Surprise findings about bone marrow transplants could lead to more effective stem cell therapies

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Bone marrow transplant: Photo courtesy FierceBiotech

Some medical therapies have been around for so long that we naturally assume we understand how they work. That’s not always the case. Take aspirin for example. It’s been used for more than 4,000 years to treat pain and inflammation but it was only in the 1970’s that we really learned how it works.

The same is now true for bone marrow transplants. Thanks to some skilled research at the Fred Hutchinson Cancer Research Center in Seattle.

Bone marrow transplants have been used for decades to help treat deadly blood cancers such as leukemia and lymphoma. The first successful bone marrow transplant was in the late 1950’s, involving identical twins, one of whom had leukemia. Because the twins shared the same genetic make-up the transplant avoided potentially fatal problems like graft-vs-host-disease, where the transplanted cells attack the person getting them. It wasn’t until the 1970’s that doctors were able to perform transplants involving people who were not related or who did not share the same genetic make-up.

In a bone marrow or blood stem cell transplant, doctors use radiation or chemotherapy to destroy the bone marrow in a patient with, say, leukemia. Then cancer-free donor blood stem cells are transplanted into the patient to help create a new blood system, and rebuild their immune system.

Surprise findings

In the study, published in the journal Science Translational Medicine, the researchers were able to isolate a specific kind of stem cell that helps repair and rebuild the blood and immune system.

The team found that a small subset of blood stem cells, characterized by having one of three different kinds of protein on their surface – CD34 positive, CD45RA negative and CD90 positive – did all the work.

In a news release Dr. Hans-Peter Kiem, a senior author on the study, says some of their initial assumptions about how bone marrow transplants work were wrong:

“These findings came as a surprise; we had thought that there were multiple types of blood stem cells that take on different roles in rebuilding a blood and immune system. This population does it all.”

Tracking the cells

The team performed bone-marrow transplants on monkeys and then followed those animals over the next seven years, observing what happened as the donor cells grew and multiplied.

They tracked hundreds of thousands of cells in the blood and found that, even though the cells with those three proteins on the surface made up just five percent of the total blood supply, they were responsible for rebuilding the entire blood and immune system.

Study co-author Dr. Jennifer Adair said they saw evidence of this rebuilding within 10 days of the transplant:

“Our ability to track individual blood cells that developed after transplant was critical to demonstrating that these really are stem cells.”

Hope for the future

It’s an important finding because it could help researchers develop new ways of delivering bone marrow transplants that are both safer and more effective. Every year some 3,000 people die because they cannot find a matching donor. Knowing which stem cells are specifically responsible for an effective transplant could help researchers come up with ways to get around that problem.

Although this work was done in monkeys, the scientists say humans have similar kinds of stem cells that appear to act in the same way. Proving that’s the case will obviously be the next step in this research.

 

Confusing cancer to kill it

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Thomas Kipps, MD, PhD: Photo courtesy UC San Diego

Confusion is not a state of mind that we usually seek out. Being bewildered is bad enough when it happens naturally, so why would anyone actively pursue it? But now some researchers are doing just that, using confusion to not just block a deadly blood cancer, but to kill it.

Today the CIRM Board approved an investment of $18.29 million to Dr. Thomas Kipps and his team at UC San Diego to use a one-two combination approach that we hope will kill Chronic Lymphocytic Leukemia (CLL).

This approach combines two therapies, cirmtuzumab (a monoclonal antibody developed with CIRM funding, hence the name) and Ibrutinib, a drug that has already been approved by the US Food and Drug Administration (FDA) for patients with CLL.

As Dr. Maria Millan, our interim President and CEO, said in a news release, the need for a new treatment is great.

“Every year around 20,000 Americans are diagnosed with CLL. For those who have run out of treatment options, the only alternative is a bone marrow transplant. Since CLL afflicts individuals in their 70’s who often have additional medical problems, bone marrow transplantation carries a higher risk of life threatening complications. The combination approach of  cirmtuzumab and Ibrutinib seeks to offer a less invasive and more effective alternative for these patients.”

Ibrutinib blocks signaling pathways that leukemia cells need to survive. Disrupting these pathways confuses the leukemia cell, leading to its death. But even with this approach there are cancer stem cells that are able to evade Ibrutinib. These lie dormant during the therapy but come to life later, creating more leukemia cells and causing the cancer to spread and the patient to relapse. That’s where cirmtuzumab comes in. It works by blocking a protein on the surface of the cancer stem cells that the cancer needs to spread.

It’s hoped this one-two punch combination will kill all the cancer cells, increasing the number of patients who go into complete remission and improve their long-term cancer control.

In an interview with OncLive, a website focused on cancer professionals, Tom Kipps said Ibrutinib has another advantage for patients:

“The patients are responding well to treatment. It doesn’t seem like you have to worry about stopping therapy, because you’re not accumulating a lot of toxicity as you would with chemotherapy. If you administered chemotherapy on and on for months and months and years and years, chances are the patient wouldn’t tolerate that very well.”

The CIRM Board also approved $5 million for Angiocrine Bioscience Inc. to carry out a Phase 1 clinical trial testing a new way of using cord blood to help people battling deadly blood disorders.

The standard approach for this kind of problem is a bone marrow transplant from a matched donor, usually a family member. But many patients don’t have a potential donor and so they often have to rely on a cord blood transplant as an alternative, to help rebuild and repair their blood and immune systems. However, too often a single cord blood donation does not have enough cells to treat an adult patient.

Angiocrine has developed a product that could help get around that problem. AB-110 is made up of cord blood-derived hematopoietic stem cells (these give rise to all the other types of blood cell) and genetically engineered endothelial cells – the kind of cell that lines the insides of blood vessels.

This combination enables the researchers to take cord blood cells and greatly expand them in number. Expanding the number of cells could also expand the number of patients who could get these potentially life-saving cord blood transplants.

These two new projects now bring the number of clinical trials funded by CIRM to 35. You can read about the other 33 here.

 

 

 

New stem cell approach targeting deadly blood cancers

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Every four minutes someone in the US is diagnosed with a blood cancer. It might be lymphoma or leukemia, myeloma or myelodysplastic syndromes (MDS). While we have made great strides in treating some of these over the years, we still have a long way to go. Need proof? Well, every nine minutes someone in the US dies from a blood cancer.

Because of that need, the CIRM Board last week approved $3.5 million to help fund the search for a more effective, more efficient way to treat people suffering from blood cancer.

The Board funded a program by Angiocrine Biosciences, a San Diego-based company that is developing a new method for transplanting cord blood into patients.

Now cord blood transplants have been around for decades and they can be very effective. But they can also cause serious, even life-threatening complications. And they have limitations. For example some cord blood units are small and don’t have as many stem cells as the doctors would like. As a result, patients may need to spend longer in the hospital recovering from the procedure, putting them at increased risk of viral infections or pneumonia. Alternatively, doctors could use more than one cord blood unit for each transplant and while that seems to be an effective alternative, some studies suggest it can also carry an increased risk for serious complications such as Graft-versus-host disease (GVHD) where the newly transplanted cells attack the patient’s body.

To get around these issues, Angiocrine is developing a product called AB-110. This takes stem cells from cord blood, uses a specialized manufacturing facility to expand their numbers and then mixes them with genetically modified endothelial cells, the kind of cell that forms the lining of blood vessels.

It’s hoped that AB-110 will reduce the complications and increase the chances the transplanted cells will successfully engraft, meaning they start growing and creating new, healthy, blood cells.

In a news release CIRM’s President and CEO, C. Randal Mills, PhD, says this program fits in perfectly with our mission of accelerating stem cell treatments to patients with unmet medical needs:

“This project aims to do precisely that, speeding up the body’s ability to create new white blood cells and platelets – both essential qualities when treating deadly diseases like leukemia and lymphoma. Under CIRM 2.0, we are trying to create a pipeline of products that move out of the lab and into clinical trials in people, and we’re hopeful this program will demonstrate it’s potential and get approval from the Food and Drug Administration (FDA) to begin a clinical trial.”

Everyone at Angiocrine and CIRM will work as hard as we can to move this research toward a clinical trial as fast as we can. But in the meantime there are tens of thousands of critically ill people in desperate need of a life-saving transplant.

One way of helping those in need is for new parents to donate their child’s umbilical cord blood to the state’s umbilical cord blood collection program. This is a safe procedure that doesn’t harm the baby but could save someone’s life.

The cord blood program is housed at the UC Davis Institute for Regenerative Cures – a facility CIRM helped build and where we fund many great projects. This program is particularly important because it collects and stores cord blood units that reflect the state’s diverse communities, and that are available to all those in need of a transplant.

The bank also is a rich source of cord blood units for research, particularly for stem cell research, which will hopefully lead to even more effective therapies in the future.