News Event

　　Today, the American biotechnology company Replimune announced that it will disclose Phase 1 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 high response rate in several skin cancers, including an 87.5% ORR and 62.5% CR in CSCC, including distant tumors not directly injected with OV. A more complex second-generation therapy RP2 used as monotherapy produced a 50% partial response rate in 6 patients with different solid tumors, also including distant tumors not directly injected with OV. The 3 responding patients had melanoma, salivary gland mucoepidermoid carcinoma, and esophageal cancer, respectively. Clinical trials combining RP2 with Opdivo are currently recruiting patients.

　　Drug Source Analysis

　　Replimune's OV technology platform is called Immulytic, reflecting dual immune and cytolytic functions. 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 enhance immune response and promote bystander killing. HSV not only has strong oncolytic activity but can also insert proteins that activate immunity or destroy tumor tissue, making it the main oncolytic virus currently. Amgen's T-VEC is an HSV expressing GM-CSF, already marketed for melanoma, so at least the basic framework of intratumoral injection of this therapy has been proven safe and effective. Its second-generation product PR2 adds a protein similar to CTLA4 antibody, further activating immune activity in the tumor microenvironment.

　　The COVID-19 pandemic this year has made viruses a topic of public attention. COVID-19 selectively infects cells expressing ACE2, and when viral replication in infected cells reaches a certain level, it causes cell death. Scientists have long hoped to use the destructive nature of viruses to selectively kill tumors and have invented many viral amplification mechanisms utilizing enzymes highly expressed in tumor cells. Passive OV therapy may have occurred earlier; very rare late-stage metastatic tumor patients can recover without any therapy, and statistics show most of these cases are related to infections. Besides tumors, viruses can also suppress other viral infections. This year, reports showed that hepatitis C virus can inhibit hepatitis B virus replication, so if a virus safer than hepatitis C is found, this strategy could be used to control hepatitis B infection.

　　Direct killing of tumor cells is only one mechanism of OV. Viral infection usually activates innate and adaptive immune systems because dealing with viral infections is one of their primary functions, thereby further increasing the survival pressure on tumors. Once the immune system is activated, it is not only effective against the treated tumor site but may produce systemic tumor control activity. This is why, although OV currently mainly relies on intratumoral injection, it can still treat advanced metastatic tumors, somewhat similar to radiotherapy. The innate immune response induced by viral infection usually upregulates checkpoints like PD-L1 expression, so combining with PD-1 drugs is more effective, which is why it is combined with Opdivo. This PR2 also contains a hidden CTLA4 blocking protein, aiming for a thorough eradication.

　　Although this strategy looks very promising, there are still many practical obstacles. First, immunotherapy and virotherapy inherently conflict because one of the immune system's duties is to clear viruses, which is like having police and robbers team up to execute a mission (illustration from the movie Blue Streak; interested readers can look it up). However, every system has loopholes; for example, COVID-19 in some populations at least initially avoids activating the innate immune system. So, by screening enough systems, this problem can be bypassed, at least potentially finding a sufficient window between clearing tumors and clearing OV. But this also carries a potential risk: if immune evasion is too successful, it may cause long-term infection in patients, especially elderly patients with immune deficiencies. A bigger obstacle is the common challenge faced by all innate immune system activator therapies: systemic toxicity. The innate immune system is an alarm system and should only be used at specific sites of severe disaster; if fire trucks watered every house, society would be in chaos. Systemic administration not only has higher toxicity but also accelerates host clearance of OV, so currently OV can only be administered intratumorally. Fortunately, many solid tumors can use this administration technique. Drugs targeting key components of the viral response system such as STING and TLR do not need to be live viruses and are currently a hot frontier in immunotherapy.