Paving the Way

When someone scores a goal in soccer all the attention is lavished on them. Fans chant their name, their teammates pile on top in celebration, their agent starts calling sponsors asking for more money. But there’s often someone else deserving of praise too, that’s the player who provided the assist to make the goal possible in the first place. With that analogy in mind, CIRM just provided a very big assist for a very big goal.

The goal was scored by Jasper Therapeutics. They have just announced data from their Phase 1 clinical trial treating people with Myelodysplastic syndromes (MDS). This is a group of disorders in which immature blood-forming cells in the bone marrow become abnormal and leads to low numbers of normal blood cells, especially red blood cells. In about one in three patients, MDS can progress to acute myeloid leukemia (AML), a rapidly progressing cancer of the bone marrow cells.

The most effective way to treat, and even cure, MDS/AML is with a blood stem cell transplant, but this is often difficult for older patients, because it involves the use of toxic chemotherapy to destroy their existing bone marrow blood stem cells, to make room for the new, healthy ones. Even with a transplant there is often a high rate of relapse, because it’s hard for chemotherapy to kill all the cancer cells.

Jasper has developed a therapy, JSP191, which is a monoclonal antibody, to address this issue. JSP191 helps supplement the current treatment regimen by clearing all the remaining abnormal cells from the bone marrow and preventing relapse. In addition it also means the patients gets smaller doses of chemotherapy with lower levels of toxicity. In this Phase 1 study six patients, between the ages of 65 and 74, were given JSP191 – in combination with low-dose radiation and chemotherapy – prior to getting their transplant. The patients were followed-up at 90 days and five of the six had no detectable levels of MDS/AML, and the sixth patient had reduced levels. None of the patients experienced serious side effects.

Clearly that’s really encouraging news. And while CIRM didn’t fund this clinical trial, it wouldn’t have happened without us paving the way for this research. That’s where the notion of the assist comes in.

CIRM support led to the development of the JSP191 technology at Stanford. Our CIRM funds were used in the preclinical studies that form the scientific basis for using JSP191 in an MDS/AML setting.

Not only that, but this same technique was also used by Stanford’s Dr. Judy Shizuru in a clinical trial for children born with a form of severe combined immunodeficiency, a rare but fatal immune disorder in children. A clinical trial that CIRM funded.

It’s a reminder that therapies developed with one condition in mind can often be adapted to help treat other similar conditions. Jasper is doing just that. It hopes to start clinical trials this year using JSP191 for people getting blood stem cell transplants for severe autoimmune disease, sickle cell disease and Fanconi anemia.

Study shows reduction in brain injury after stroke patients were treated with their own stem cells

Illustration showing the mechanism of an ischemic stroke. In an ischemic stroke, blood supply to part of the brain is decreased, leading to dysfunction of that area of the brain. Here, a blood clot is the reason for restricted blood flow.

Stroke is the third leading cause of death and serious long-term disability and affects nearly 800,000 Americans a year, with someone in the U.S. suffering a stroke every 40 seconds. Roughly 87% of all strokes are ischemic strokes, meaning that a clot blocks blood flow to the brain. Unfortunately 90% of those who suffer an ischemic stroke also end up suffering from weakness or paralysis to one side of the body.

A study conducted by Muhammad Haque, Ph.D. and Sean Savitz, M.D. at The University of Texas Health Science Center at Houston (UTHealth) found that treating patients with stem cells from their own bone marrow could lead to a reduction in brain injury after a stroke caused by a blood clot.

For this study, there were 37 patients from ages 18 to 80. While all received the standard stroke treatment and rehabilitation follow-up, 17 patients whose strokes were the most severe received a bone marrow stem cell therapy. To measure any improvement, the UTHealth team used 3D brain imaging of the patients obtained from MRI scans. They used these images to compare changes in white matter of those treated with their own bone marrow stem cells to those who were not treated.

White matter is a specific type of tissue in the brain that is critical for motor function because it is responsible for carrying movement-related information to the spinal cord.

Three months after the stroke, the MRI scans of each patient showed the expected decrease after a stroke. However, scans taken 12 months after the stroke occurred showed an improvement on average in the 17 patients who received bone marrow cell therapy.

In a press release from UTHealth, Dr. Haque elaborates on what these results could mean for developing treamtents for stroke patients.

“We envision that future clinical trials might be directed toward identifying white matter protection or repair as an important mechanistic target of efficacy studies and potency assays for bone marrow cell therapies.”

The full results to this study were published in STEM CELLS Translational Medicine.

Surviving with Joy

Dr. Tippi MacKenzie (left) of UCSF Benioff Children’s Hospital San Francisco, visits with newborn Elianna and parents Nichelle Obar and Chris Constantino. Photo by Noah Berger

Alpha thalassemia major is, by any stretch of the imagination, a dreadful, heart breaker of a disease. It’s caused by four missing or mutated genes and it almost always leads to a fetus dying before delivery or shortly after birth. Treatments are limited and in the past many parents were told that all they can do is prepare for the worst.

Now, however, there is new hope with new approaches, including one supported by CIRM, helping keep these children alive and giving them a chance at a normal life.

Thalassemias are a group of blood disorders that affect the way the body makes hemoglobin, which helps in carrying oxygen throughout the body. In alpha thalassemia major it’s the lack of alpha globin, a key part of hemoglobin, that causes the problem. Current treatment requires in blood transfusions to the fetus while it is still in the womb, and monthly blood transfusions for life after delivery, or a bone marrow transplant if a suitable donor is identified.

A clinical trial run by University of California San Francisco’s Dr. Tippi MacKenzie – funded by CIRM – is using a slightly different approach. The team takes stem cells from the mother’s bone marrow and then infuses them into the fetus. If accepted by the baby’s bone marrow, these stem cells can then mature into healthy blood cells. The hope is that one day this method will enable children to be born with a healthy blood supply and not need regular transfusions.

Treating these babies, saving their lives, is the focus of a short film from UCSF called “Surviving with Joy”. It’s a testament to the power of medicine, and the courage and resilience of parents who never stopped looking for a way to help their child.

Tissues are optional but advised.

CIRM funded trial for sickle cell disease gives patient a chance for a better future

Evie Junior is participating in a CIRM funded clinical trial for sickle cell disease that uses a stem cell gene therapy approach. Image credit: UCLA Broad Stem Cell Research Center

For Evie Junior, personal health and fitness have always been a top priority. During his childhood, he was active and played football, basketball, and baseball in the Bronx, New York. One would never guess that after playing these sports, some nights he experienced pain crises so severe that he was unable to walk. One would also be shocked to hear that he had to have his gallbladder and spleen removed as a child as well.

The health issues that Evie has faced all of his life are related to his diagnosis of sickle cell disease (SCD), a genetic, blood related disorder. SCD causes blood stem cells in the bone marrow, which make blood cells, to produce hard, “sickle” shaped red blood cells. These “sickle” shaped blood cells die early, causing there to be a lack of red blood cells to carry oxygen throughout the body. Due to their “sickle” shape, these cells also get stuck in blood vessels and block blood flow, resulting in excruciating bouts of pain that come on with no warning and can leave patients hospitalized for days.

SCD affects 100,000 people in the United States, the majority of whom are from the Black and Latinx communities, and millions more people around the world,. It can ultimately lead to strokes, organ damage, and early death.

Growing up with SCD inspired Evie to become an emergency medical technician, where he would be able to help patients treat their pain en route to the hospital, in much the same way he has managed his own pain crises for his whole life. Unfortunately as time passed, Evie’s pain crises became harder and harder to manage.

Then in July 2019, Evie decided to enroll in a CIRM funded clinical trial for a stem cell gene therapy to treat SCD. The therapy, developed by Dr. Don Kohn at UCLA, is intended to correct the genetic mutation in a patient’s blood stem cells to allow them to produce healthy red blood cells. Dr. Kohn has already applied the same concept to successfully treat several genetic immune system deficiencies in two other CIRM funded trials, including a cure for a form of Severe Combined Immunodeficiency, also known as bubble baby disease, as well as X-Linked Chronic Granulomatous Disease.

After some delays related to the coronavirus pandemic, Evie finally received an infusion of his own blood stem cells that had been genetically modified to overcome the mutation that causes SCD in July 2020.

Although the results are still very preliminary, so far they look very promising. Three months after his treatment, blood tests indicated that 70% of Evie’s blood stem cells had the new corrected gene. The UCLA team estimates that a 20% correction would be enough to prevent future sickle cell complications. What is also encouraging is that Evie hasn’t had a pain crisis since undergoing the treatment.

In a press release from UCLA, Dr. Kohn discusses that he is cautiously optimistic about these results.

“It’s too early to declare victory, but it’s looking quite promising at this point. Once we’re at six months to a year, if it looks like it does now, I’ll feel very comfortable that he’s likely to have a permanent benefit.”

In the same press release, Evie talks about what a cure would mean for his future and his life going forward.

“I want to be present in my kids’ lives, so I’ve always said I’m not going to have kids unless I can get this cured. But if this works, it means I could start a family one day.”

You can learn more about Evie’s story and the remarkable CIRM funded work at UCLA by watching the video below.

CIRM funded trial for LAD-I announces positive results

Leukocyte Adhesion Deficiency-I (LAD-I) is a rare pediatric disease caused by a mutation in a specific gene that causes low levels of a protein called CD18. Due to low levels of CD18, the adhesion of immune cells is affected, which negatively impacts the body’s ability to combat infections.

Rocket Pharmaceuticals has announced positive results from a CIRM-funded clinical trial that is testing a treatment that uses a gene therapy called RP-L201. The therapy uses a patient’s own blood stem cells and inserts a functional version of the gene.  These modified stem cells are then reintroduced back into the patient. The goal is to establish functional immune cells, enabling the body to combat infections.  

The two patients enrolled in the CIRM funded trial have shown restored levels of CD18. Previous studies have indicated that an increase in CD18 to 4-10% is associated with survival into adulthood. The two patients demonstrated CD18 levels that exceeded this threshold.

In a news release, Jonathan Schwartz, M.D. Chief Medical Officer and Senior Vice President of Rocket, elaborated on these positive results.

“Patients with LAD-I have markedly diminished expression of the integrin CD18 and suffer from life-threatening bacterial and fungal infections. Natural history studies indicate that an increase in CD18 expression to 4-10% is associated with survival into adulthood. The two patients enrolled in our Phase 1 trial demonstrated restored CD18 expression substantially exceeding this threshold. In addition, we continue to observe a durable treatment effect in the patient followed through one year, with improvement of multiple disease-related skin lesions after therapy and no further requirements for prophylactic anti-infectives.”

Cord blood transplants help children fighting deadly diseases

Dr. Paul Szabolcs: Photo courtesy of UPMC

A simple blood stem cell transplant is showing tremendous promise in treating a wide range of metabolic, blood and immune disorders such as thalassemia and some leukodystrophies.

These are considered rare diseases – meaning there are fewer than 200,000 people with them in the US – so there is often little funding available to develop new therapies to help people suffering from them. So, researchers at UPMC Children’s Hospital of Pittsburgh set out to develop a therapy that could help several different disorders without having to craft individual approaches for each condition.

The team used blood stem cells from donated umbilical cords and placentas. In a news article, study senior author Dr. Paul Szabolcs, said they then used a combination of chemotherapy and immunotherapy to prepare the patients for the transplant and increase the chance of success.

“We approached the topic with the mindset to design a regimen that carefully balances low-intensity chemo (bringing safety) with sufficiently effective immunotherapy to blast away the patients’ immune system, therefore preventing rejection. Rejection has been a common failure when other centers explored the reduced-intensity conditioning (RIC) approach with cord blood. We are the first to prove the RIC is able to give reliable results in long-term engraftment.”

Szabolcs says another advantage to their approach was that it meant there didn’t need to be a perfect immune system match of donor and recipient.

“That’s huge for ethnic minorities. The probability of a perfect match is very low, but with a cord blood graft, we have a chance to overcome this discrepancy over the course of a couple months and then taper immunosuppressants away.”

Altogether 44 children were treated this way. After undergoing the preparation, they had the blood stem cells transfused into them and, once those cells had integrated into the body they got a second, smaller, transfusion a few weeks later to help kick start their immune system.

Most of the complications from the infusions were mild, and while around 5 percent of children died from viral infection due to the immune suppression this was much lower than in earlier studies. Another encouraging sign was that none of the children suffered severe Graft vs Host disease which can be fatal.

Thirty of the children in the trial suffered from metabolic disorders, meaning their bodies were unable to remove dangerous toxins, and this led to developmental delays in their brains. One year after the treatment all 30 children had normal enzyme levels and their neurological decline had stopped. Some of the children even showed improvements and gained new skills.

Most of the children with metabolic disorders had leukodystrophies. These are usually fatal within a few years of diagnosis. Even with a cord blood transplant the three-year survival rate is only 60 percent. In this trial more than 90 percent of children with leukodystrophies were alive after three years.

Dr. Szabolcs says this approach has a lot of advantages over existing approaches, including cost.

“There has been a lot of emphasis placed on cool new technologies that might address these diseases, but — even if they prove effective — those aren’t available to most centers. The regimen we developed is more robust, readily applicable and will remain significantly less expensive.”

The study was published in the journal Blood Advances.

Scientists Engineer Stem Cells to Fight HIV

Image of the virus that causes AIDS – courtesy NIH

If that headline seems familiar it should. It came from an article in MIT Technology Review back in 2009. There have been many other headlines since then, all on the same subject, and yet here we are, in 2020, and still no cure for HIV/AIDS. So what’s the problem, what’s holding us back?

First, the virus is incredibly tough and wily. It is constantly mutating so trying to target it is like playing a game of ‘whack a mole’. Secondly not only can the virus evade our immune system, it actually hijacks it and uses it to help spread itself throughout the body. Even new generations of anti-HIV medications, which are effective at controlling the virus, can’t eradicate it. But now researchers are using new tools to try and overcome those obstacles and tame the virus once and for all.

Dr. Scott Kitchen: Photo David Geffen School of Medicine, UCLA

UCLA researchers Scott Kitchen and Irvin Chen have been awarded $13.65 million by the National Institutes of Health (NIH) to see if they can use the patient’s own immune system to fight back against HIV.

Dr. Irvin Chen: Photo UCLA

Dr. Kitchen and Dr. Chen take the patient’s own blood-forming stem cells and then, in the lab, they genetically engineer them to carry proteins called chimeric antigen receptors or CARs. Once these blood cells are transplanted back into the body, they combine with the patient’s own immune system T cells (CAR T). These T cells now have a newly enhanced ability to target and destroy HIV.

That’s the theory anyway. Lots of research in the lab shows it can work. For example, the UCLA team recently showed that these engineered CAR T cells not only destroyed HIV-infected cells but also lived for more than two years. Now the team at UCLA want to take the lessons learned in the lab and apply them to people.

In a news release Dr. Kitchen says the NIH grant will give them a terrific opportunity to do that: “The overarching goal of our proposed studies is to identify a new gene therapy strategy to safely and effectively modify a patient’s own stem cells to resist HIV infection and simultaneously enhance their ability to recognize and destroy infected cells in the body in hopes of curing HIV infection. It is a huge boost to our efforts at UCLA and elsewhere to find a creative strategy to defeat HIV.”

By the way, CIRM helped get this work off the ground with an early-stage grant. That enabled Dr. Kitchen and his team to get the data they needed to be able to apply to the NIH for this funding. It’s a great example of how we can kick-start projects that no one else is funding. You can read a blog about that early stage research here.

CIRM has already funded three clinical trials targeting HIV/AIDS. Two of these are still active; Dr. Mehrdad Abedi at UC Davis and Dr. John Zaia at City of Hope.

Novel clinical trial for COVID-19 using immune cells

This scanning electron microscope image shows SARS-CoV-2 (yellow)—also known as 2019-nCoV, the virus that causes COVID-19—isolated from a patient in the U.S., emerging from the surface of cells (blue/pink) cultured in the lab.
Image Credit: National Institute of Allergy and Infectious DiseasesRocky Mountain Laboratories

During this global pandemic, many scientists are pursuing various avenues for potential treatments of COVID-19.  The Infectious Disease Research Institute (IDRI), in collaboration with Celularity Inc., will conduct a clinical trial with 100 patients using an immunotherapy for treatment of COVID-19.

The treatment will involve administering specialized immune cells called Natural Killer (NK) cells, which are a type of white blood cell that are a vital part of the immune system. Previously, these cells have been administered in early safety studies to treat patients with blood cancers. NK cells play an important role in fighting off viral infections. In initial patients with severe cases of COVID-19, low NK cell counts were observed.

The NK cells used in this study are derived from blood stem cells obtained from the placenta. They will be administered to patients diagnosed with a COVID-19 infection causing pneumonia.

In a press release, IDRI’s CEO Corey Casper talks in more detail about how the NK cells could help treat patients with COVID-19.

“The hypothesis is that administering NK cells to patients with moderate to severe COVID-19 will allow the immune cells find the sites of active viral infection, kill the virus, and induce a robust immune response that will help heal the damage and control the infection.”

In the same press release, Corey Casper also mentions the other applications this treatment could have.

“Beyond its promise as a critically needed treatment for COVID-19, the biology of NK cells indicates a possibility that this immunotherapy could be used as an off-the-shelf treatment for future pandemic infections.”

Breakthrough image could lead to better therapies

Image of a blood stem cell in its natural environment: Photo courtesy UC Merced

When it comes to using stem cells for therapy you don’t just need to understand what kinds of cell to use, you also need to understand the environment that is best for them. Trying to get stem cells to grow in the wrong environment would be like trying to breed sheep in a pond. It won’t end well.

But for years scientists struggled to understand how to create the right environment, or niche, for these cells. The niche provides a very specific micro-environment for stem cells, protecting them and enabling them to self-renew over long periods of time, helping repair damaged tissues and organs in the body.

But different stem cells need different niches, and those involve both physical and chemical properties, and getting that mixture right has been challenging. That in turn has slowed down our ability to use those cells to develop new therapies.

UC Merced’s Joel Spencer in the lab: Photo courtesy UC Merced

Now UC Merced’s Professor Joel Spencer and his team have developed a way of capturing an image of hematopoietic or blood stem cells (HSCs), inside their niche in the bone marrow. In an article on UC Merced News, he says this could be a big step forward.

“Everyone knew black holes existed, but it took until last year to directly capture an image of one due to the complexity of their environment. It’s analogous with stem cells in the bone marrow. Until now, our understanding of HSCs has been limited by the inability to directly visualize them in their native environment.

“This work brings an advancement that will open doors to understanding how these cells work which may lead to better therapeutics for hematologic disorders including cancer.”

In the past, studying HSCs involved transplanting them into a mouse or other animal that had undergone radiation to kill off its own bone marrow cells. It enabled researchers to track the HSCs but clearly the new environment was very different than the original, natural one. So, Spencer and his team developed new microscopes and imaging techniques to study cells and tissues in their natural environment.  

In the study, published in the journal Nature, Spencer says all this is only possible because of recent technological breakthroughs.

“My lab is seeking to answer biological questions that were impossible until the advancements in technology we have seen in the past couple decades. You need to be able to peer inside an organ, inside a live animal and see what’s happening as it happens.”

Being able to see how these cells behave in their natural environment may help researchers learn how to recreate that environment in the lab, and help them develop new and more effective ways of using those cells to repair damaged tissues and organs.

Researchers create a better way to grow blood stem cells

UCLA’s Dr. Hanna Mikkola and Vincenzo Calvanese, lead scientists on the study. Photo courtesy UCLA

Blood stem cells are a vital part of us. They create all the other kinds of blood cells in our body and are used in bone marrow transplants to help people battling leukemia or other blood cancers. The problem is growing these blood stem cells outside the body has always proved challenging. Up till now.

Researchers at UCLA, with CIRM funding, have identified a protein that seems to play a key role in helping blood stem cells renew themselves in the lab. Why is this important? Because being able to create a big supply of these cells could help researchers develop new approaches to treating a wide array of life-threatening diseases.

One of the most important elements that a stem cell has is its ability to self-renew itself over long periods of time. The problem with blood stem cells has been that when they are removed from the body they quickly lose their ability to self-renew and die off.

To discover why this is the case the team at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA analyzed blood stem cells to see which genes turn on and off as those cells turn into other kinds of blood cells – red, white and platelets. They identified one gene, called MLLT3, which seemed to play a key role in helping blood stem cells self-renew.

To test this finding, the researchers took blood stem cells and, in the lab, inserted copies of the MLLT3 gene into them. The modified cells were then able to self-renew at least 12 times; a number far greater than in the past.

Dr. Hanna Mikkola, a senior author of the study says this finding could help advance the field:

“If we think about the amount of blood stem cells needed to treat a patient, that’s a significant number. But we’re not just focusing on quantity; we also need to ensure that the lab-created blood stem cells can continue to function properly by making all blood cell types when transplanted.”

Happily, that seemed to be the case. When they subjected the MLLT3-enhanced blood stem cells to further analysis they found that they appeared to self-renew at a safe rate and didn’t multiply too much or mutate in ways that could lead to leukemia or other blood cancers.

The next steps are to find more efficient and effective ways of keeping the MLLT3 gene active in blood stem cells, so they can develop ways of using this finding in a clinical setting with patients.

Their findings are published in the journal Nature.