Combination therapy of oncolytic virus

Combination therapy of oncolytic virus.  The first anti-cancer drug approved by the FDA in 2015 was oncolytic herpes virus.

Preface

The development of oncolytic virus (OV) is based on observations as early as a century ago. At that time, after a naturally-acquired virus infection, cancer would naturally subside. The initial effort was to use virus-containing body fluids for treatment, but subsequent studies have shown that natural virus tropism has caused severe limitations in clinical transformation. With this understanding, the emergence of genetic engineering has promoted the optimization of viruses, and they have a clear selectivity for different cancers. Almost all kinds 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 the virus and the small horn virus were designed in this context, and different types of tumors were tested clinically. This project usually requires mutations in some key genes for virus replication, which not only confers tumor selectivity on the virus, but also greatly weakens the killing ability of the host cell.

Most notably, the first anti-cancer drug approved by the FDA 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 the subsequent milestone phase I/II clinical trials, tumor recurrence is almost universal. With the deepening of the understanding of the inherent intratumoral and inter-tumor heterogeneity of most solid cancers, people gradually realize that the best therapeutic effect of OV may require a more reasonable combination. Emerging data indicate that OVs interact with a variety of cellular processes during their life cycle, and the FDA-approved drugs that regulate these cellular processes may release the true therapeutic potential of OVs. In view of the remarkable success of immunotherapy in certain cancers and the observation that OVs may stimulate anti-tumor immune responses, the combination of OVs and FDA-approved immune checkpoint inhibitors has become the focus of attention.

OV combined with chemotherapy

Chemotherapy is one of the main treatment methods that uses intracellular poisons and other chemicals to inhibit DNA synthesis, mitosis and cell division of cancer cells, and induce DNA damage. During virus replication, these cellular pathways will be interfered by OV. Temozolomide (TMZ) is an alkylating agent and is considered an effective anticancer drug for the treatment of various solid tumors (including glioma and melanoma). TMZ alkylation/methylation mainly occurs at the N-7 or O-6 position of guanine residues, destroying DNA and triggering tumor cell death. 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. In the glioblastoma stem cell (GSC) model, the combined effect of oHSV G47Δ and TMZ caused strong DNA damage. The relocation of activated ATM to the HSV DNA replication region may enhance the replication of oHSV and make it unable to participate in the repair of TMZ-induced DNA damage. G47Δ and TMZ synergistically kill GSC in vitro, prolong the survival period of mice with GSC-derived intracranial tumors, and achieve long-term remission in 50% of mice.

The oncolytic adenovirus (OAd) combined with TMZ has been evaluated for the treatment of lung cancer cells in vitro and in vivo. TMZ enhances the viral therapy of OAd Adhz60 by increasing the replication of the virus in lung cancer cells but not other normal cells. At the same time, Adhz60 down-regulates the expression of MGMT in lung cancer cells, and the combined use of Adhz60 and TMZ can increase autophagy and apoptosis, thereby producing a synergistic lung cancer killing effect and inhibiting the growth of subcutaneous lung cancer in the body. Since oHSV manipulates cell DNA damage and repair during replication, oHSV depletes Rad51, a key protein of homologous recombination (HR), and inhibits HR repair, thereby synergistically with poly ADP ribose polymerase (PARP) inhibitors and improve efficacy. PARP is a key enzyme that repairs single-strand breaks. These studies show that understanding the interaction between the virus and the host is of great significance for the development of combination therapy with anti-tumor drugs such as OV.

OV combined with targeted therapy

During the process of infection, replication, and release from cancer cells, oncolytic viruses interact with specific genes, proteins, or tissue environment of cancer, which may promote tumor growth and survival. This makes it possible for OVs to act synergistically with targeted therapy, which prevents 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 inhibits 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-galactoside Armed immunotherapeutic vaccinia virus with enzyme transgene expression. Due to the inhibition of the EGFR/Ras/Raf pathway, the formation and replication of JX-594 plaques are inhibited in a dose-dependent manner. In two mouse liver cancer models, the sequential combination of JX-594 and sorafenib improved the anti-tumor effect. Subsequently, a preliminary clinical study was carried out to explore the safety and effectiveness of JX-594 combined with sorafenib in the treatment of 3 cases of liver cancer. Studies have shown that sequential treatment is well tolerated and is associated with a significant reduction in tumor blood perfusion and objective tumor response in all patients. 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 combinations to minimize adverse effects.

OV combined with hormone therapy

The goal of hormone therapy is to target hormone signaling pathways to inhibit the growth of cancer cells that require hormone growth. An early study showed that estrogen β-estradiol increased the replication of oncolytic HSV-1 NV1066 in estrogen receptor-positive (ER+) human breast cancer. Estrogen enhanced the oncolytic effect of NV1066. When the MOI was 0.1 and 0.5, the cell killing rate was 95% and 97%, respectively, and when estrogen was not used, it was 53% and 87%, respectively. The enhanced viral oncolysis is related to the increase of cell proliferation by estrogen and the decrease of ER+ breast cancer cell apoptosis. So far, there have not been too many reports on the combination of OV with approved hormone therapy drugs. More efforts are needed to understand the role of OVs in hormone-related signaling pathways in order to seek a theoretical basis for the combination of viral therapy and hormone therapy.

OV combined immunotherapy

Immunotherapy, represented by immune checkpoint inhibitors, activates or suppresses the immune system 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 can induce long-term animal survival in a variety of tumor models (including melanoma, colon cancer, and lung cancer models). Compared with treatment alone, the combination of the virus with anti-PD-1 or anti-CTLA4 antibodies further improved the anti-tumor activity. In addition, the virus alone or in combination with immune checkpoint blockade showed that through changes in immune status, it also showed anti-tumor activity in distant uninjected tumors. The benefits of viral expression of IL-7 and IL-12 were also observed in humanized mice carrying human cancer cells. Other OVs combined with immune checkpoint inhibitors include oHSV, adenovirus and measles virus and other cancer treatments.

Clinical trials of OV combination therapy

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.

Outlook

In the past two decades, the application of OVs has been rapidly expanded through genetic engineering. In 2015, the US FDA approved T-VEC as a single drug for melanoma immunotherapy, which was a turning point in the history of viral therapy. With the sustainable development of OV, researchers have a clearer understanding of its mechanism of action. OVs can not only dissolve tumor cells replicated by the virus, but also change the local immune microenvironment of the tumor. In the past few years, checkpoint immunotherapy has changed the pattern of cancer treatment and changed the treatment standards for many cancers, such as melanoma. Therefore, in preclinical and clinical studies, OV and checkpoint inhibitors are actively combined for cancer treatment. A number of OV joint clinical trials are actively underway.

Although many exciting preclinical and clinical studies have shown the powerful potential of OVs, their unsatisfactory efficacy indicates the limitations of OVs in clinical trials. Recent studies have shown that patients with extensive-stage small cell lung cancer cannot benefit from treatment with the oncolytic virus NTX-010 after receiving platinum-based chemotherapy. After the failure of sorafenib in patients with advanced hepatocellular carcinoma, vaccinia virus-based oncolytic immunotherapy did not improve overall survival (OS). 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, the antiviral immune response must be minimized in order to successfully replicate the virus and spread within the tumor. On the other hand, the anti-tumor response must be carried out under maximum stimulation. The latter needs to regulate the innate and adaptive immune response and activate 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. G47Δ-mIL12 is a genetically engineered oHSV with the immunomodulatory cytokine interleukin 12, which increases the release of IFN-γ and reduces the number of regulatory T cells in the tumor. G47Δ-mIL12 significantly improves the survival rate of syngeneic mice with intracerebral glioblastoma, and this improved efficacy depends on T cells. Xu et al constructed oHSV to express CDH1, which encodes E-cadherin (the ligand of KLRG1). KLRG1 is an inhibitory receptor expressed on NK cells to inhibit the killing of oHSV by NK cells and enhance intratumoral virus transmission. OHSV expressing CDH1 significantly improved the survival rate of the mouse glioblastoma model, which was mainly due to the improvement of virus transmission rather than the inhibition of NK cell activity.

OVs target multiple molecules or signaling pathways in tumor cells and TME 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 lead to cell death and trigger the host’s anti-tumor immune response, thereby further destroying 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. In future research, we will gain in-depth understanding of the interaction between OV and tumors, including the interaction of virus-tumor cells and virus-tumor microenvironment, in order to develop more powerful OVs that can activate and evade immune response and can According to the specific mechanism of action, it is combined with different anti-tumor drugs.

(source:internet, reference only)

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