Tumor immunotherapy has made significant progress in recent years, and has improved the treatment of a variety of tumors. However, the application of immunotherapy is limited by the bottleneck of insufficient effective population. In order for immunotherapy to show its greater potential, the academic community has been committed to finding effective helpers for immunotherapy and forming effective combination therapies. Among many candidate helpers, oncolytic viruses are the most noticeable.
Oncolytic viruses and the common targeting mechanisms
Oncolytic viruses are a class of viruses that can effectively infect and destroy tumor cells. Based on the characteristics of the virus, oncolytic virus therapy can be applied either systemically or locally to treat primary lesions and metastases. When tumor cells rupture and die under virus infection, newly generated virus particles are released, further infecting surrounding tumor cells. Not only can the tumor be directly killed, but it is also expected to stimulate the human immune response and enhance the effect of anti-tumor treatment.
Specific targeting of tumors is a major focus in research and development, with the goal of efficiently targeting oncolytic viruses to tumor cells. Interestingly, tumors are inherently well-suited to be attacked by oncolytic viruses-when genes such as RAS, TP53, RB1, and PTEN are mutated, the ability of tumor cells to weaken the virus becomes weaker.
To address these weaknesses in tumor cells, researchers have developed a variety of viruses that can effectively target tumors. For example, vesicular stomatitis virus (VSV) and Maraba virus (MG1). Modified rhabdoviruses can specifically target tumor cells by relying on defects in the interferon signaling pathway. The first oncolytic virus that received FDA approval to treat melanoma is a modification of herpes simplex virus (HSV-1). The design of these viruses is related to the immune response.
Other oncolytic viruses can additionally target metabolic abnormalities of malignant tumors. For example, pexastimogene devacirepvec (Pexa-Vec) itself has a defective thymidine kinase gene, which can only be replicated in tumor cells with excess thymidine kinase activity. In addition, the B18R gene in the virus carries an early stop codon, making its encoded protein difficult to recognize and bind to interferons. These characteristics allow such viruses to effectively target tumor cells while minimizing the effects on normal cells.
Progress of clinical application of oncolytic virus
In 2015, Amgen's T-Vec was officially approved, becoming the first oncolytic virus therapy approved by the US FDA.
T-VEC is a genetically modified herpes virus that is used to treat advanced malignant melanoma. It is administered intratumorally. The launch of T-Vec confirms the feasibility of oncolytic viruses as anti-cancer therapies, and "awakens" developments in this area.
Compared to FDVA, the first oncolytic virus approved by CFDA was the H101 gene-modified oncolytic adenovirus developed by Shanghai Sunway Biotechnology Co., Ltd., which was approved in 2005 for the treatment of head and neck tumors.
Clinical stage III
Reolysin is in a phase III clinical trial for head and neck cancer. Clinical data show that this phase III clinical trial showed statistically significant tumor shrinkage. In addition, a total of 31 clinical studies of early results for colon and rectal cancer have been completed or are in progress, including many Reolysin trials and various entities and standard chemotherapy regimens for tumors.
Clinical Phase II
1. Jennerex's JX-594 is currently in the phase II clinical trial of hepatocellular carcinoma. JX-594 is a thymidine kinase-deficient vaccinia virus and is fused with GM-CSF.
2. Seneca Valley virus (NTX-010) and (SVV-001) are oncolytic small ribonucleic acid viruses used to treat small cell lung cancer and neuroblastoma;
3. ColoAd1, an oncolytic virus developed by Psioxus Therapeutics using directed evolution, has successfully completed clinical phase I trials. The viral samples used by these patients after intravenous delivery showed a large amount of virus replication in the tumor site with little effect on normal tissues.
4. Cavatak is a Coxsackie virus that is in phase II clinical trials for the treatment of malignant melanoma.
5. ONCOS-102 is a human serotype 5/3 adenovirus encoding human GM-CSF, which is optimized to induce a systemic anti-tumor T cell response in cancer patients. The treatment of malignant pleural mesothelioma has entered a phase II clinical trial.
Clinical Phase I
1. Virttu Biologics' SEPREHVIR (HSV-1716) completed phase I clinical trials of glioblastoma, squamous cell carcinoma of the head and neck, and melanoma;
2. Oncos Therapeutics' CGTG-102 (Ad5 / 3-D24-GMCSF) has been used in the company's AdvancedTherapy Access Program to treat 200 patients with advanced cancer.
3. GL-ONC1 developed by Genelux is in the Phase Ib clinical trial of intravenous administration for solid tumors. Other trials are underway, including intrapleural administration in patients with malignant pleural effusion, intraperitoneal injection in patients with advanced peritoneal cancer, and intraperitoneal injection of recurrent ovarian cancer in head and neck cancer. (Data source: Tumor)
Other research progress
In last February, Merck acquired an Australian company focused on oncolytic viruses for $ 394 million. In May, Johnson & Johnson's company Jansen announced that it would acquire BeneVir Biopharm, a biopharmaceutical company that owns the T-Stealth oncolytic virus platform, to advance preclinical drug candidates as stand-alone therapies or in combination with other immunotherapies to treat lung cancer, prostate cancer, and colorectal cancer.
Recently, Bristol-Myers Squibb (BMS) and PsiOxus Therapeutics in the UK developed an oncolytic adenovirus therapy drug. The treatment, called NG-348, uses viruses to transfer two therapeutic genes directly into the tumor, thereby recruiting immune cells to attack the cancer.
The future of oncolytic virus therapy
The review concludes with two potential directions for oncolytic viruses. One is to combine with T cell therapy to help T cells proliferate and move in the local tumor microenvironment to achieve therapeutic effects. The second is to develop a better oncolytic virus through further understanding of the immune mechanism and further expand its potential.
The development of oncolytic viruses is full of opportunities. It should be combined with existing therapies to take advantage of the former's effect on immune response to effectively remove residual tumor lesions. As the antitumor mechanism of the immune system continues to be elucidated, oncolytic viruses are expected to provide an important boost to immunotherapy.