STM: Three Strategies to Achieve a New Generation of Lysolyvirus Development (Jia for National Review)

Man, source: The pharmaceutical Rubik's Cube Pro lysomavirus (oncolytic viruses) is a class of viruses that prioritize infection and killing of cancer cells and has the potential to improve clinical outcomes in patients who are unresponsive or resistant to immunotherapy or chemotherapy drugs.
, however, although such anticancer therapies have been studied for decades, only one type of T-VEC based on herpes simplex virus has been approved by the FDA.
T-VEC injected with melanoma has shown efficacy in patients treating local lesions of melanoma, metastasis melanoma is largely resistant to T-VEC.
the virus has been facing a huge obstacle in the fight against metastasis cancer, namely the human immune system.
when the lysovirus is systematically drugied into the bloodstream, the immune system quickly captures them.
natural immunoglobulin M (IgM) antibodies and complements in the blood degrade them by regulating, inactivation, and targeting blood-source viruses.
Source: Science Translational Medicine In a new study published in the journal Science Translational Medicine on November 25, a team of researchers from Emory University and Case Western Reserve University in the United States said they had found a way to overcome the barrier.
through multiple modifications, they succeeded in keeping the human adenovirus (HAdv) from being easily captured by the innate immune system, making it possible to treat metastatic cancers by systematically delivering the lysosovirus.
engineered adenovirus Ad5-3M is introduced with mutations to reduce inflammation after systemic drugation and to avoid interaction with blood factors and immune cells (video source: Dmitry Shayakhmetov) Human adenovirus (HAdv) is very effective in infecting and killing various types of cancer cells.
While these properties make HAdv attractive for the development of lysovirus candidate therapies, systematic delivery of HAdv can trigger strong systemic inflammatory responses and hepatotoxicity, limiting the clinical use of the virus platform.
studies have shown that after intravenous HAdv-C5 serotonin, viral particles are quickly conditioned by the blood's coagulation factor X.
although the combination of coagulation factor X and HAdv-C5 protects the virus from complement-mediated ineration, the combination of the two promotes effective liver cell infection and leads to liver toxicity.
addition, the combination of coagulation factor X and HAdv-C5 also enhances the identification of viruses by innate immune cells, thereby promoting the activation of inflammation throughout the body.
intravenous infusion, HAdv particles are quickly removed from the blood by phagocytosis cells, especially Kupffer cells in the liver (special macrophages located in the liver).
When captured by phagocytos, HAdv interacts with beta-3 integrator (beta-containing integrins) in cells through the Arg-Gly-Asp (RGD) amino acid sequence in the penton base protein of the virus.
high-dose intravenous injections, this interaction triggers activation of the IL-1 alpha-dependent signaling, triggering an acute cytokine storm.
, developing a safe and effective solution for systemic drugation requires a multi-pronged approach to regulating the virus's interaction with body fluid factors and tissue phagocytosis cells.
Dmitry Shayakhmetov, of Emory University, has been working with Dr. Phoebe Stewart, a structural biologist at case the University of Western Reserve, for 15 years, and their research has focused on "transforming adenovirus."
2012, their team published a paper in the journal Science that revealed how adenovirus interacts with coagulation factor X.
the new study, scientists reported on Ad5-3M, a new adenovirus that can still be assembled after multiple modifications and retains the function of infecting and killing tumor cells.
that modified adenovirus was effective in suppressing tumor growth in mouse models without showing toxic effects.
. Shayakhmetov and his partners first discovered that natural IgM antibodies bind to the high-variable zone 1 (HVR1) of the Ad5-3M virus, which mutates in the hexon HVR1 and HVR7 rings, as well as the penton base RGD ring.
this, using targeted mutation, the researchers made three modifications to the adenovirus and obtained an improved version of the adenovirus, Ad5-3M.
Ad5-3M contains three mutations, one in the hexon HVR1 ring that blocks the virus from binding to IgM, and one mutation in the hexon HVR7 ring that prevents the virus from binding to the clotting factor X. Inhibits coagulation factor X dependent liver cell infection; 1 penton-integrator redirects mutations that cause the virus to interact not with beta-3 integrators in macrophages, but with other β-subi integrators present in epithympornic tumor cells. After delivery of the
system, the Ad5-3M virus can evade the capture of macrophages in the liver without triggering liver toxicity and inflammatory cytokine activation (Source: Science Translational Medicine) Research confirms for the first time that the binding of human adenovirus (HAdv) to natural IgM can be modified by introducing mutations at IgM binding points in the virus.
Ad5-3M not only resists ineration caused by blood factors, avoids being caught in liver macrophages, but also does not trigger liver toxicity after intravenous drugging.
addition, the Ad5-3M system can cause the virus to replicate in tumor cells. After delivery of the
system, Ad5-3M inhibits tumor growth and prolongs the survival of mice with local or diffuse tumors (Source: Science Translational Medicine) Anti-cancer efficacy assessment shows that high doses of standard adenoviruses injected into mice trigger liver damage and mice die within a few days.
, the modified version of the adenovirus Ad5-3M was able to remove diffuse tumors from mice that had human lung cancer cells transplanted.
35 percent of animals showed complete remission (tumors can no longer be detected) and had longer survival.
scientists believe the results suggest that engineering to transform the virus to escape the "attack" of the innant immune system could provide a scalable way to develop systematic delivery of virus therapies for human cancer resistant to existing treatments.
"For a long time, when the lysovirus is delivered intravenously, the innate immune system delivers the virus quickly and efficiently to the liver.
this allows most lysovirus to be delivered directly to the tumor via intra-tumor injection, limiting its effect on metastasis tumors.
and our study reveals that it is possible to systematically deliver an improved version of the lysovirus at a sufficiently high dose to inhibit tumor growth without triggering life-threatening systemic toxicity.
," concluded Dr Shayakhmetov.
it is understood that Dr. Shayakhmetov started a company called AdCure Bio in 2016 to develop safe and effective solid tumor lysovirus therapies, and that his team will further explore ways to improve the full remission rate of modified adenovirus therapies.
Review Dr. Jia Weiguo, co-founder and chief scientist, has made three simultaneous modifications to the Hexon and penton proteins on the shell of type 5 adenovirus, which is commonly used in the solute virus, in the latest study published in the journal Science Translational Medicine. The aim is to reduce the nonsexual immunogenicity of the virus in three ways: 1) to cancel the binding to IgM, 2) to cancel the binding to the coagulation factor X, and 3) to prevent binding to beta3 integrin and to other integrin bindings with the high expression of the endothotic tumor cells.
this is because IgM's binding to adenovirus may have contributed to the virus being devoured by kupffer cells in the liver, while coagulation factors X and beta3 integrin combined with adenovirus mediate the liver toxicity of the virus.
the above-mentioned modified adenovirus hAd5-3M showed a significant improvement in inactivation in the blood and showed the efficacy of intravenous injections on tumor cell strains and PDX tumors in immunodeficiency mice.
this study seems to solve the problem of hepatotoxicity of adenovirus systems.
, these modifications may still not be enough for intravenous drugation of adenovirus.
The mesothetic effects of anti-adenovirus antibodies in the blood are still not resolved, and it is not clear whether the adenovirus replication activity that reaches the tumor can resist virus removal caused by other immune factors (e.g. T cells, NK cells, etc.).
The study demonstrated that the tumor activity administered by the hAd5-3M system was clearly not sufficient to explain the problem, and that they needed to demonstrate the true effectiveness of intravenous injections on tumor models in immunosuppressive mice or humanized mice.
of course, the study's genetic modification of the adenovirus' crust proteins is significant both in terms of basic virological research and in terms of the application prospects of the lysovirus.
the scientific community's attention in the early 1990s with cancer treatments such as the multi-year lysolytic virus, which is rooted in the lysovirus.
when I was doing postdoctoral research at UDC in Canada, I started studying the lysovirus.
first article published in 1994, I have been working on lysovirus research at university.
based on these research foundations, in 2015, I co-founded ViroGin, a biotechnology company in Canada focused on the development of lysovirus therapies, which recently completed more than $60 million in round C financing.
, our first product, VG161, has entered clinical Phase I trials in Australia and China.
VG161 is an HSV-1 virus based on a detoxifying skeleton that carries four genes, IL12, IL15, IL15 alpha- subject sub-base, and PD-L1 block peptides.
company's second-generation products are based on non-detoxifying skeleton, through transcription translation dual regulation method to ensure the tumor specificity of the virus, in a high degree of safety at the same time, has a strong solubility activity.
on this skeleton, our product pipelines carry a variety of exonyms of the virus, the next generation of products will be in the clinical stage next year.
next-generation lysovirus development at present, it seems to me that the key obstacle in the field of lysovirus is not intravenous injection.
because existing cancer surgery and interventional imaging techniques have made intracerine injection clinically not a major barrier.
more importantly, T-VEC and other lysovirus that are conducting clinical trials have shown that localized viral injections can have systemic effects, causing distant tumors to disappear.
premise, I think the ultimate goal of the lysovirus is to turn the antiviral immune response of the virus-induced body into a long-lasting anti-tumor immune response.
To achieve this, the main objectives of the development of a new generation of lysoviruses are: 1) to have sufficient tumor activity to release enough tumor antigens to achieve antigen spread in a strong immune-activated background, so that the body's immune system reacts to tumor antigens; The time is not long, so it is necessary to produce a "micro" cytokine storm in the tumor, so what kind of external factors can be associated with the virus infection itself induced by multiple immune-related factors need to be carefully studied;
may contribute to the anti-tumor immune response induced by the lysovirus, while others may be antagonized.
how to combine tumor micro-environments altered by lysovirus with these therapies to achieve maximum efficacy is a direction that needs to be explored.
outlook for the next 3-5 years, I believe that the field of lysovirus is currently on the eve of a clinical breakthrough.
the first wave of lysolysis virus since the 1990s, with the exception of T-VEC and H101 in China, all other candidate therapies are within clinical stage III, and few single-drug use is obviously effective.
the main way out for this generation of lysolytic viruses is in association with other immunotherapy drugs.
and the next generation of lysolytic viruses after T-VEC have significantly improved their ability to dissolve tumors and stimulate anti-tumor immunity.
this generation of viruses is currently mostly in phase I or phase II clinical stage, so it will take time to see.
I am optimistic that in the next 3-5 years there will be several new varieties that are more efficient than T-VEC.
the same time, there will be a wave of lysovirus in association with other drugs, especially as it can significantly improve the efficacy of immunosuppressors.
resources: 1 svetlana Atasheva et al. Systemic cancer therapy with engineered adenovirus that evades innate imm。