Today, the American biotechnology company Replimune announced that it will announce the Phase I clinical progress of two oncolytic virus (OV) therapies at this year’s SITC annual meeting. The first-generation HSV oncolytic virus RP1 combined with Opdivo produced a higher response rate in several skin cancers. Among them, 87.5% of the ORR was generated in CSCC and 62.5% was CR, including remote tumors without direct injection of OV. A more complex second-generation therapy, RP2, was used as a single prescription to produce a 50% partial response rate in 6 patients with different solid tumors, including remote tumors without direct injection of OV. The 3 patients who responded had malignant melanoma, salivary mucoepidermoid carcinoma, and esophageal cancer. Clinical trials of the combination of RP2 and O drugs are recruiting patients.
Drug source analysis
Replimune's OV technology platform is called Immulytic, which can see the dual functions of immunity and killing. This platform is based on HSV and simultaneously expresses granulocyte-macrophage colony stimulating factor (GM-CSF) and a cell fusion protein called GALV-GP-R- to strengthen the immune response and promote the killing of bystanders. HSV not only has strong oncolytic activity, but also can insert some immune activation or other proteins that destroy tumor tissues, so it is now the main oncolytic virus. Amgen’s T-VEC is HSV expressing GM-CSF and has been marketed for malignant melanoma, so at least the basic framework of intratumoral injection has proven to be safe and effective. Its second-generation product PR2 adds a protein similar to CTLA4 antibody to further activate the immune activity of the tumor microenvironment.
The epidemic of the new crown this year has made the virus a topic of attention. COVID-19 selectively infects cells expressing ACE2, and when the virus in the infected cell replicates to a certain extent, it will cause cell death. Scientists have long hoped to use the destructive nature of viruses to selectively kill tumors, and have also invented many virus amplification mechanisms that use highly expressed enzymes in tumor cells. Passive OV treatment may occur early, and very few patients with advanced metastatic tumors can recover on their own 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 has been reported that hepatitis C virus can inhibit the proliferation of hepatitis B virus, so if you find a virus safer than hepatitis C, you can also use this divider to control hepatitis B infection.
Directly killing tumor cells is just one of the working mechanisms of OV. Virus infection usually activates the natural and acquired immune system. Because dealing with virus infection is one of the duties of this system, it further increases the pressure of tumor survival. After the immune system is activated, it is not only effective for the treatment of tumors, but may produce systemic tumor control activity. This is why although OV basically relies on intratumoral injection, it can still treat advanced metastatic tumors, which is similar to radiotherapy. The natural 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. This PR2 also hides a CTLA4 blocking protein, which is a bit of a stance to eliminate the roots.
Although this strategy seems very attractive, there are still many practical obstacles. First of all, there is a conflict between immunotherapy and virus therapy, because one of the duties of the immune system is to remove the virus, which is like having the police and robbers work together to perform tasks (the illustration is from the movie Blue Streak, interested readers can search). However, there are always loopholes in any system. For example, the new crown has avoided the activation of the natural immune system at least in the early stages of infection. So as long as the screening of enough systems can still avoid this problem, at least it is possible to find a sufficient window between removing the tumor and removing the OV. But this of course also has a potential risk, that is, if the immune system is too successful, it may cause long-term infections in patients, especially in elderly patients with defective immune systems. The bigger obstacle is the common problem faced by all innate immune system activator therapy, which is the toxicity problem of systemic administration. The natural immune system is an alarm system that can only be used in specific locations where severe disasters occur. If the fire truck goes door to door to water the society, it will be a mess. Systemic administration is not only more toxic, but also accelerates the elimination of OV from the host, so OV can only be administered intratumorally. Fortunately, many solid tumors can use this drug delivery technology. Drugs targeting key components of the virus response system such as STING and TLR do not need to be live viruses, and they are also the current hot frontier of immunotherapy.