Equipping the Immune System to Fight Against COVID-19
The coronavirus that causes COVID-19 has one major advantage over us – it is a new human virus. Most people have not encountered the virus before, meaning their immune system is not primed and ready to fight it. When someone gets sick with COVID-19, there is a lag in an efficient immune response, giving the virus time to do significant damage before the immune system can reign in the infection.
“It essentially becomes a race between how fast your immune system can clear the virus and how quickly the virus can replicate and induce damage,” Agustin Melian, MD, Chief Medical Officer and Head of Global Medical Sciences at AlloVir, told BioSpace.
To develop an effective treatment or vaccine for COVID-19, scientists must understand how the immune system is impacted during the disease. One type of immune cell that is particularly important in the body’s response to COVID-19 is T-cells. T-cells perform many functions, including recognizing invading viruses such as the coronavirus that causes COVID-19.
Multiple studies from Wuhan, China reported that COVID-19 patients had very low T-cell counts; the sicker the patient, the lower their T-cell count. Lower T-cell counts were correlated with poorer outcomes (including higher risk of death) and T-cells isolated from COVID-19 patients also showed signs of exhaustion.
“The elderly, patients with low T-cell numbers, and patients who express ‘exhaustion markers’ on their T-cells are high risk groups in which naïve cell responses (responses against a virus they have never seen before) may be deficient or delayed, thus allowing the virus to induce a large amount of damage,” Dr. Melian explained. “These patients may, therefore, benefit from AlloVir’s approach which is designed to restore natural T-cell immunity in high risk patients.
Could giving high-risk COVID-19 patients functional T-cells against the coronavirus boost their immune system and help them recover? This is the question AlloVir aims to answer.
AlloVir creates allogeneic (off-the-shelf) virus-specific T-cells designed to treat common and devastating viral-associated diseases in vulnerable patients, such as those who are immunocompromised or patients who received an organ or stem cell transplant. Now, they are expanding their anti-viral T-cell arsenal and taking aim at COVID-19.
“We believe AlloVir’s technology is well positioned to treat patients with COVID-19 because our technology is designed to provide SARS-CoV-2 specific T-cell immunity while leaving non-infected cells intact,” Dr. Melian commented. “Our virus-specific T-cell candidates have been used to treat more than 275 immunocompromised patients with life-threatening viral infections and diseases and we believe it our approach may also have promise in treating COVID-19.”
Fighting viruses with T-cells in immunocompromised patients
When you get infected with a virus, your immune system responds to the foreign threat by making specific T-cells that can recognize the virus. These specific T-cells prompt your immune system to destroy any cells infected by the virus.
However, if you have a T-cell deficiency, your immune system cannot robustly protect you. This is a major problem because an otherwise innocuous virus can become a serious infection, causing complications, and possibly even be life-threatening.
That is where AlloVir comes in. They address the underlying problem – the weakened immune system. A weakened immune system can be ‘beefed up’ by giving patients with T-cell deficiencies off-the-shelf virus-specific T-cells (VSTs) originally taken from healthy people. This restores their natural T-cell immunity and helps their immune system fight off the viruses.
“At AlloVir, we are a leading innovator in discovering and developing allogeneic, virus-specific T-cell immunotherapies,” Dr. Melian said. “We are now excited to be applying our capabilities in discovering and developing SARS-CoV-2 specific T-cells to join the fight in developing a COVID-19 program for patients at high risk of severe and devastating disease.”
AlloVir’s virus-specific T-cell platform
To create AlloVir’s T-cell therapies, the target virus is first studied carefully to identify its specific antigens (unique molecules on the outside of each virus that are specific to the virus and alert the immune system). The best antigens – those that induce a strong T-cell response – are used to create the therapy.
Next, blood is taken from healthy donors who have been exposed to the virus of interest and T-cells are isolated from the blood. The T-cells are activated in the lab – they are ‘trained’ to recognize the identified viral antigens, enabling the T-cells to selectively recognize only the desired virus.
After the T-cells have learned to recognize the specific virus, they are expanded to generate multitudes of cells. Once the activated, specific T-cells are created, they can be cryopreserved and kept for a long time, making them readily available as soon as a patient needs them. The entire process, from antigen selection to donor to ready-to-go T-cell treatment, can be completed in a matter of weeks. This process can be seen in the visual below.
Patients are matched using the company’s proprietary human leukocyte antigen (HLA)-matching formula. HLAs are proteins on the surface of cells that regulate the immune system.
“Our proprietary donor selection algorithm, known as Cytokin enables us to cover >95 percent of patients in our target population from cells derived from a small number of donors,” Dr. Melian said. “This proprietary process of prospectively manufacturing cells for off-the-shelf use enables us to study our allogeneic cell therapies in large numbers of patients that suffer from global health crises, like seasonal influenza and, as we are discussing, the COVID-19 pandemic.”
These T-cells are advantageous because they are active against a single virus or multiple viruses, are not patient-specific (so they are readily available) and are a single treatment that provides lasting protection. “The biggest bonus is the immediate off-the-shelf use for time-sensitive infections in vulnerable populations,” added Dr. Melian.
In addition to developing their COVID-19 therapy (called ALVR109), AlloVir has two other multi-virus specific T-cell therapies in development: Viralym-M (ALVR105) and ALVR106. Both therapies focus on treating viral diseases common to stem cell and solid organ transplant patients and other vulnerable populations.
Viralym-M targets six common viruses: BK virus (BKV), cytomegalovirus (CMV), adenovirus (AdV), Epstein-Barr virus (EBV, also called human herpesvirus 4), human herpesvirus 6, and JC virus (also called human polyomavirus 2). Although these viruses are widespread and infect most people, they only cause severe problems in people with weakened immune systems due to age, organ or stem cell transplant, or disease (such as diabetes or AIDS). In a Phase 2 study, 93 percent of 38 allogeneic stem cell transplant patients had a clinical response to Viralym-M treatment and functional Viralym-M cells lasted up to 12 weeks in the patients.
ALVR106 targets four common respiratory viruses: influenza, parainfluenza virus, respiratory syncytial virus (RSV), and human meta-pneumovirus (HMPV). While these viruses tend to cause mild to moderate respiratory illnesses, they can cause severe, life-threatening illness, especially in people with weakened immune systems. ALVR106 is still in preclinical development but clinical trials are expected to begin this year. Overall, AlloVir expects to have three new proof-of-concept (POC) Phase 1b/2 and three pivotal Phase 3 studies started over the next 6-18 months.
Off-the-shelf T-cells against COVID-19
While AlloVir originally designed their T-cell therapies for transplant patients, their platform can potentially be applied to any virus to create virus-specific T-cells. This versatility allowed AlloVir to pivot and create T-cells against SARS-CoV-2, the virus that causes COVID-19. This new investigational therapy, called ALVR109, is being developed as a stand-alone treatment, though it may also be incorporated into their ALVR106 respiratory virus therapy at some point in the future.
“Normally, the body would make virus-specific T-cells on their own and these would clear the virus,” commented Dr. Melian. “We enable that process in patients who otherwise would be T-cell deficient to restore T-cell immunity by giving ex vivo expanded cells that come from patients who already have demonstrated a potent immune response and have cleared the infection.”
The process of creating coronavirus-specific T-cells is the same as creating their other virus-specific T-cell therapies. First, blood is taken from people who have recovered from COVID-19 and the T-cells are isolated. Then, the cells are stimulated with viral antigens in the lab, expanded, and cryopreserved.
“We purposely choose a broad range of viral antigens to stimulate the T-cells to ensure the virus can’t circumvent the virus-specific T-cell therapy by mutating or developing resistance,” Dr. Melian said. “Working with a wide spectrum of viral activity is different than other approaches that just focus on one viral antigen.”
An open-label Phase 1 trial (called BAT IT) is anticipated to start within the next few months. Initial clinical studies of ALVR109 aim to treat high-risk COVID-19 patients, such as the elderly, to prevent organ damage. Prophylaxis studies, where the T-cells could be given to high-risk or immunocompromised patients who are not currently sick with COVID-19, may be considered later.
Coronavirus-specific T-cells vs. COVID-19 convalescent plasma
You may be wondering if another treatment that uses blood from COVID-19 survivors, called convalescent plasma therapy, is similar to AlloVir’s T-cell therapy. In convalescent plasma treatment, antibodies from COVID-19 survivors are isolated from their blood by separating out their plasma (the liquid part of the blood). The plasma is given to COVID-19 patients to help their immune system fight off the infection.
Although convalescent plasma and AlloVir’s coronavirus-specific T-cell treatments are both derived from COVID-19 survivors’ blood, the two treatments are fundamentally different.
“Antibodies and T-cells work in different areas of the immune system,” explained Dr. Melian. “Antibodies can go after viruses in circulating blood but can’t necessarily see viruses in infected cells. On the other hand, T-cells are pleotropic and directly attack virally infected cells, turning off the viral factories. T-cells are interesting because it is a live therapy – they can home to virally-infected cells and direct the immune system.”
Dr. Melian went on to explain that T-cell approach may be more comprehensive because they can support other immune cells that work against viruses, such as B-cells that make viral-specific antibodies. T-cells can also stimulate cytokines including interferon (a group of signaling proteins the immune system uses to respond to viruses), which further activates the body’s antiviral response.
“Providing virus-specific antibodies may be beneficial and protective for some viral infections,” Dr. Melian added. “We don’t know how these antibodies affect COVID-19 patients yet, but COVID-19 has a high mortality rate despite standard of care treatment. In this respect, it is important that all viable approaches to treatment be evaluated and I am very pleased to see these therapies have entered clinical testing.”
Convalescent plasma and AlloVir’s coronavirus-specific T-cell therapies are not mutually exclusive, so they could even be used together.