Development of vectors based on herpesvirus and poliovirus for oncolytic biotherapy/Разработка векторов на основе герпесвируса и полиовируса для онколитической биотерапии тема диссертации и автореферата по ВАК РФ 00.00.00, кандидат наук Хамад Аззам Нассерович

• Хамад Аззам Нассерович
• кандидат наук
• 2023

Оглавление диссертации кандидат наук Хамад Аззам Нассерович

Table of Contents

Relevance of the research

Primary goals and objectives of the study

Scientific novelty

Theoretical and practical significance

Author's contribution

Statements to be defended

Structure and scope of the dissertation

Approbation of the results' work

Publications

Chapter 1. Literature review

1.1 Introduction

1.2 Oncolytic viruses in glioblastoma

1.3 Current Standard care for gliomas

1.4 Oncolytic Virotherapy for glioblastoma

1.5 DNA viruses

1.6 RNA Viruses

1.7 Immunotherapy approaches

1.8 Novel Potential Oncolytic viruses

1.9 Combined therapies

1.10 Novel approaches in glioblastoma

1.10.1 Nanoparticles in glioblastoma

1.10.2 Multiomics in glioblastoma

1.10.3 3D Organoid models in glioblastoma

1.11 Epidermal growth factor receptor (EGFR) targeting with oncolytic viruses

1.12 General information about herpesvirus Saimiri

1.12.1 Genomic structure and replication

1.12.2 General functions of HVS genes

1.12.3 Transforming functions of HVS

1.12.4 Human T cells transformation

1.13 Future perspectives and conclusion

Chapter 2. Materials and Methods

2.1 Materials and reagents used in the work

2.2 Virus strains

2.3 Cell Culture

2.4 Plasmid construction

2.5 Plasmid propagation in Escherichia Coli

2.6 DNA restriction

2.7 DNA extraction

2.8 DNA ligation

2.9 PCR

2.10 Gel electrophoresis

2.11 Transfection

2.12 Recombination

2.13 Virus propagation

2.14 Virus titration

2.15 Viral Cytotoxicity and Sensitivity of tumor cell lines to viral strains

2.16 Establishment of tumor xenografts in immunodeficient mice

2.17 Viral injection into the mice

2.18 Caliper volumetric measurements of subcutaneous xenografts

2.19 Cryopreservation of tumor cell cultures

2.20 Production of anti-PV3 sheep antiserum and virus neutralization micro tests

2.21 Treatment of cell cultures with interferon and gefitinib

2.22 VSV cytotoxicity

2.23 Western Blotting

2.24 PBMC isolation

2.25 Virus reproduction in the suspension of T cells and PBMCs in vitro

2.26 Statistical analysis

Chapter 3. Results

3.1 Development of two recombinant strains (RVP3 and Russo) of type 3 poliovirus vaccine strain Sabin with altered cellular tropism

3.1.1 RVP3 propagation in cell cultures

3.1.2 RVP3 retains the serotype of poliovirus type

3.1.3 Sensitivity of different cell lines to the recombinant RVP3

3.1.4 Replication efficiency of the recombinant RVP3 in different cell lines

3.1.5 Sensitivity of different cell lines to the recombinant strain Russo

3.1.6 Replication efficiency of the recombinant Russo in different cell lines

3.1.7 Sensitivity of different cell lines to oncolytic viruses

3.1.8 Replication efficiency of several viruses in different cell lines

3.2 In vitro relevance assessment of recombinant Russo and PV3

3.2.1 Sensitivity and replication efficiency of recombinant RVP3 and Russo in conditionally-hypoxic conditions

3.2.2 Evaluation of Replication efficiency of Russo on HeLa cell line cultured in human plasma-like medium (HPLM)

3.3 In vivo experiment of Russo in glioblastoma xenograft model

3.4 Combination therapy of epidermal growth factor receptor inhibitor (gefitinib) with oncolytic viruses

3.4.1 Type I Interferon Treatment Protects the DBTRG-05MG Cell Line but Not HOS Cell Line from VSV Infection

3.4.2 Levels of HER2 Protein Are Higher in Cell Lines with Attenuated Type I Interferon Response to VSV Infection

3.4.3 Combination effect of anti-EGFR therapy on the sensitivity to VSV

3.4.4 Gefitinib enhances the effect of oncolytic polioviruses in HER2-positive cells

3.5 Developing a cell-carrier delivery method of immortalized T cells by herpesvirus Saimiri

3.5.1 Immortalization of T cells using herpesvirus Saimiri (HVS)

3.5.2 Characterization of HVS-immortalized T cells

3.5.3 Virus replication in HVS-immortalized T cells and PBMCs

3.5.4 Developing a recombinant HVS variant expressing OFP

Chapter 4 Discussion

Conclusion

Main results and the outlook

List of Abbreviations

Acknowledgment References

101

Введение диссертации (часть автореферата) на тему «Development of vectors based on herpesvirus and poliovirus for oncolytic biotherapy/Разработка векторов на основе герпесвируса и полиовируса для онколитической биотерапии»

Relevance of the research

The advancements in understanding tumor immunology led to several discoveries in immunotherapy rather than traditional therapies such as chemotherapy and radiotherapy. Oncolytic viruses represent a novel type of cancer therapy using natural or recombinant variants that can selectively kill cancer cells without harming normal cells.

The history of using viruses in clinical use goes back to the nineteenth century when studying natural infections [1]. Traditional approaches to treating cancer include surgery, chemotherapy, radiotherapy, targeted therapy, and other new immunotherapies. All these approaches seek to eliminate malignant cancerous cells and boost the immunological response of the organism toward destroying the cancer cells and prolonging the overall survival of the patients [2].

Introducing a novel treatment based on the oncolytic viruses (OVs) is a recent addition to these approaches that give rise to combating cancer cells. Oncolytic viruses are naturally occurring viruses that lead to cancer cell oncolysis by two main mechanisms: preferentially targeting cancer cells and initiating an immune response against malignant cells [3].

The discovery of OVs paved the way for the development of recombinant oncolytic viruses, which are genetically modified to enhance their effectiveness against cancer cells. Talimogene laherparepvec (T-VEC) - a herpes simplex virus (HSV) type 1 (HSV-1), is the first FDA-approved OV for melanoma treatment [4]. T-VEC is derived from a natural HSV strain, modified by adding granulocyte-macrophage colony-stimulating factor (GM-CSF) to its genomic structure to enhance the antitumor immune response [4].

Developing new recombinant oncolytic viruses represents an immense potential for this treatment to improve tropism towards cancer cells by strengthening the immune mechanisms and arming OVs with antitumor immune modulators and therapeutics.

Targeting is achieved by using viruses with natural tropisms for specific types of cells and improving this tropism by targeting special receptors on cancer cells, where viral entry is carried out, and by introducing immunological modulators into their genomes [5]. Targeting special extracellular receptors like integrins, ICAMs, laminin receptors, CD155,

and others, that are naturally expressed on some tumor cells allows for better effectiveness [6]. CD155 is an overexpressed cell surface marker in cancer cells that protects from innate immunity by limiting Natural killer (NKs) response [7]. Also, OVs utilize some of the cancer cells' receptors, such as laminin receptors, to achieve metastasis potentials and invasions to other cells [8].

Recombinant OVs also use some cancer mechanism pathways to improve their tropism toward cancers. One of these mechanisms is manipulating the viral genome to be under the control of modified promoters that allow for permanent viral replication in the infected cells [9]. Another mechanism is using upregulated transcription factors in the cancer cells, like in a hypoxic environment, which is abundant for cancer cells [10]. Using suicide genes under the control of promoters that have increased activity in cancer cells is a strategy for engineered OVs to enrich the tissue-specific permissiveness [11]. Other mechanisms use cancer cells' same pathways to elevate cell proliferation and disrupt the immune response. That gives OVs an advantage from the disabled antiviral response, preferentially infecting the cancer cells [12].

The bi-lateral mechanism of OVs led to the use of combinations of OVs, immunotherapy, chemotherapy, and radiotherapy to target immune-mediated and nonimmune pathways to increase the tumor antigen presentation and, as a result, simultaneously strengthen the immune response against cancer cells [13].

Neutralizing antibodies remains one of the main obstacles in implementing OVs, as many humans are exposed to such viruses during their lifetime [14]. That leads to the importance of the development of new recombinant viruses that will be less immunogenic based on less commonly occurring natural OVs. Using several natural serotypes of OVs gives an advantage to them not being neutralized by the immune system [15]. Another way is using polymer coatings to the OVs or, most recently, delivering OVs in carrier cells like dendritic cells [16].

Developing new recombinant oncolytic viruses based on polioviruses represents a promising mechanism for several cancer types, especially glioblastoma, for several reasons: poliovirus receptor nectin-like molecule 5 (Necl-5, also called CD155) is broadly upregulated in glioblastoma, the release of antigens and pro-inflammatory signaling,

immunogenic response, well-studied biology, ability to infect a wide range of model and primary cell cultures in vitro. Recently, a recombinant Poliovirus-Rhinovirus Chimera (PVSRIPO) showed promise in developing glioblastoma in clinical trials [17]. All that led us to create two new recombinant polioviruses based on poliovirus type 3 vaccine strain Sabin, named Russo and RVP3, to increase the effectiveness and lessen the harmful effects and tropism towards neural cells.

Epidermal growth factor receptor (EGFR) is the most amplified receptor in glioblastoma and is noted in the classical glioma subtype [18]. EGFR gene amplification is detected in 57.4% of primary glioblastoma patients, leading to high levels of EGFR protein, contributing to the progress of tumorigenesis [19]. Epidermal growth factor receptor (EGFR), also HER1/ErbB1, belongs to a more prominent family of ErbB receptors with tyrosine kinase activity. Other HER family members include ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4 [20]. EGFR is frequently overexpressed and hyper-activated in human malignancies, including glioblastoma; therefore, EGFR-directed therapeutic strategies are often utilized. In addition, around 50% of patients with EGFR amplification harbor a specific mutation - EGFRvIII - resulting in an in-frame deletion of exons 2-7 [21]. Due to the frequency of EGFR aberrations, many EGFR-targeted therapies are in development or clinical trials [22]. Although EGFR kinase inhibitor therapy has shown initial success in other cancers, such as non-small cell lung cancer [23], previous trials in glioblastoma have been unsuccessful to date [24].

Epidermal growth factor receptor TKIs gefitinib and erlotinib have been found to significantly increase progression-free survival in non-small cell lung carcinoma (NSCLC) patients, with one meta-analysis reporting 42.9% of patients receiving TKI therapy reaching at least one year of progression-free survival compared to 9.7% with chemotherapy [25]. A study of Gefitinib as palliative therapy for patients with brain metastases from NSCLC found that 45% of patients experienced symptom improvement, with the experimental group maintaining progression-free survival for six months longer than the control group [26].

Safety considerations related to OVs are mainly divided into two aspects. Firstly the common side effects of all-natural viral infections, like fever and fatigue, are simple

compared to their therapeutic effects. Secondly, the transmissibility of the live OVs in the organism is mainly attenuated by extensive passaging and the fact that most humans have neutralizing antibodies. Nevertheless, precautions should always be a matter of issue to remember here.

Alongside, attempts to improve gene therapy approaches by using new and effective gene delivery vectors are crucial to the long-term success of several diseases, including cancer therapy. Herpesvirus saimiri (HVS) is a DNA virus and the prototype of gamma-2 herpesvirus, or rhadinovirus, originally isolated from its natural host, the squirrel monkey [27]. HVS can infect several human cancer cell lines without integrating with their genomes and persist as circular non-integrated episomes that replicate upon cell division. That allows it to infect dividing cell populations and ensures transgene expression stably. A novel new approach to immortalizing human T cells was observed for the first time [28]. HVS C488 can transform human T cells into stable antigen-independent growth in cell culture while retaining many essential T-cell functions, including the MHC complexes and T-cell-receptor specificity [29]. This approach opened a whole new research area that moved the oncogenic HVS to an immunological tool and linked the T-cell function mechanism to the transforming capabilities of HVS. Our work represents for the first time the idea of using these immortalized T-cells by a new recombinant HVS to enhance the effect of other oncolytic viruses in cancer cells by increasing the infiltration of T-cells.

Overall, OVs have an enormous potential to be an effective method against cancer cells by direct oncolysis and triggering the antitumor immune response. With OVs already in practice and clinical trials, with significant results in tumor regression and promising ones for many others, OVs represent an excellent approach to implement it thoroughly in the future.

In this dissertation, we aimed to identify new recombinant viruses based on herpesvirus saimiri and poliovirus to enhance the therapeutic effect of oncolytic virotherapy. We have developed new recombinant enteroviruses based on poliovirus type 3 strain Sabin to target better glioblastoma, one of the most aggressive brain tumors. Next, use EGFR inhibitors such as Gefitinib to increase the therapeutic effect of oncolytic viruses, as EGFR is overexpressed in several cancer cell types. Finally, we studied the possibility

of employing herpesvirus saimiri as an oncolytic virus carrier using its unique characteristic of immortalizing T-cells. All these concepts put forward the novelty of this dissertation work to better understand the molecular mechanism of oncolytic viruses and enhance their therapeutic results.

Primary goals and objectives of the study

The study's primary goal is developing and characterizing vectors based on herpesvirus and poliovirus for oncolytic virotherapy. We set the following objectives according to the goal:

1. Characterization of the new recombinant strains (RVP3 and Russo) in primary human glioblastoma cell cultures.

2. Assessment of the oncolytic properties of Russo strain on a model of subcutaneous xenografts in nude mice.

3. Evaluation of combining EGFR inhibitor (Gefitinib) with oncolytic viruses in different cell models in vitro.

4. Developing a protocol for T-cells immortalization by herpesvirus Saimiri (HVS).

Scientific novelty

1. A new recombinant non-pathogenic strain of human enterovirus Russo and RVP3, created based on a vaccine strain of type 3 poliovirus (Sabin), has been characterized for the first time.

2. The oncolytic properties of the isolated strain have been demonstrated with a wide range of model and primary tumor cell lines and in combination with an EGFR inhibitor (Gefitinib).

3. After infection with the herpesvirus Saimiri, a new cell-carrier delivery method was optimized using immortalized human T cells.

Theoretical and practical significance

Two new non-pathogenic strains (Russo and RVP3) were obtained and characterized. These strains have demonstrated high oncolytic potential in various cultures of primary models of glioblastoma in vitro and in vivo on a model of subcutaneous xenografts in T cells immunodeficient mice. These strains would be further tested in pre-clinical studies to validate them in clinical trials and used as therapeutic agents on cancer patients, especially glioblastoma. Using oncolytic viruses with other combination therapies is an important aspect to be studied. Our study showed that an inhibitor of the epidermal growth factor receptor (Gefitinib) has a controversial effect on oncolytic viruses depending on their types and the expression of HER2 receptors in cancer cells. These results could be used to consider the optimal oncolytic virus in parallel with targeted therapy. New carrier-cell delivery methods are necessary to avoid the neutralizing antibodies of oncolytic viruses. Our study investigated the role of immortalized T cells after infection with herpesvirus saimiris (HVS) to deliver different oncolytic viruses. Those immortalized human T cells preserved the functional markers of T cells.

Author's contribution

The results presented in this thesis were obtained from 4 years-long scientific work as a PhD student of Moscow Institute of Physics and Technology (MIPT) and a junior researcher at the cell proliferation laboratory of Engelhardt Institute of Molecular Biology. The author developed and corrected the complete study. The analysis of special modern domestic and foreign literature in the field of the stated problem was carried out independently. The author participated in all experimental studies in vitro and in vivo. The applicant worked as a part of a scientific group under the supervision of a Ph.D. Anastasia Lipatova and Prof. Peter Chumakov. Data analysis, preparation of manuscripts, and conference posters were done by the applicant or with active cooperation with the applicant. In vivo experiments were conducted at the laboratory of cell proliferation, Engelhardt Institute of Molecular Biology.

Statements to be defended

1. The ability of the recombinant viruses (PV3-Russo and PV3-RVP3) strains to infect and multiply on a panel of conditionally normal and human tumor cells were tested. Significant differences in the virus production, independent of the tissue type of tumor cells, have been established.

2. The replication efficiency of the original strains and the new recombinants was determined.

3. Determination of the effect of targeted anti-EGFR therapy (Gefitinib) on the replication efficiency of oncolytic viruses.

4. A new recombinant herpesvirus saimiri (HVS) was developed as a vector carrier to deliver oncolytic viruses to the tumor by immortalizing the patient's T-cells.

Structure and scope of the dissertation

The dissertation work is presented on 119 pages of typewritten text and includes the following parts: Relevance, Literature Review, Materials and Methods, Results, Discussion, Conclusions and Outlook, and References. The work includes 8 tables and 37 figures. The references include 267 publications.

Approbation of the results' work

Results from this thesis were presented at the following conferences:

1. Poster Presentation in 4th ISFMS—Biochemistry, Molecular Biology and Druggability of Proteins, Florence, Italy, 2022. Title thesis: Epidermal growth factor receptor (EGFR) signaling inhibits type I interferon response in models of oncolytic therapy by vesicular stomatitis virus.

2. Oral Presentation. Annual conference of the Syrian Association of Pathology, Syrian Molecular Pathology Assembly (2nd SMGA), 2022, Damascus, Syria. Title thesis: Development of vectors based on Saimiri herpesvirus and Poliovirus for oncolytic biotherapy.

3. Poster participation in All-Russian conference "synthetic biology and biopharmaceuticals" - Novosibirsk 2022, Title thesis: Assessment of oncolytic polioviruses in different cell models in vitro and in vivo.

4. Poster Presentation. 20th FEBS Young Scientists' Forum ('YSF20') and 45th FEBS 2020 Congress, Slovenia & Croatia, 2021. Title thesis: Herpesvirus-based vectors for oncolytic biotherapy.

5. Poster Presentation. Lomonosov 2021 conference, Moscow, Russia. Title thesis: EGFR inhibition triggers an adaptive response against vesicular stomatitis virus (VSV) by activating antiviral signaling pathways in human osteosarcoma and glioblastoma.

6. Participation in the 64th All-Russian Scientific Conference of MIPT, 2021. Thesis title: Development of new recombinant oncolytic poliovirus for glioblastoma treatment.

7. Poster Presentation. Annual Summit of Young Scientists and Engineers "Big Challenges for Society, State, and Science," Sochi, Russia. 2019. Thesis title: vector based on recombinant primate herpesvirus as a potential tool for cancer immunotherapy.

8. Thesis: 2020 - "Herpesvirus-based vectors for oncolytic biotherapy," XV International (XXIV All-Russian) Pirogov Scientific Medical Conference of Students and Young Scientists

Publications

1. A. Hamad, G.M. Yusubalieva, V.P. Baklaushev, P.M. Chumakov, A.V. Lipatova, Recent developments in oncolytic viruses for glioblastoma: emerging therapies and future perspectives, 2022, Viruses. doi: 10.3390/v15020547.

2. A. Hamad; A.V Soboleva; P.O. Vorobyev; M. Mahmoud; K.V. Vasilenko; P.M. Chumakov; A.V. Lipatova, Development of a recombinant oncolytic poliovirus type 3 strain with altered cell tropism, Bulletin of Russian State Medical University, 2022, doi: 10.24075/brsmu.2022.023.

3. A. Hamad, S. Chumakov, Obtaining a recombinant strain of Herpesvirus saimiri by co-cultivation of transfected and permissive cell culture, 2019 es, Bulletin of Russian State Medical University, doi: 10.24075/brsmu.2019.079.

4. A. S. Nikitina, A. V. Lipatova, A. O. Goncharov, A. A. Kliuchnikova, M. A. Pyatnitskiy, K. G. Kuznetsova, P. O. Vorobyev, A. Hamad, M. V. Ivanov, I. A. Tarasova, M. V. Gorshkov, P. M. Chumakov, S. A. 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 Science. Int. J. Mol. Sci. 2021. doi: 10.3390/ijms23095244.

5. Y. Shakiba, P.O. Vorobyev, M. Mahmoud, A.Hamad, D.V. Kochetkov A.V. Lipatova, Recombinant strains of oncolytic vaccinia virus for cancer immunotherapy, Biochemistry (Moscow), doi: 10.31857/S0320972523060106.

Patent

O. Zheltykhin, A. Hamad, Y. Shakiba, 2020 - Patent: Number 2020612286 titled "a program for searching for a specific repertoire of codon use in stem tumor cells of various tissue origins

Заключение диссертации по теме «Другие cпециальности», Хамад Аззам Нассерович

Conclusion

The comparative study represents an insight into characterizing more specific tumor-targeted oncolytic viruses for biotherapy, especially for glioblastoma. The present research suggests that polioviruses are a promising platform for further developing viral oncolytic agents with excellent oncolytic potency and reduced side effects of viral off-target replication, especially in highly aggressive glioblastoma. We showed that IRES substitution leads to an altered tropism in the poliovirus type 3 vaccine strain Sabin. Next, recombinant Russo demonstrated a therapeutic effect in glioblastoma xenografts in nude mice. The epidermal growth factor receptor inhibitor (gefitinib), in combination with oncolytic polioviruses, revealed an enhanced effect in HER2-overexpressed cells. In contrast, this effect was not observed in other cells with low expression of HER2. In addition, the combination of gefitinib with vesicular stomatitis virus (VSV) strain Indiana indicated a decreased cytopathic effect in cell lines with overexpression of HER2. Finally, immortalized T cells with herpesvirus Saimiri may be considered a delivery approach for oncolytic viruses. This study represents a step in developing a promising platform for further clinical trials of oncolytic therapy of glioblastoma therapy. All the effects are oriented to transform the immune-deprived microenvironment of glioblastoma into an immune-responsive one by using promising oncolytic viruses with other combinations and enhancing the delivering methods. Future studies in this direction will be followed up and should concentrate on testing these viruses on new panels of cell lines in different tumors and optimizing the in vivo models in order to reach the clinical steps of testing these viruses on patients.

Main results and the outlook

I. Recombinant oncolytic strain Russo and RVP3 effectively lyse tumor cells (p<. 001) in vitro and in vivo. In contrast, the sensitivity of conditionally normal cell lines is reduced (p<.01) compared to the original strain of type 3 poliovirus.

II. The recombinant strain Russo demonstrated oncolytic activity and enhanced survival rate in vivo (p<.001) on a model of subcutaneous xenografts of glioblastoma DBTRG-05MG in Balb/c nude mice.

III. The combination of targeted anti-EGFR therapy (gefitinib) reduces the efficiency of VSV (p < .01) while enhancing (p < .01) poliovirus efficiency in HER2+ cell lines in vitro.

IV. Optimized a protocol for HVS-immortalized T cells as a possible delivery method of OVs with preserving the functional markers of T cells.

Список литературы диссертационного исследования кандидат наук Хамад Аззам Нассерович, 2023 год

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