News eventToday, US biotechnology company Replimune announced that it will present Phase 1 clinical advances for two oncolytic virus (OV) therapies at this year's SITC annual Meeting. The combination of first-generation HSV oncolytic virus RP1 and Opdivo produced a high response rate in several skin cancers, producing 87.5% ORR and 62.5% CR in CSCC, including distal tumors without direct injection of OV. A more complex-designed second-generation therapy, RP2 alone, produced a 50% partial response rate in six patients with different solid tumors, including distal tumors without direct injection of OV. The three patients who responded had malignant melanosis, salivary gland mucoepidermoid carcinoma, and esophageal carcinoma. A clinical trial of RP2 in combination with O is enrolling patients.
　　Analysis of drug sourceReplimune's OV technology platform, called Immulytic, can see the dual function of immunity and killing. This platform is based on HSV and expresses both granulocyte-macrophage colony-stimulating factor (GM-CSF) and a cell fusion protein called GALV-GP-R- to enhance the immune response and promote bystander killing. HSV not only has strong oncolytic activity, but also can insert some immunoactivated or other proteins that destroy tumor tissue, so it is the main oncolytic virus at present. Amgen's T-VEC, which is HSV expressing GM-CSF, is already on the market for anti-melanoma, so at least the basic skeleton of intratumoral injection of this therapy has been shown to be safe and effective. The second generation of PR2 adds a protein similar to the CTLA4 antibody to further activate the immune activity of the tumor microenvironment.
　　The coronavirus pandemic has put the virus in the spotlight this year. COVID-19 selectively infects cells that express ACE2, causing cell death when the virus in the infected cells replicates to a certain extent. Scientists have long hoped to use the destructive nature of viruses to selectively kill tumors, and have also invented many viral amplification mechanisms that use high expression of enzymes in tumor cells. Passive OV treatment may occur early, and very few patients with advanced metastatic tumors can recover without any therapy. According to statistics, most of these cases are related to infection. In addition to tumors, viruses can also inhibit other viral infections. This year, it was reported that hepatitis C virus can inhibit the proliferation of hepatitis B virus, so if a virus that is safer than hepatitis C can be used to control hepatitis B infection.
　　The direct killing of tumor cells is only one of the working mechanisms of OV. Viral infections usually activate the natural and acquired immune systems, and because fighting viral infections is part of the system's job, it further increases the survival pressure on tumors. Activation of the immune system is not only effective against tumors at the point of treatment, but may result in systemic tumor control activity. This is also the reason why although OV currently relies on intratumoral injection, it can still treat advanced metastatic tumors, which is somewhat similar to radiation therapy. The innate immune response induced by viral infection usually up-regulates the expression of checkpoints such as PD-L1, so the combination with PD-1 drugs is more effective, which is the reason for the combination with O drugs. The PR2 also hides a CTLA4 blocking protein, which acts as a kind of root killer.
　　While this strategy may seem tempting, there are practical obstacles. For one thing, immunotherapy is inherently in conflict with viral therapy, because one of the immune system's jobs is to get rid of viruses, which is like having cops and robbers on a mission together (illustrated by the movie Blue Streak, if you're interested). But there are always loopholes in any system, and COVID-19, for example, prevents the activation of the natural immune system in some people, at least in the early stages of infection. So as long as you screen enough systems you can still get around this problem, at least you might be able to find enough of a window between tumor clearance and OV clearance. But of course there is a potential risk that too much success in evading the immune system could lead to long-term infections in patients, especially in older patients with compromised immune systems. A bigger obstacle is the common problem faced by all natural immune system activator therapies, which is the toxicity of systemic administration. The natural immune system is an alarm system that can only be used in certain places where there is a serious disaster. If the fire truck goes from house to house to water, society will be in chaos. Systemic administration is not only highly toxic, but also speeds up the host's clearance of OV, so now OV can only be administered within the tumor, and fortunately, there are many solid tumors that can use this drug delivery technology. Drugs that target key components of the viral response system, such as STING and TLR, do not need to be live viruses, and are now at the forefront of hot immunotherapy.