Overview of the pre-clinical and clinical studies about the use of CAR-T cell therapy of cancer combined with oncolytic viruses

Background Cancer is one of the critical issues of the global health system with a high mortality rate even with the available therapies, so using novel therapeutic approaches to reduce the mortality rate and increase the quality of life is sensed more than ever. Main body CAR-T cell therapy and oncolytic viruses are innovative cancer therapeutic approaches with fewer complications than common treatments such as chemotherapy and radiotherapy and significantly improve the quality of life. Oncolytic viruses can selectively proliferate in the cancer cells and destroy them. The specificity of oncolytic viruses potentially maintains the normal cells and tissues intact. T-cells are genetically manipulated and armed against the specific antigens of the tumor cells in CAR-T cell therapy. Eventually, they are returned to the body and act against the tumor cells. Nowadays, virology and oncology researchers intend to improve the efficacy of immunotherapy by utilizing CAR-T cells in combination with oncolytic viruses. Conclusion Using CAR-T cells along with oncolytic viruses can enhance the efficacy of CAR-T cell therapy in destroying the solid tumors, increasing the permeability of the tumor cells for T-cells, reducing the disturbing effects of the immune system, and increasing the success chance in the treatment of this hazardous disease. In recent years, significant progress has been achieved in using oncolytic viruses alone and in combination with other therapeutic approaches such as CAR-T cell therapy in pre-clinical and clinical investigations. This principle necessitates a deeper consideration of these treatment strategies. This review intends to curtly investigate each of these therapeutic methods, lonely and in combination form. We will also point to the pre-clinical and clinical studies about the use of CAR-T cell therapy combined with oncolytic viruses.

Systemic Delivery of mLIGHT-Armed Myxoma Virus Is Therapeutic for Later-Stage Syngeneic Murine Lung Metastatic Osteosarcoma

Cancers that metastasize to the lungs represent a major challenge in both basic and clinical cancer research. Oncolytic viruses are newly emerging options but successful delivery and choice of appropriate therapeutic armings are two critical issues. Using an immunocompetent murine K7M2-luc lung metastases model, the efficacy of MYXV armed with murine LIGHT (TNFSF14/CD258) expressed under virus-specific early/late promoter was tested in an advanced later-stage disease K7M2-luc model. Results in this model show that mLIGHT-armed MYXV, delivered systemically using ex vivo pre-loaded PBMCs as carrier cells, reduced tumor burden and increased median survival time. In vitro, when comparing direct infection of K7M2-luc cancer cells with free MYXV vs. PBMC-loaded virus, vMyx-mLIGHT/PBMCs also demonstrated greater cytotoxic capacity against the K7M2 cancer cell targets. In vivo, systemically delivered vMyx-mLIGHT/PBMCs increased viral reporter transgene expression levels both in the periphery and in lung tumors compared to unarmed MYXV, in a tumor- and transgene-dependent fashion. We conclude that vMyx-mLIGHT, especially when delivered using PBMC carrier cells, represents a new potential therapeutic strategy for solid cancers that metastasize to the lung.

Immunotherapy for Colorectal Cancer: Mechanisms and Predictive Biomarkers

Though early-stage colorectal cancer has a high 5-year survival rate of 65-92% depending on the specific stage, this probability drops to 13% after the cancer metastasizes. Frontline treatments for colorectal cancer such as chemotherapy and radiation often produce dose-limiting toxicities in patients and acquired resistance in cancer cells. Additional targeted treatments are needed to improve patient outcomes and quality of life. Immunotherapy involves treatment with peptides, cells, antibodies, viruses, or small molecules to engage or train the immune system to kill cancer cells. Preclinical and clinical investigations of immunotherapy for treatment of colorectal cancer including immune checkpoint blockade, adoptive cell therapy, monoclonal antibodies, oncolytic viruses, anti-cancer vaccines, and immune system modulators have been promising, but demonstrate limitations for patients with proficient mismatch repair enzymes. In this review, we discuss preclinical and clinical studies investigating immunotherapy for treatment of colorectal cancer and predictive biomarkers for response to these treatments. We also consider open questions including optimal combination treatments to maximize efficacy, minimize toxicity, and prevent acquired resistance and approaches to sensitize mismatch repair proficient patients to immunotherapy.

NEW POTENTIAL TREATMENT FOR BRAIN GLIOMA

According to the latest statistics, brain gliomas are the most common cause of death from CNS tumors. Brain gliomas are also ranked as the second (after stroke) cause of brain surgery The mortality rate from gliomas is high and sometimes reaches 80 %. It is because the tumor grows from undifferentiated cells, which causes its peracute development and malignant transformation. Symptoms of glioma occur at stages 3 and 4, when all treatment is symptomatic, and operations are palliative. In this regard, it is necessary to develop and introduce methods for non-surgical glioma treatment. These methods include the use of antisense oligonucleotides, optogenetics, and oncolytic viruses. The aim of antisense oligonucleotides is to replace a section in a glioma cell genome with a foreign one, which disrupts cell division and leads to apoptosis and necrosis of the entire tumor. Optogenetics excludes the introduction of substances into the body. It provides a certain light signal to glioma cells, which also suppresses the growth of an undifferentiated tumor. Oncolytic viruses are genetically modified viruses that identify tumor cells, penetrate into them and start a cascade of apoptotic reactions Despite all success, such methods are still studied at the laboratory level, their implementation in practical medicine is slow and cautious. However, insufficient knowledge retards the widespread use of potentially promising and effective drugs. Scientists around the world are developing methods to treat brain gliomas at different stages of their development. This article reflects modern achievements of scientists and neurosurgeons, describing new methods for brain glioma treatment. Key words: brain glioma, optogenetics, antisense oligonucleotides, oncolytic viruses, p53 gene. Согласно последним данным статистики, глиомы мозга являются наиболее частой причиной смертей от онкологии центральной нервной системы, а также занимают второе место по частоте как причина хирургических вмешательств на головной мозг, уступая инсультам. Смертность от глиом высока и порой достигает 80 %. Причина этого заключается в том, что опухоль растет из недифференцированных клеток, что обусловливает её молниеносный рост и быстрое озлокачествление. Симптомы глиомы возникают на 3–4 стадии развития, когда все лечение направлено на ликвидацию симптомов, а операции носят паллиативный характер. В связи с этим необходима разработка и внедрение методов по нехирургическому лечению глиом. Такими методами являются использование антисмысловых олигонуклеотидов, оптогенетика, применение онколитических вирусов. Суть использования антисмысловых олигонуклеотидов заключается в замене участка генома клетки глиомы на инородный, попавший извне, что нарушает деление клеток и приводит к апоптозу и некрозу всей опухоли. Оптогенетика исключает введение веществ в организм и заключается в подаче определенного светового сигнала на глиозные клетки, что также тормозит рост недифференцированной опухоли. Онколитические вирусы – это генномодифицированные вирусы, которые определяют опухолевые клетки, проникают в них и запускают каскад апоптотических реакций. Несмотря на все успехи, данные методы продолжают изучаться на уровне лабораторий, их внедрение в практическую медицину происходит медленно и со страхом. Однако недостаточная изученность тормозит широкое применение потенциально перспективных и эффективных лекарств. Учеными мира разрабатываются методы, позволяющие лечить глиомы мозга на разных стадиях их развития. Данная статья отображает современные достижения ученых и нейрохирургов в поисках возможности применения такого рода методов. Ключевые слова: глиома мозга, оптогенетика, антисмысловые олигонуклеотиды, онколитические вирусы, ген р53.

Clinical Trials of Oncolytic Viruses in Breast Cancer

Breast cancer is the second most common kind of cancer worldwide and oncolytic viruses may offer a new treatment approach. There are three different types of oncolytic viruses used in clinical trials; (i) oncolytic viruses with natural anti-neoplastic properties; (ii) oncolytic viruses designed for tumor-selective replication; (iii) oncolytic viruses modified to activate the immune system. Currently, fourteen different oncolytic viruses have been investigated in eighteen published clinical trials. These trials demonstrate that oncolytic viruses are well tolerated and safe for use in patients and display clinical activity. However, these trials mainly studied a small number of patients with different advanced tumors including some with breast cancer. Future trials should focus on breast cancer and investigate optimal routes of administration, occurrence of neutralizing antibodies, viral gene expression, combinations with other antineoplastic therapies, and identify subtypes that are particularly suitable for oncolytic virotherapy.

Oncolytic Viruses and Cancer, Do You Know the Main Mechanism?

The global rate of cancer has increased in recent years, and cancer is still a threat to human health. Recent developments in cancer treatment have yielded the understanding that viruses have a high potential in cancer treatment. Using oncolytic viruses (OVs) is a promising approach in the treatment of malignant tumors. OVs can achieve their targeted treatment effects through selective cell death and induction of specific antitumor immunity. Targeting tumors and the mechanism for killing cancer cells are among the critical roles of OVs. Therefore, evaluating OVs and understanding their precise mechanisms of action can be beneficial in cancer therapy. This review study aimed to evaluate OVs and the mechanisms of their effects on cancer cells.

Giving Oncolytic Viruses a Free Ride: Carrier Cells for Oncolytic Virotherapy

Oncolytic viruses (OVs) are an emerging class of therapeutics which combine multiple mechanisms of action, including direct cancer cell-killing, immunotherapy and gene therapy. A growing number of clinical trials have indicated that OVs have an excellent safety profile and provide some degree of efficacy, but to date only a single OV drug, HSV-1 talimogene laherparepvec (T-Vec), has achieved marketing approval in the US and Europe. An important issue to consider in order to accelerate the clinical advancement of OV agents is the development of an effective delivery system. Currently, the most commonly employed OV delivery route is intratumoral; however, to target metastatic diseases and tumors that cannot be directly accessed, it is of great interest to develop effective approaches for the systemic delivery of OVs, such as the use of carrier cells. In general, the ideal carrier cell should have a tropism towards the tumor microenvironment (TME), and it must be susceptible to OV infection but remain viable long enough to allow migration and finally release of the OV within the tumor bed. Mesenchymal stem cells (MSCs) have been heavily investigated as carrier cells due to their inherent tumor tropism, in spite of some disadvantages in biodistribution. This review focuses on the other promising candidate carrier cells under development and discusses their interaction with specific OVs and future research lines.

Generation of a Retargeted Oncolytic Herpes Virus Encoding Adenosine Deaminase for Tumor Adenosine Clearance

Background: Oncolytic viruses are immunotherapeutic agents that can be engineered to encode payloads of interest within the tumor microenvironment to enhance therapeutic efficacy. Their therapeutic potential could be limited by many avenues for immune evasion exerted by the tumor. One such is mediated by adenosine, which induces pleiotropic immunosuppression by inhibiting antitumor immune populations as well as activating tolerogenic stimuli. Adenosine is produced starting from the highly immunostimulatory ATP, which is progressively hydrolyzed to ADP and adenosine by CD39 and CD73. Cancer cells express high levels of CD39 and CD73 ectoenzymes, thus converting immunostimulatory purinergic signal of ATP into an immunosuppressive signal. For this reason, CD39, CD73 and adenosine receptors are currently investigated in clinical trials as targets for metabolic cancer immunotherapy. This is of particular relevance in the context of oncovirotherapy, as immunogenic cell death induced by oncolytic viruses causes the secretion of a high amount of ATP which is available to be quickly converted into adenosine. Methods: Here, we took advantage of adenosine deaminase enzyme that naturally converts adenosine into the corresponding inosine derivative, devoid of immunoregulatory function. We encoded ADA into an oncolytic targeted herpes virus redirected to human HER2. An engineered ADA with an ectopic signal peptide was also generated to improve enzyme secretion (ADA-SP). Results: Insertion of the expression cassette was not detrimental for viral yield and cancer cell cytotoxicity. The THV_ADA and THV_ADA-SP successfully mediated the secretion of functional ADA enzyme. In in vitro model of human monocytes THP1, this ability of THV_ADA and THV_ADA-SP resulted in the retrieval of eADO-exposed monocytes replication rate, suggesting the proficiency of the viruses in rescuing the immune function. Conclusions: Encoding ADA into oncolytic viruses revealed promising properties for preclinical exploitation.

The Metabolic Relationship Between Viral Infection and Cancer

Viruses are fundamental tools in cancer research. They were used to discover the first oncogenes in the 1970s, and they are now being modified for use as antitumor therapeutics. Key to both of these oncogenic and oncolytic properties is the ability of viruses to rewire host cell metabolism. In this review, we describe how viral oncogenes alter metabolism to increase the synthesis of macromolecules necessary for both viral replication and tumor growth. We then describe how understanding the specific metabolic requirements of virus-infected cells can help guide strategies to improve the efficacy of oncolytic viruses, and highlight immunometabolism and tumor microenvironment research that could also increase the therapeutic benefits of oncolytic viruses. We also describe how studies describing the therapeutic effects of dietary nutrient restriction in cancer can suggest new avenues for research into antiviral therapeutics. Expected final online publication date for the Annual Review of Cancer Biology, Volume 6 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.