What are the latest advances in stem cell research targeting cancer? Can stem cells help people battling COVID-19 or even help develop a vaccine to stop the virus? What are researchers and the scientific community doing to help address the unmet medical needs of underserved communities? Those are just a few of the topics being discussed at the Annual CIRM Alpha Stem Cell Clinic Network Symposium on Thursday, October 8th from 9am to 1.30pm PDT.
Like pretty nearly everything these days the symposium is going to be a virtual event, so you can watch it from the comfort of your own home on a phone or laptop. And it’s free.
The CIRM Alpha Clinics are a network of leading medical centers here in California. They specialize in delivering stem cell and gene therapies to patients. So, while many conferences look at the promise of stem cell therapies, here we deal with the reality; what’s in the clinic, what’s working, what do we need to do to help get these therapies to patients in need?
It’s a relatively short meeting, with short presentations, but that doesn’t mean it will be short on content. Some of the best stem cell researchers in the U.S. are taking part so you’ll learn an awful lot in a short time.
We’ll hear what’s being done to find therapies for
Rare diseases that affect children
Type 1 diabetes
We’ll discuss how to create a patient navigation system that can address social and economic determinants that impact patient participation? And we’ll look at ways that the Alpha Clinic Network can partner with community care givers around California to increase patient access to the latest therapies.
It’s going to be a fascinating day. And did I mention it’s free!
One of our favorite things to do at CIRM is deliver exciting news about CIRM projects. This usually entails discussion of recent discoveries that made headlines, or announcing the launch of a new CIRM-funded clinical trial …. tangible signs of progress towards addressing unmet medical needs through advances in stem technology.
But there are equally exciting signs of progress that are not always so obvious to the untrained eye- those that we are privileged to witness behind the scenes at CIRM. These efforts don’t always lead to a splashy news article or even to a scientific publication, but they nonetheless drive the evolution of new ideas and can help steer the field away from futile lines of investigation. Dozens of such projects are navigating uncharted waters by filling knowledge gaps, breaking down technical barriers, and working closely with regulatory agencies to define novel and safe paths to the clinic.
These efforts can remain “hidden” because they are in the intermediate stages of the long, arduous and expensive journey from “bench to beside”. For the pioneering projects that CIRM funds, this journey is unique and untrod, and can be fraught with false starts. But CIRM has developed tools to track the momentum of these programs and provide continuous support for those with the most promise. In so doing, we have watched projects evolve as they wend their way to the clinic. We wanted to share a few examples of how we do this with our readers, but first… a little background for our friends who are unfamiliar with the nuts and bolts of inventing new medicines.
A common metaphor for bringing scientific discoveries to market is a pipeline, which begins in a laboratory where a discovery occurs, and ends with government approval to commercialize a new medicine, after it is proven to be safe and effective. In between discovery and approval is a stage called “Translation”, where investigators develop ways to transition their “research level” processes to “clinically compatible” ones, which only utilize substances that are of certified quality for human use.
Investigators must also work out novel ways to manufacture the product at larger scale and transition the methods used for testing in animal models to those that can be implemented in human subjects.
A key milestone in Translation is the “preIND” (pre Investigational New Drug (IND) meeting, where an investigator presents data and plans to the US Food and Drug Administration (FDA) for feedback before next stage of development begins, the pivotal testing needed to show it is both safe and effective.
These “IND enabling studies” are rigorous but necessary to support an application for an IND and the initiation of clinical trials, beginning with phase 1 to assess safety in a small number of individuals, and phase 2, where an expanded group is evaluated to see if the therapy has any benefits for the patient. Phase 3 trials are studies of very large numbers of individuals to gain definitive evidence of safety and therapeutic effect, generally the last step before applying to the FDA for market approval. An image of the pipeline and the stages described are provided in our diagram below.
The pipeline can be notoriously long and tricky, with plenty of twists, turns, and unexpected obstacles along the way. Many more projects enter than emerge from this gauntlet, but as we see from these examples of ‘works in progress”, there is a lot of momentum building.
Caption for Graphic:This graphic shows the number of CIRM-funded projects and the stages they have progressed through multiple rounds of CIRM funding. For example, the topmost arrow shows that are about 19 projects at the translational stage of the pipeline that received earlier support through one of CIRM’s Discovery stage programs. Many of these efforts came out of our pre-2016 funding initiatives such as Early Translation, Basic Biology and New Faculty Awards. In another example, you can see that about 15 awards that were first funded by CIRM at the IND enabling stage have since progressed into a phase 1 or phase 2 clinical trials. While most of these efforts also originated in some of CIRM’s pre-2016 initiatives such as the Disease Team Awards, others have already progressed from CIRM’s newer programs that were launched as part of the “2.0” overhaul in 2016 (CLIN1).
The number of CIRM projects that have evolved and made their way down the pipeline with CIRM support is impressive, but it is clearly an under-representation, as there are other projects that have progressed outside of CIRM’s purview, which can make things trickier to verify.
We also track projects that have spun off or been licensed to commercial organizations, another very exciting form of “progression”. Perhaps those will contribute to another blog for another day! In the meantime, here are a just a few examples of some of the progressors that are depicted on the graphic.
Project: stem cell therapy to enhance bone healing in theelderly
– Currently funded stage: IND enabling development, CLIN1-11256 (Dr. Zhu, Ankasa Regenerative Therapeutics)
Every so often you hear a story and your first reaction is “oh, I have to share this with someone, anyone, everyone.” That’s what happened to me the other day.
I was talking with Kristin MacDonald, an amazing woman, a fierce patient advocate and someone who took part in a CIRM-funded clinical trial to treat retinitis pigmentosa (RP). The disease had destroyed Kristin’s vision and she was hoping the therapy, pioneered by jCyte, would help her. Kristin, being a bit of a pioneer herself, was the first person to test the therapy in the U.S.
Anyway, Kristin was doing a Zoom presentation and wanted to look her best so she asked a friend to come over and do her hair and makeup. The woman she asked, was Rosie Barrero, another patient in that RP clinical trial. Not so very long ago Rosie was legally blind. Now, here she was helping do her friend’s hair and makeup. And doing it beautifully too.
That’s when you know the treatment works. At least for Rosie.
There are many other stories to be heard – from patients and patient advocates, from researchers who develop therapies to the doctors who deliver them. – at our CIRM 2020 Grantee Meeting on next Monday September 14th Tuesday & September 15th.
It’s two full days of presentations and discussions on everything from heart disease and cancer, to COVID-19, Alzheimer’s, Parkinson’s and spina bifida. Here’s a link to the Eventbrite page where you can find out more about the event and also register to be part of it.
Like pretty much everything these days it’s a virtual event so you’ll be able to join in from the comfort of your kitchen, living room, even the backyard.
And it’s free!
You can join us for all two days or just one session on one day. The choice is yours. And feel free to tell your friends or anyone else you think might be interested.
Don’t you love it when someone does your job for you and does it so well you have no need to add anything to it! Doesn’t happen very often – sad to say – but this week our friends at UCLA wrote a great article describing the work they are doing to target COVID-19. Best of all, all the work described is funded by CIRM. So read, and enjoy.
Two scientists in a lab at the UCLA Broad Stem Cell Research Center
By Tiare Dunlap, UCLA
As the COVID-19 pandemic rages on, UCLA researchers are rising to the occasion by channeling their specialized expertise to seek new and creative ways to reduce the spread of the virus and save lives. Using years’ — or even decades’ — worth of knowledge they’ve acquired studying other diseases and biological processes, many of them have shifted their focus to the novel coronavirus, and they’re collaborating across disciplines as they work toward new diagnostic tests, treatments and vaccines.
“As a result of the pandemic, everyone on campus is committed to finding ways that their unique expertise can help out,” said Dr. Brigitte Gomperts, professor and vice chair of research in pediatric hematology-oncology and pulmonary medicine at the David Geffen School of Medicine at UCLA and a member of the UCLA Children’s Discovery and Innovation Institute. “So many of my colleagues have repurposed their labs to work on the virus. It’s very seldom that you have one thing that everybody’s working on, and it has been truly inspiring to see how everyone has come together to try and solve this.”
Here’s a look at five projects in which UCLA scientists are using stem cells — which can self-replicate and give rise to all cell types — to take on COVID-19.
Using lung organoids as models to test possible treatments
Dr. Brigitte Gomperts
Gomperts has spent years perfecting methods for creating stem cell–derived three-dimensional lung organoids. Now, she’s using those organoids to study how SARS-CoV-2, the virus that causes COVID-19, affects lung tissue and to rapidly screen thousands of prospective treatments. Because the organoids are grown from human cells and reflect the cell types and architecture of the lungs, they can offer unprecedented insights into how the virus infects and damages the organ.
Gomperts is collaborating with UCLA colleagues Vaithilingaraja Arumugaswami, a virologist, and Robert Damoiseaux, an expert in molecular screening. Their goal is to find an existing therapy that could be used to reduce the spread of infection and associated damage in the lungs.
“We’re starting with drugs that have already been tested in humans because our goal is to find a therapy that can treat patients with COVID-19 as soon as possible,” Gomperts said. Read more.
Repurposing a cancer therapy
Vaithilingaraja Arumugaswami, associate professor of molecular and medical pharmacology at the Geffen School of Medicine
In addition to collaborating with Gomperts, Arumugaswami and Damoiseaux identified the cancer drug Berzosertib as a possible treatment for COVID-19 after screening 430 drug candidates. The drug, which is currently being tested in clinical trials for cancer, works by blocking a DNA repair process that is exploited by solid cancers and the SARS-CoV-2 virus, and the UCLA scientists found that it is very effective at limiting viral replication and cell death.
“Clinical trials have shown that Berzosertib blocks the DNA repair pathway in cancer cells, but has no effects on normal, healthy cells,” Arumugaswami said.
Now, Arumugaswami and Gustavo Garcia Jr., a staff research associate, are testing Berzosertib and additional drug combinations on lung organoids developed in Gomperts’ lab and stem cell–derived heart cells infected with SARS-CoV-2. They suspect that if the drug is administered soon after diagnosis, it could limit the spread of infection and prevent complications. Read more.
Studying the immune response to the virus
Dr. Gay Crooks, professor of pathology and laboratory medicine and of pediatrics at the Geffen School of Medicine, and co-director of the Broad Stem Cell Research Center; and Dr. Christopher Seet,
assistant professor of hematology-oncology at the Geffen School of Medicine
Crooks and Seet are using stem cells to model how immune cells recognize and fight the virus in a lab dish. To do that, they’re infecting blood-forming stem cells — which can give rise to all blood and immune cells — from healthy donors with parts of the SARS-CoV-2 virus and then coaxing the stem cells to produce immune cells called dendritic cells. Dendritic cells devour viral proteins, chop them up into pieces and then present those pieces to other immune cells called T cells to provoke a response.
By studying that process, Crooks and Seet hope to identify which parts of the virus provoke the strongest T-cell responses. Developing an effective vaccine for SARS-CoV-2 will require a deep understanding of how the immune system responds to the virus, and this work could be an important step in that direction, giving researchers and clinicians a way to gauge the effectiveness of possible vaccines.
“When we started developing this project some years ago, we had no idea it would be so useful for studying a viral infection — any viral infection,” Crooks said. “It was only because we already had these tools in place that we could spring into action so fast.” Read more.
Developing a booster that could help a vaccine last longer
A COVID-19 vaccine will need to provide long-term protection from infection. But how long a vaccine protects from infection isn’t solely dependent on the vaccine.
The human body relies on long-living immune cells called T memory stem cells that guard against pathogens such as viruses and bacteria that the body has encountered before. Unfortunately, the body’s capacity to form T memory stem cells decreases with age. So no matter how well designed a vaccine is, older adults who don’t have enough of a response from T memory stem cells will not be protected long-term.
To address that issue, Li is developing an injectable biomaterial vaccine booster that will stimulate the formation of T memory stem cells. The booster is made up of engineered materials that release chemical messengers to stimulate the production of T memory stem cells. When combined with an eventual SARS-CoV-2 vaccine, they would prompt the body to produce immune cells primed to recognize and eliminate the virus over the long term.
“I consider it my responsibility as a scientist and an engineer to translate scientific findings into applications to help people and the community,” Li said. Read more.
Invariant natural killer T cells, or iNKT cells, are the special forces of the immune system. They’re extremely powerful and can immediately recognize and respond to many different intruders, from infections to cancer.
Yang is testing whether iNKT cells would make a particularly effective treatment for COVID-19 because they have the capacity to kill virally infected cells, offer protection from reinfection and rein in the excessive inflammation caused by a hyperactive immune response to the virus, which is thought to be a major cause of tissue damage and death in people with the disease.
One catch, though, is that iNKT cells are incredibly scarce: One drop of human blood contains around 10 million blood cells but only around 10 iNKT cells. That’s where Yang’s research comes in. Over the past several years, she has developed a method for generating large numbers of iNKT cells from blood-forming stem cells. While that work was aimed at creating a treatment for cancer, Yang’s lab has adapted its work over the past few months to test how effective stem cell–derived iNKT cells could be in fighting COVID-19. With her colleagues, she has been studying how the cells work in fighting the disease in models of SARS-CoV-2 infection that are grown from human kidney and lung cells.
“My lab has been developing an iNKT cell therapy for cancer for years,” Yang said. “This means a big part of the work is already done. We are repurposing a potential therapy that is very far along in development to treat COVID-19.” Read more.
“Our center is proud to join CIRM in supporting these researchers as they adapt projects that have spent years in development to meet the urgent need for therapies and vaccines for COVID-19,” said Dr. Owen Witte, founding director of the UCLA Broad Stem Cell Research Center. “This moment highlights the importance of funding scientific research so that we may have the foundational knowledge to meet new challenges as they arise.” Crooks, Gomperts, Seet and Yang are all members of the UCLA Jonsson Comprehensive Cancer Center. Damoiseaux is a professor of molecular and medical pharmacology and director of the Molecular Shared Resource Center at the California NanoSystems Institute at UCLA
Type 1 diabetes affects millions of people. It is a disease where beta islet cells in the pancreas are targeted by the body’s own immune system, destroying the ability to produce insulin. Without insulin, the body cannot break down sugars from the bloodstream that produce energy for organs and that can lead to many significant health problems including damage to the eyes, nerves, and kidneys. It is a life-long condition, most commonly triggered in children and teenagers. However, type 1 diabetes can manifest at any time. I have a family member who developed type 1 diabetes well into adulthood and had to dramatically alter his lifestyle to live with it.
Fortunately most people can now live with the disease. There was a time, dating back to ancient civilizations when getting type 1 diabetes meant early death. Thankfully, over the past hundred years, treatments have been developed to address the disease. The first widespread treatment developed in the 1920s was injections of animal insulin isolated from pancreatic islets in cattle and pigs. Over 50 years later the first genetically engineered human insulin was produced using E. coli bacteria, and variations of this are still used today. However, the disease is still very challenging to manage. My family member constantly monitors his blood sugar and gives himself injections of insulin to regulate his blood sugar.
A therapy that can self-regulate blood sugar levels for diabetes would greatly improve the lives of millions of people that deal with the disease. Pancreatic islet cells transplanted into patients can act as a natural rheostat to continually control blood sugar levels. Pancreas organ transplantation and islet cell transplantation are treatment options that will accomplish this. Both options are limited in supply and patients must be kept on life-long immunosuppression so the body does not reject the transplant. Pancreatic beta cells are also being developed from pluripotent stem cells (these are cells that have the ability to be turned into almost any other kind of cell in the body).
Now in an advance using pluripotent stem cells, Dr. Ronald Evans and his team at the Salk Institute have created cell clusters called organoids that mimic several properties of the pancreas. Previously, in work supported by CIRM, the team discovered that a genetic switch called ERR-gamma caused the cells to both produce insulin and be functional to respond to sugar levels in the bloodstream. They incorporated these findings to create their functional islet clusters that they term “human islet-like islet organoids” (HILOs). Knowing that the immune system is a major barrier for long term cell replacement therapy, Dr. Evans’ team engineered the HILOs, in work also funded by CIRM, to be resistant to immune cells by expressing the checkpoint protein PD-L1. PD-L1 is a major target for immunotherapies whose discovery led to a Nobel Prize in 2018. Expressing PD-L1 acts as an immune blocker.
When the PD-L1 engineered HILOs were transplanted into diabetic mice with functioning immune systems, they were able to sustain blood glucose control for time periods up to 50 days. The researchers also saw significantly less mobilization of immune cells after transplantation. The hope is that these engineered HILOs can eventually be developed as a long term therapy for type 1 diabetes patients without the need for lifelong immunosuppression.
In a press release, the Salk researchers acknowledge that more research needs to be done before this system can be advanced to clinical trials. For example, the transplanted organoids need to be tested in mice for longer periods of time to confirm that their effects are long-lasting. More work needs to be done to ensure they would be safe to use in humans, as well. However, the proof of concept has now been established to move forward with these efforts. Concludes Dr. Evan’s in the announcement, “We now have a product that could potentially be used in patients without requiring any kind of device.”
It’s not often you get a chance to hear some of the brightest minds around talk about their stem cell research and what it could mean for you, me and everyone else. That’s why we’re delighted to be bringing some of the sharpest tools in the stem cell shed together in one – virtual – place for our CIRM 2020 Grantee Meeting.
The event is Monday September 14th and Tuesday September 15th. It’s open to anyone who wants to attend and, of course, it’s all being held online so you can watch from the comfort of your own living room, or garden, or wherever you like. And, of course, it’s free.
Dr. Daniela Bota, UC Irvine
The list of speakers is a Who’s Who of researchers that CIRM has funded and who also happen to be among the leaders in the field. Not surprising as California is a global center for regenerative medicine. And you will of course be able to post questions for them to answer.
Dr. Deepak Srivastava, Gladstone Institutes
The key speakers include:
Larry Goldstein: the founder and director of the UCSD Stem Cell Program talking about Alzheimer’s research
Irv Weissman: Stanford University talking about anti-cancer therapies
Other topics include the latest stem cell approaches to COVID-19, spinal cord injury, blindness, Parkinson’s disease, immune disorders, spina bifida and other pediatric disorders.
You can choose one topic or come both days for all the sessions. To see the agenda for each day click here. Just one side note, this is still a work in progress so some of the sessions have not been finalized yet.
And when you are ready to register go to our Eventbrite page. It’s simple, it’s fast and it will guarantee you’ll be able to be part of this event.
It’s been a long time coming. Eighteen months to be precise. Which is a peculiarly long time for an Annual Report. The world is certainly a very different place today than when we started, and yet our core mission hasn’t changed at all, except to spring into action to make our own contribution to fighting the coronavirus.
This latest CIRM Annual Reportcovers 2019 through June 30, 2020. Why? Well, as you probably know we are running out of money and could be funding our last new awards by the end of this year. So, we wanted to produce as complete a picture of our achievements as we could – keeping in mind that we might not be around to produce a report next year.
It’s a pretty jam-packed report. It covers everything from the 14 new clinical trials we have funded this year, including three specifically focused on COVID-19. It looks at the extraordinary researchers that we fund and the progress they have made, and the billions of additional dollars our funding has helped leverage for California. But at the heart of it, and at the heart of everything we do, are the patients. They’re the reason we are here. They are the reason we do what we do.
There are stories of people like Byron Jenkins who almost died from multiple myeloma but is now back leading a full, active life with his family thanks to a CIRM-funded therapy with Poseida. There is Jordan Janz, a young man who once depended on taking 56 pills a day to keep his rare disease, cystinosis, under control but is now hoping a stem cell therapy developed by Dr. Stephanie Cherqui and her team at UC San Diego will make that something of the past.
These individuals are remarkable on so many levels, not the least because they were willing to be among the first people ever to try these therapies. They are pioneers in every sense of the word.
There is a lot of information in the report, charting the work we have done over the last 18 months. But it’s also a celebration of everyone who made it possible, and our way of saying thank you to the people of California who gave us this incredible honor and opportunity to do this work.
If someone told you they were working on lungs in a dish you might be forgiven for thinking that’s the worst idea for a new recipe you have ever heard of. But in the case of Dr. Evan Snyder and his team at Sanford Burnham Prebys Medical Discovery Institute it could be a recipe for a powerful new tool against COVID-19.
Earlier this month the CIRM Board approved almost $250,000 for Dr. Snyder and his team to use human induced pluripotent stem cells (hiPSCs), a type of stem cell that can be created by reprogramming skin or blood cells, to create any other cell in the body, including lung cells.
These cells will then be engineered to become 3D lung organoids or “mini lungs in a dish”. The importance of this is that these cells resemble human lungs in a way animal models do not. They have the same kinds of cells, structures and even blood vessels that lungs do.
These cells will then be infected with the coronavirus and then be used to test two drugs to see if those drugs are effective against the virus.
In a news release Dr. Snyder says these cells have some big advantages over animal models, the normal method for early stage testing of new therapies.
“Mini lungs will also help us answer why some people with COVID-19 fare worse than others. Because they are made from hiPSCs, which come from patients and retain most of the characteristics of those patients, we can make ‘patient-specific’ mini lungs. We can compare the drug responses of mini lungs created from Caucasian, African American, and Latino men and women, as well as patients with a reduced capacity to fight infection to make sure that therapies work effectively in all patients. If not, we can adjust the dose or drug regime to help make the treatment more effective.
“We can also use the mini lungs experimentally to evaluate the effects of environmental toxins that come from cigarette smoking or vaping to make sure the drugs are still effective; and emulate the microenvironmental conditions in the lungs of patients with co-morbidities such as diabetes, and heart or kidney disease.”
To date CIRM has funded 15 projects targeting COVID-19, including three that are in clinical trials.
Out of 100 couples in the US, around 12 or 13 will have trouble starting a family. In one third of those cases the problem is male infertility (one third is female infertility and the other third is a combination of factors). In the past treatment options for men were often limited. Now a new study out of the University of California San Diego (UCSD) could help lead to treatments to help these previously infertile men have children of their own.
The study, led by Dr. Miles Wilkinson of UCSD School of Medicine, targeted spermatogonial stem cells (SSCs), which are the cells that develop into sperm. In the past it was hard to isolate these SSCs from other cells in the testes. However, using a process called single cell RNA sequencing – which is like taking a photo of all the gene expression happening in one cell at a precise moment – the team were able to identify the SSCs.
In a news release Dr. Wilkinson, the senior author of the study, says this is a big advance on previous methods: “We think our approach — which is backed up by several techniques, including single-cell RNA-sequencing analysis — is a significant step toward bringing SSC therapy into the clinic.”
Identifying the SSCs was just the first step. Next the team wanted to find a way to be able to take those cells and grow and multiply them in the lab, an important step in having enough cells to be able to treat infertility.
So, they tested the cells in the lab and identified something called the AKT pathway, which controls cell division and survival. By blocking the AKT pathway they were able to keep the SSCs alive and growing for a month. Next they hope to build on the knowledge and expand the cells for even longer so they could be used in a clinical setting.
The hope is that this could ultimately lead to treatments for men whose bodies don’t produce sperm cells, or enough sperms cells to make them fertile. It could also help children going through cancer therapy which can destroy their ability to have children of their own later in life. By taking sperm cells and freezing them, they could later be grown and expanded in the lab and injected back into the testes to restore sperm production.
In late March the CIRM Board approved $5 million in emergency funding for COVID-19 research. The idea was to support great ideas from California’s researchers, some of which had already been tested for different conditions, and see if they could help in finding treatments or a vaccine for the coronavirus.
Less than a month later we were funding a clinical trial and two other projects, one that targeted a special kind of immune system cell that has the potential to fight the virus.
Researchers use stem cells to model the immune response to COVID-19
By Tiare Dunlap
Cities across the United States are opening back up, but we’re still a long way from making the COVID-19 pandemic history. To truly accomplish that, we need to have a vaccine that can stop the spread of infection.
But to develop an effective vaccine, we need to understand how the immune system responds to SARS-CoV-2, the virus that causes COVID-19.
Vaccines work by imitating infection. They expose a person’s immune system to a weakened version or component of the virus they are intended to protect against. This essentially prepares the immune system to fight the virus ahead of time, so that if a person is exposed to the real virus, their immune system can quickly recognize the enemy and fight the infection. Vaccines need to contain the right parts of the virus to provoke a strong immune response and create long-term protection.
Most of the vaccines in development for SARS CoV-2 are using part of the virus to provoke the immune system to produce proteins called antibodies that neutralize the virus. Another way a vaccine could create protection against the virus is by activating the T cells of the immune system.
T cells specifically “recognize” virus-infected cells, and these kinds of responses may be especially important for providing long-term protection against the virus. One challenge for researchers is that they have only had a few months to study how the immune system protects against SARS CoV-2, and in particular, which parts of the virus provoke the best T-cell responses.
For years, they have been perfecting an innovative technology that uses blood-forming stem cells — which can give rise to all types of blood and immune cells — to produce a rare and powerful subset of immune cells called type 1 dendritic cells. Type 1 dendritic cells play an essential role in the immune response by devouring foreign proteins, termed antigens, from virus-infected cells and then chopping them into fragments. Dendritic cells then use these protein fragments to trigger T cells to mount an immune response.
Using this technology, Crooks and Seet are working to pinpoint which specific parts of the SARS-CoV-2 virus provoke the strongest T-cell responses.
Building long-lasting immunity
“We know from a lot of research into other viral infections and also in cancer immunotherapy, that T-cell responses are really important for long-lasting immunity,” said Seet, an assistant professor of hematology-oncology at the David Geffen School of Medicine at UCLA. “And so this approach will allow us to better characterize the T-cell response to SARS-CoV-2 and focus vaccine and therapeutic development on those parts of the virus that induce strong T-cell immunity.”
Crooks’ and Seet’s project uses blood-forming stem cells taken from healthy donors and infected with a virus containing antigens from SARS-CoV-2. They then direct these stem cells to produce large numbers of type 1 dendritic cells using a new method developed by Seet and Suwen Li, a graduate student in Crooks’ lab. Both Seet and Li are graduates of the UCLA Broad Stem Cell Research Center’s training program.
“The dendritic cells we are able to make using this process are really good at chopping up viral antigens and eliciting strong immune responses from T cells,” said Crooks, a professor of pathology and laboratory medicine and of pediatrics at the medical school and co-director of the UCLA Broad Stem Cell Research Center.
When type 1 dendritic cells chop up viral antigens into fragments, they present these fragments on their cell surfaces to T cells. Our bodies produce millions and millions of T cells each day, each with its own unique antigen receptor, however only a few will have a receptor capable of recognizing a specific antigen from a virus.
When a T cell with the right receptor recognizes a viral antigen on a dendritic cell as foreign and dangerous, it sets off a chain of events that activates multiple parts of the immune system to attack cells infected with the virus. This includes clonal expansion, the process by which each responding T cell produces a large number of identical cells, called clones, which are all capable of recognizing the antigen.
“Most of those T cells will go off and fight the infection by killing cells infected with the virus,” said Seet, who, like Crooks, is also a member of the UCLA Jonsson Comprehensive Cancer Center. “However, a small subset of those cells become memory T cells — long-lived T cells that remain in the body for years and protect from future infection by rapidly generating a robust T-cell response if the virus returns. It’s immune memory.”
Producing extremely rare immune cells
This process has historically been particularly challenging to model in the lab, because type 1 dendritic cells are extremely rare — they make up less than 0.1% of cells found in the blood. Now, with this new stem cell technology, Crooks and Seet can produce large numbers of these dendritic cells from blood stem cells donated by healthy people, introduce them to parts of the virus, then see how T cells taken from the blood can respond in the lab. This process can be repeated over and over using cells taken from a wide range of healthy people.
“The benefit is we can do this very quickly without the need for an actual vaccine trial, so we can very rapidly figure out in the lab which parts of the virus induce the best T-cell responses across many individuals,” Seet said.
The resulting data could be used to inform the development of new vaccines for COVID-19 that improve T-cell responses. And the data about which viral antigens are most important to the T cells could also be used to monitor the effectiveness of existing vaccine candidates, and an individual’s immune status to the virus.
“There are dozens of vaccine candidates in development right now, with three or four of them already in clinical trials,” Seet said. “We all hope one or more will be effective at producing immediate and long-lasting immunity. But as there is so much we don’t know about this new virus, we’re still going to need to really dig in to understand how our immune systems can best protect us from infection.”
Supporting basic research into our body’s own processes that can inform new strategies to fight disease is central to the mission of the Broad Stem Cell Research Center.
“When we started developing this project some years ago, we had no idea it would be so useful for studying a viral infection, any viral infection,” Crooks said. “And it was only because we already had these tools in place that we could spring into action so fast.”