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Oncolytic virus combined with FDA-approved drugs to treat tumors
Oncolytic virus combined with FDA-approved drugs to treat tumors. Tumor immunotherapy has now become the backbone of the anti-tumor drug market.
Oncolytic viruses (OVs) are an important branch of tumor immunotherapy. The approval of T-vec in 2015 marked the maturity of oncolytic virus therapy.
Oncolytic virus refers to a type of virus that can specifically attack and destroy cancer cells after being genetically modified, while causing less damage to normal cells.
Recently, a breakthrough has been made in clinical trials of oncolytic virus combination drugs. Wei Zhang and others in the Department of Neurosurgery, University of Minnesota School of Medicine published an article in Expert Opinion on Biological Therapy.
The article reviewed preclinical and clinical data and proved that OV-based combination therapy is compatible with The principle and potential efficacy of anti-cancer drugs approved by the FDA.
Experts believe that although the cytolytic activity of OV is still a key driver of its anti-tumor effect, understanding the interaction between the virus and the host may provide an opportunity for potential synergy with FDA-approved treatments for these interactions.
The most interesting thing is that the immunostimulatory effect of OVs makes the combination with FDA-approved immunotherapy more effective. Although there are more and more clinical trials using this combination therapy, there is a need to improve the understanding of virus-host interactions in order to make more meaningful progress.
Oncolytic viruses (OVs) are designed to replicate selectively in cancer cells. Although it was originally thought to exert its anti-cancer effect through direct cell lysis, it is increasingly recognized that OVs interact with a variety of cellular processes during their life cycle; FDA-approved drugs that regulate these cellular processes have been shown to enhance the effectiveness of OVs. Anti-tumor effect.
In addition, due to the release of tumor antigens and the inherent immune stimulation of the virus, OVs can induce an effective immune response and enhance the anti-tumor effect of FDA-approved immunotherapy. In this context, the interest of OV as a combined anti-cancer treatment platform is increasing day by day.
• Oncolytic virus (OV) interacts with multiple cellular pathways during its life cycle, including DNA repair and mitosis.
• FDA-approved pharmaceutical preparations targeting the OV regulatory cell pathway enhance or synergize the anti-cancer effect of OV.
• In addition to directly dissolving cancer cells, OV can also induce an effective immune response and enhance the anti-tumor effect of FDA-approved immunotherapy.
• As a platform for rationally designing multi-plan anti-cancer treatments, OVs is gaining clinical interest
The development of the oncolytic virus (OV) is based on observations as early as a century ago, when the cancer subsided naturally after infection with a naturally acquired virus.
Although the initial efforts aimed to use virus-containing body fluids to spread this therapeutic infection, subsequent studies have shown that natural virus chemotaxis has caused great limitations in clinical transformation.
With this understanding, the emergence of genetic engineering has led to the production of many viruses with clear selectivity for different cancers.
Almost all types of viruses, including herpes simplex virus, adenovirus, vaccinia virus, measles virus, parvovirus, polio virus, Malaba virus, reovirus, Coxsackie virus, vesicular stomatitis virus, Newcastle disease Both viruses and picornaviruses are engineered in this context, and different types of tumors have been tested clinically (see Table 1).
This project usually requires mutation of some key genes related to virus replication, which greatly weakens the killing ability of host cells and at the same time gives the virus selectivity to tumors.
Most notably, the first OV approved by the FDA as an anti-cancer treatment in 2015 was oncolytic herpes virus. This approval has aroused interest in OVs as an anti-cancer treatment platform. Although anti-tumor signals were observed in subsequent milestone phase I/II clinical trials, tumor recurrence is almost common.
With the increasing awareness of the inherent intratumoral and inter-tumor heterogeneity of most solid cancers, a hypothesis has been proposed that the optimal therapeutic effect of OV may require a reasonable combination. Emerging data indicate that OVs are combined with a variety of cellular processes during their life cycle, and FDA-approved drugs that regulate these cellular processes can release the true therapeutic potential of OVs.
In view of the remarkable success of immunotherapy in certain cancers, and the observation that OVs can effectively stimulate anti-tumor immune responses, the combination of OVs and FDA-approved immune checkpoint inhibitors has become the center. In this review, we will provide an overview of the current state of knowledge regarding the combination of OVs and various FDA-approved drugs.
2. Combination chemotherapy
Chemotherapy is one of the main cancer treatment methods that use chemicals as intracellular poisons to inhibit DNA synthesis, mitosis and cell division, and cause DNA damage. In the process of virus replication, these cellular pathways will be interfered by the virus.
Temozolomide (TMZ) is an alkylating agent and an effective anticancer drug for the treatment of various solid tumors, including glioma and melanoma.
TMZ shows better anti-tumor effects in killing glioblastoma, lung cancer, melanoma and breast cancer through oncolytic herpes simplex virus, adenovirus, Newcastle disease virus and myxoma virus.
The therapeutic effect of oncolytic adenovirus (OAd) combined with TMZ on lung cancer cells was evaluated in vitro and in vivo. TMZ enhances the viral therapy of OAd Adhz60 by increasing virus replication in lung cancer cells but not other normal cells. These studies show that understanding the interaction between the virus and the host is of great significance for the development of combination therapy with OV and other anti-tumor drugs.
3. Combined targeted therapy
Oncolytic viruses interact with specific genes, proteins or tissue environments of cancer. These genes, proteins or tissue environments contribute to the growth and survival of cancer during the process of infection, replication, and release from cancer cells.
This makes it possible for OVs to work together with targeted therapies, which block tumor growth by interfering with specific molecules required for carcinogenesis and tumor growth.
Sorafenib is a targeted anticancer drug and a tyrosine kinase inhibitor that can inhibit a variety of protein kinases, including VEGFR, PDGFR and RAF kinases. Heo et al. demonstrated the preclinical and clinical efficacy of the sequential combination of oncolytic poxvirus JX-594 and sorafenib in the treatment of hepatocellular carcinoma (HCC). JX-594, also known as Pexa-Vec (pexastimogene devacirepvec), is a virus thymidine kinase (TK) gene deletion, human granulocyte macrophage colony stimulating factor (hGM-CSF) and β-galactosidase transgene Expressed Armed Immunotherapeutic Vaccinia Virus.
In two mouse liver cancer models, the sequential combination therapy of JX-594 and sorafenib can improve the anti-tumor efficacy. They further conducted a preliminary clinical study to explore the safety and effectiveness of JX-594 combined with sorafenib in the treatment of 3 patients with liver cancer.
Studies have shown that sequential treatment is well tolerated and is associated with a significant reduction in tumor perfusion, and the objective tumor response of all patients is also significantly reduced. This is a good example to illustrate that when designing a combination therapy, it is important to consider whether the drug will offset the efficacy of OVs, and to consider sequential combination to minimize the offset.
4. OV combined with hormone therapy
Hormone therapy targets the hormone signaling pathway to inhibit the growth of cancer cells and requires hormones to grow. Early studies have shown that estrogen β-estradiol increases the replication of oncolytic HSV-1nv1066 cancers in estrogen receptor-positive (ER+) human breasts.
Estrogen enhances the oncolytic effect of NV1066, and the killing rates of tumor cells are 95% and 97%, respectively. When MOIs are 0.1 and 0.5, compared with 53% and 87% when there is no estrogen.
This enhanced viral oncolytic effect is related to the increase of cell proliferation and apoptosis by estrogen, which reduces the apoptosis of ER+ breast cancer cells. So far, there have not been too many reports on the combination of OV with approved hormone therapy drugs.
5. OV combined immunotherapy
Immunotherapy is an immunotherapy that activates or suppresses the immune system, represented by immune checkpoint inhibitors, and has been successfully applied to various cancers, including melanoma, lung cancer and bladder cancer.
Since the FDA approved the first checkpoint inhibitor ipilimumab (CTLA-4 antibody) for melanoma in 2011, in 2014 and 2018, the FDA approved three more PD-1s (Nivolumab, Pembrolizumab and Cemiplimab) and three PD-L1 (Atezolizumab, Avelumab and Durvalumab) checkpoint inhibitor.
As a subtype of immunotherapy, OV has been widely combined with checkpoint inhibitors in preclinical and clinical studies. OV infection can stimulate the anti-tumor immune response and transform the “cold” tumor microenvironment that does not respond to checkpoint blockade into a “hot” environment that activates and increases the checkpoint blockade response of immune cells, which enhances the checkpoint Suppressive effect.
An oncolytic vaccinia virus encoding interleukin 7 (IL-7) and IL-12 induces long-term survival benefits in various tumor models such as melanoma, colon cancer, and lung cancer models. Combining the virus with anti-PD-1 or anti-CTLA4 antibodies further improves the anti-tumor activity compared to a single treatment.
In addition, viruses blocked by immune checkpoints alone or in combination show anti-tumor activity in remote non-invasive tumors through changes in immune status.
This phenomenon has also been observed in humanized mice carrying human cancer cells. In many cancer treatments, additional OVs and immune checkpoint inhibitors include oHSV, adenovirus, and measles virus.
6. Clinical trials of combined application of OVs and FDA-approved anti-tumor drugs
Since preclinical studies have proved the effectiveness of combining OVs with other methods, OVs combined therapy has been widely used in the treatment of different types of cancer.
A phase 1b trial investigated the safety and effectiveness of oncolytic reovirus Pelareorep combined with anti-PD1 antibody Pembrolizumab immunotherapy and 5-fluorouracil, gemcitabine, or irinotecan chemotherapy. Among the 10 patients with evaluable efficacy, disease control was observed in 3 patients, one had a partial remission of 17.4 months, and the other two were stable for more than 9 months and 4 months, and the treatment was well tolerated.
Virus replication was observed in the tumor biopsy under treatment. By analyzing the sequencing of T cell receptors in peripheral blood, it was found that new T cell clones appeared during treatment, and changes in immune gene expression in clinically beneficial patients were observed. This test proved that the combination of Pelareorep and pembrolizumab chemotherapy did not cause obvious toxicity, showing an encouraging effect.
In addition to immune checkpoint inhibitors, clinical trials are testing combined immunotherapy of OVs and cytokines (such as IFN-γ) to enhance the overall anti-tumor immune response or combination of OVs and immunosuppressants (such as cyclophosphamide) to protect OV Activity in tumors.
In addition, clinical trials have reported that the anti-tumor effect of the combined use of oncolytic vaccine virus, reovirus, herpes simplex virus or adenovirus for chemotherapy in patients with advanced malignant tumors is encouraging.
7. Expert advice
In the past two decades, genetic engineering has accelerated the rapid expansion of oocytes by generating more potentially pathogenic viruses for cancer treatment. In 2015, the US FDA approved T-VEC as a single agent for melanoma immunotherapy, which was a turning point in the field of viral therapy. With the continuous development of OV,
Researchers have a clearer understanding of its mechanism of action. Oocytes not only dissolve tumor cells due to virus replication, but also change the local immune microenvironment of the tumor. In the past few years, checkpoint immunotherapy has changed the pattern of cancer treatment, changing the standard of treatment for many cancers, such as melanoma.
Therefore, in preclinical and clinical studies, inhibitors are actively used for cancer treatment.
For example, the phase III trial of Talimogene Laherparepvec combined with the anti-PD-1 antibody pembrolizumab is ongoing; the trial for melanoma patients (NCT02263508); the significant combination of OV and other therapies includes: Phase II trial adenovirus LOAd703 plus chemotherapy gemcitabine and paclitaxel Pancreatic cancer (NCT02705196); vaccinia virus GL-ONC1 plus chemotherapy and bevacizumab, combined treatment of patients with ovarian cancer, etc.
Although many exciting preclinical and clinical studies have shown that OV has strong potential, its unsatisfactory efficacy indicates its limitations in clinical trials. Recent studies have shown that large-scale small cell lung cancer patients do not benefit from the oncolytic pickup virus NTX-010 after platinum chemotherapy.
Vaccine virus-based oncolytic immunotherapy did not improve the overall survival rate (OS) of patients with advanced liver cancer after the failure of sorafenib as a second-line treatment. The combined application of the oncolytic wild-type reovirus pelareorep and FOLFOX6/Bevacizumab is tolerable, and the objective response rate (ORR) is increased, but the progression-free survival rate (PFS) is low. These clinical limitations are probably due to the transmission and spread of the virus, drug resistance, and the impact of antiviral immune responses.
The immune system is a double-edged sword for viral therapy. On the one hand, to successfully replicate the virus and spread within the tumor, the antiviral immune response must be minimized. On the other hand, the anti-tumor response must be stimulated to the maximum.
The latter requires both the regulation of innate immune response and the activation of the immunosuppressive tumor microenvironment. In order to improve the efficacy of anti-tumor, people have been committed to cultivating new OVs to enhance the stimulation of the host immune response or protect OV from immune clearance.
OVs target multiple molecules or signaling pathways in cancer cells or tumor microenvironment during their life cycle, which provides opportunities for anti-tumor drugs targeting these cellular pathways to combine with OVs.
The infection and replication of OVs in cancer cells directly leads to cell death and triggers the host’s anti-tumor immune response to further destroy cancer cells. This is the basis for the combination of OVs and different immunotherapies approved by the FDA, and has shown a good combined effect in many cancers.
As a platform for combined treatment with other anti-cancer drugs, OVs has attracted more and more clinical attention. With the faster and faster development of OVs, we have learned the advantages and disadvantages of OVs from current clinical trials.
In future studies, we will gain in-depth understanding of the interaction between OV and tumors, including virus-tumor cells and virus-tumor microenvironment, in order to develop more effective OVs, which can activate OVs while evading immune responses, and interact with them according to specific mechanisms. Different anti-tumor agents are combined.
(source:internet, reference only)