK gene expression in vitro and in vivo.

- Developing LIVP strain expressing murine IL-15 and IL-15Ra and evaluating their oncolytic properties in combination with each other or alone in 4T1breast carcinoma, B16 melanoma, and CT26 colon carcinoma in vitro and in vivo.

- Developing LIVP strain expressing B subunit of flagellin from Vibrio vulnificus (FlaB) and evaluating its oncolytic properties in 4T1breast carcinoma, B16 melanoma, and CT26 colon carcinoma in vitro and in vivo.

- Investigation of the immune response modulation by the recombinant variants via analyzing the level of thirteen different cytokines in tumor-infiltrated fluids and sera of the treated mice, and by examination of the tumor-infiltrated lymphocytes.

- Developing LIVP strain expressing firefly luciferase (Fluc) for in vivo bioluminescence imaging.

SCIENTIFIC NOVELTY

All the results presented in this Thesis are original. In this study, we offer facile and versatile approaches for cancer treatment based on the LIVP strain of VV for the first time. We demonstrated this strain has the potential for further genetic modifications. We showed a simultaneous injection of two recombinant variants, one expressing IL-15 and another expressing IL-15Ra can form the bioactive complex of IL15/IL15Ra to treat a highly invasive breast cancer model. Moreover, another strain encoding

bacterial flagellin is an excellent variant for the melanoma treatment.

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PRACTICAL SIGNIFICANCE

Vaccinia virus Lister strain from the Institute of Virus Preparations, Moscow, Russia (LIVP) expressing bacterial flagellin, causes significant tumor regression, up to 50%, in B16 melanoma syngeneic mice models. In addition, the same strain (LIVP) expressing interleukin-15 in combination with the strain expressing interleukin-15 receptor alpha resulted in significant tumor regression, up to 80%, in 4T1 breast cancer mice models. In both cases survival rate of treated mice significantly prolonged.

STRUCTURE AND SCOPE OF THE DISSERTATION

The Thesis includes the following parts: Abstract, Literature Review, Materials and Methods, Results, Discussion, Conclusion, Outlook, and References. The Thesis has three independent sets of experiments, and the results are shown in three sections. The work includes 126 pages and 35 figures. The references include 192 publications.

AUTHOR'S CONTRIBUTION

The results presented in this Thesis were obtained by the applicant from 4 years-long

scientific work as a Ph.D. student of Moscow Institute of Physics & Technology in

collaboration with the Engelhardt Institute of Molecular Biology, Russian Academy

of Science (EIMB, RAS). The applicant worked in a scientific group supervised by

Dr. Anastasia Lipatova and Prof. Peter Chumakov. Laboratory experiments, data

analysis, preparation of manuscripts, and conference posters were done by the

applicant or with active cooperation with the applicant. In vivo imaging was

conducted at the Department of Neurobiology, V. Serbsky Federal Medical Research

Centre of Psychiatry and Narcology of the Ministry of Health of the Russian

Federation, with assistance of Dr. Victor Naumenko. Histological analysis was

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conducted at the Federal Research and Clinical Center for Specialized Types of Medical Care and Medical Technologies FMBA of Russia with assistance of Dr. Vladimir Baklaushev. Sequencing was carried out at the Genome Center, EIMB RAN.

APPROBATION OF THE WORK

The main provisions of the Thesis were reported at the Interlaboratory Colloquium of the Institute of Molecular Biology named after Engelhardt RAS (2023) and at the following conference:

- Y. Shakiba, "Simultaneous injection of recombinant vaccinia virus expressing interleukin-15 with interleukin-15 receptor alpha has synergistic effects on solid tumors", LOMONOSOV international conference, April 2022. (Selected as the best poster presentation in a Virology section).

- Y. Shakiba, "Monitoring of the oncolytic recombinant vaccinia virus infection in different tumor cell lines in vitro and in vivo," LOMONOSOV international conference, April 2021.

- Y. Shakiba. "Recombinant oncolytic Vaccinia Virus strains for treatment of malignant neoplasms" FEBS CONGRESS, July 2021.

PUBLICATIONS

1. Y Shakiba, P. Vorobyev, V Naumenko, D Kochetkov, K Zajtseva, M Valikhov, G. Yusubalieva, Y Gumennaya, E Emelyanov, A Semkina, V Baklaushev, P Chumakov, A Lipatova. Oncolytic Efficacy of a Recombinant Vaccinia Virus Strain Expressing Bacterial Flagellin in Solid Tumor Models. Viruses, 2023, 15(4), 828. DOI: 10.3390/v15040828.

2. Y Shakiba, M Volskaya, O Tikhonova, P Vorobyov, A Lipatova. Oncolytic Vaccinia Virus Strains for The Immunotherapy of Malignant Diseases. OHKorHHeKonoraa, 2020, T. 3. C. 4. DOI: 10.52313/22278710_2020_2_4.

3. Y. Shakiba, E Naberezhnaya, D Kochetkov, G Yusubalieva, V Baklaushev, P

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Chumakov, A Lipatova A comparative study of oncolytic efficacy of thymidine kinase deficient LIVP-RFP and MVA-RFP strains of vaccinia virus in solid tumors. Bulletin of Russian State Medical University. 2023 (2). DOI: 10.24075/brsmu.2023.010.

4. A Nikitina, A Lipatova, A Goncharov, P Vorobyev, O Alekseeva, M Mahmoud, Y Shakiba, K Anufrieva, G Arapidi, M Ivanov, I Tarasova, M Gorshkov, P Chumakov, S Moshkovskii. Multiomic Profiling Identified EGF Receptor Signaling as a Potential Inhibitor of Type I Interferon Response in Models of Oncolytic Therapy by Vesicular Stomatitis Virus. International journal of molecular sciences. - 2022. - T. 23. - №. 9. - C. 5244. DOI: 10.3390/ijms23095244

In press:

5. Y. Shakiba, P Vorobyev, D Kochetkov, K Zajtseva, M Valikhov, G Yusubalieva, V Kalsin, F Zabozlaev, A Semkina, A Troitskiy, P Chumakov, V Baklaushev, A Lipatova.Oncolytic therapy with recombinant vaccinia viruses targeting the interleukin-15 pathway elicits a synergistic response. Molecular therapy (Oncolytics) - (Accepted, May 2023). DOI: 10.1016/j.omto.2023.05.002.

6. Y. Shakiba, P.Vorobyev, M. Mahmoud, A. Hamad , D.Kochetkov, G. Yusubalieva, V.Baklaushev, P Chumakov, A.Lipatova. Recombinant strains of oncolytic vaccinia virus for cancer immunotherapy. Biochemistry (Moscow) -(Accepted, April 2023).

PATENT

- A program for searching the specific repertoire of codon usage in stem tumor cells of various tissue origins. Patent number: 2020612286. Andrei Zheltukhin, Azzam Hammad, Yasmin Shakiba. 2020.

Заключение диссертации по теме «Другие cпециальности», Шакиба Йасмин

Conclusion

This work aimed to evaluate the oncolytic activity of new promising recombinant oncolytic strains of the vaccinia virus. Our study represents simple approaches to exploiting immune-suppressive tumors and converting them into opportunities for targeted immunotherapy, and give insight to the more selective choice of oncolytic virus strain for specific tumor treatment. Our results support that the vaccinia virus LIVP strain is a prospective oncolytic agent. Arming it with immunomodulatory agents mediates its oncolytic efficacy via direct cytolysis and activation of the immune response at the TME. Administration of LIVP recombinant strains expressing IL-15 and IL-15Ra together elicits significant tumor regression in 4T1 models and LIVP strain expressing bacterial flagellin optimized treatment of B16 melanoma models by enhancing tumor infiltrated lymphocytes while inflammatory responses were minimized. These recombinant variants create optimistic platforms for further investigation of immune-virotherapy. We presume that immunization by these recombinant variants jointly with other anti-cancer medications would improve treatment outcomes.

Findings and outlook

- LIVP strain of the VV is a safe vector for developing the genetically modified oncolytic virus. Treatment of murine CT26, B16, and 4T1 tumor models with LIVP showed a better response than MVA associated with a longer survival rate. In addition, in 4T1, tumor regression was significantly higher than MVA.

- Combination of the recombinant LIVP strain expressing IL-15 with another variant expressing IL-15Ra results in significant tumor regression in the 4T1 breast adenocarcinoma syngeneic mice by promoting the formation of IL-1,5/IL-15Ra complex which is the stable bioactive form of IL-15 and enhance filtration of CD8+ T cells and the increased level of TNF-a, GM-CSF, and CXCL9-10.

- Treatment by the LIVP recombinant variant expressing bacterial flagellin results in significant tumor regression in B16 melanoma syngeneic mice by activating the macrophages and increasing the level of local TNF-a and GM-CSF.

- In vivo imaging showed favorable biodistribution and persistent virus replication in the host. Six hours post-infection, the virus was only detectable in the tumor up to 168 hours.

Ethics

The in vivo experiments were reviewed and approved by the local Ethical Committee of the Engelhardt Institute of Molecular Biology, Moscow, Russia. Experiments were conducted per directive 2010/63/EU on protecting animals used for scientific purposes by the European Parliament and the Council of European Union dated September 22, 2010. Mice were housed under standard conditions with controlled temperature and air ventilation and were given access to water and diet. All efforts were made to minimize the pain and reduce the number of mice in the experiments.

Список литературы диссертационного исследования кандидат наук Шакиба Йасмин, 2023 год

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