Stem cell progress and promise in fighting leukemia

Computer illustration of a cancerous white blood cell in leukemia.

There is nothing you can do to prevent or reduce your risk of leukemia. That’s not a very reassuring statement considering that this year alone almost 62,000 Americans will be diagnosed with leukemia; almost 23,000 will die from the disease. That’s why CIRM is funding four clinical trials targeting leukemia, hoping to develop new approaches to treat, and even cure it.

That’s also why our next special Facebook Live “Ask the Stem Cell Team” event is focused on this issue. Join us on Thursday, August 29th from 1pm to 2pm PDT to hear a discussion about the progress in, and promise of, stem cell research for leukemia.

We have two great panelists joining us:

Dr. Crystal Mackall, has many titles including serving as the Founding Director of the Stanford Center for Cancer Cell Therapy.  She is using an innovative approach called a Chimeric Antigen Receptor (CAR) T Cell Therapy. This works by isolating a patient’s own T cells (a type of immune cell) and then genetically engineering them to recognize a protein on the surface of cancer cells, triggering their destruction. This is now being tested in a clinical trial funded by CIRM.

Natasha Fooman. To describe Natasha as a patient advocate would not do justice to her experience and expertise in fighting blood cancer and advocating on behalf of those battling the disease. For her work she has twice been named “Woman of the Year” by the Leukemia and Lymphoma Society. In 2011 she was diagnosed with a form of lymphoma that was affecting her brain. Over the years, she would battle lymphoma three times and undergo chemotherapy, radiation and eventually a bone marrow transplant. Today she is cancer free and is a key part of a CIRM team fighting blood cancer.

We hope you’ll join us to learn about the progress being made using stem cells to combat blood cancers, the challenges ahead but also the promising signs that we are advancing the field.

We also hope you’ll take an active role by posting questions on Facebook during the event, or sending us questions ahead of time to info@cirm.ca.gov. We will do our best to address as many as we can.

Here’s the link to the event, feel free to share this with anyone you think might be interested in joining us for Facebook Live “Ask the Stem Cell Team about Leukemia”

Seeing is believing: A new tool to help us learn about stem cells.

Cave paintings from Libya: evidence humans communicated through visual images long before they created text

There’s a large body of research that shows that many people learn better through visuals. Studies show that much of the sensory cortex in our brain is devoted to vision so our brains use images rather than text to make sense of things.

That’s why we think it just makes sense to use visuals, as much as we can, when trying to help people understand advances in stem cell research. That’s precisely what our colleagues at U.C. San Diego are doing with a new show called “Stem Cell Science with Alysson Muotri”.

Alysson is a CIRM grantee who is doing some exciting work in developing a deeper understanding of autism. He’s also a really good communicator who can distill complex ideas down into easy to understand language.

The show features Alysson, plus other scientists at UCSD who are working hard to move the most promising research out of the lab and into clinical trials in people. Appropriately the first show in the series follows that path, exploring how discoveries made using tiny Zebrafish could hopefully lead to stem cell therapies targeting blood diseases like leukemia. This first show also highlights the important role that CIRM’s Alpha Stem Cell Clinic Network will play in bringing those therapies to patients.

You can find a sneak preview of the show on YouTube. The series proper will be broadcast on California local cable via the UCTV channel at 8:00 pm on Thursdays starting July 8, 2019. 

And if you really have a lot of time on your hands you can check out the more than 300 videos CIRM has produced on every aspect of stem cell research from cures for fatal diseases to questions to ask before taking part in a clinical trial.

CIRM-funded clinical trial shows encouraging results for patients with chronic lymphocytic leukemia & mantle cell lymphoma

Illustration courtesy of Oncternal Therapeutics

I often joke that my job here at CIRM is to be the official translator for the stem cell agency. I have to translate complex science into everyday English that people without a science background – that includes me – can understand.

Think I’m joking? Try making sense of this.

See what I mean. If you are a scientist this is not only perfectly clear, it’s also quite exciting. But for the rest of us……..

Actually, it is really quite exciting news. It’s about a CIRM-funded clinical trial being run by Oncternal Therapeutics to treat people with chronic lymphocytic leukemia (CLL), a kind of cancer where our body makes too many white blood cells. The study is using a combination therapy of Cirmtuzumab (a monoclonal antibody named after us because we helped fund its development) and ibrutinib, a conventional therapy used to treat cancers like CLL.

Cirmtuzumab recognizes and then attaches itself to a protein on the surface of cancer stem cells that the cancer needs to survive and spread. This attachment disables the protein (called ROR1) which slows the growth of the leukemia and makes it more vulnerable to anti-cancer drugs like ibrutinib.

In this Phase 1/2 clinical trial 12 patients were given the combination therapy for 24 weeks or more, making them eligible to determine how effective, or ineffective, the therapy is:

  • 11 of the 12 patients had either a partial response – meaning a reduction in the amount of detectable cancer – or a complete response to the treatment – meaning no detectable cancer.
  • None of the patients saw their cancer spread or grow
  • Three of the patients completed a year of treatment and they all showed signs of a complete response including no enlarged lymph nodes and white blood cell counts in the normal range.  

The combination therapy is also being used to treat people with Mantle Cell Lymphoma (MCL), a rare but fast-growing form of blood cancer. The results from this group, while preliminary, are also encouraging. One patient, who had experienced a relapse following a bone marrow transplant, experienced a complete response after three months of cirmtuzumab and ibrutinib.  

The data on the clinical trial was presented at a poster session (that’s the poster at the top of this blog) at the annual meeting of the American Society of Clinical Oncology.

In a news release Dr. James Breitmeyer, the President & CEO of Oncternal, said the results are very encouraging:  

“These data presented today, taken together with an earlier Phase 1 study of cirmtuzumab as a monotherapy in relapsed/refractory CLL, give us increased confidence in the potential for cirmtuzumab as a treatment for patients with ROR1-expressing lymphoid malignancies, particularly in combination with ibrutinib as a potential treatment for patients with CLL and MCL. We believe that the data also help to validate the importance of ROR1 as a therapeutic target,”

How a see-through fish could one day lead to substitutes for bone marrow transplants

Human blood stem cells

For years researchers have struggled to create human blood stem cells in the lab. They have done it several times with animal models, but the human kind? Well, that’s proved a bit trickier. Now a CIRM-funded team at UC San Diego (UCSD) think they have cracked the code. And that would be great news for anyone who may ever need a bone marrow transplant.

Why are blood stem cells important? Well, they help create our red and white blood cells and platelets, critical elements in carrying oxygen to all our organs and fighting infections. They have also become one of the most important weapons we have to combat deadly diseases like leukemia and lymphoma. Unfortunately, today we depend on finding a perfect or near-perfect match to make bone marrow transplants as safe and effective as possible and without a perfect match many patients miss out. That’s why this news is so exciting.

Researchers at UCSD found that the process of creating new blood stem cells depends on the action of three molecules, not two as was previously thought.

Zebrafish

Here’s where it gets a bit complicated but stick with me. The team worked with zebrafish, which use the same method to create blood stem cells as people do but also have the advantage of being translucent, so you can watch what’s going on inside them as it happens.  They noticed that a molecule called Wnt9a touches down on a receptor called Fzd9b and brings along with it something called the epidermal growth factor receptor (EGFR). It’s the interaction of these three together that turns a stem cell into a blood cell.

In a news release, Stephanie Grainger, the first author of the study published in Nature Cell Biology, said this discovery could help lead to new ways to grow the cells in the lab.

“Previous attempts to develop blood stem cells in a laboratory dish have failed, and that may be in part because they didn’t take the interaction between EGFR and Wnt into account.”

If this new approach helps the team generate blood stem cells in the lab these could be used to create off-the-shelf blood stem cells, instead of bone marrow transplants, to treat people battling leukemia and/or lymphoma.

CIRM is also funding a number of other projects, several in clinical trials, that involve the use of blood stem cells. Those include treatments for: Beta Thalassemia; blood cancer; HIV/AIDS; and Severe Combined Immunodeficiency among others.

Antibody effective in cure for rare blood disorders

3D illustration of an antibody binding to a designated target.
Illustration created by Audra Geras.

A variety of diseases can be traced to a simple root cause: problems in the bone marrow. The bone marrow contains specialized stem cells known as hematopoietic stem cells (HSCs) that give rise to different types of blood cells. As mentioned in a previous blog about Sickle Cell Disease (SCD), one problem that can occur is the production of “sickle like” red blood cells. In blood cancers like leukemia, there is an uncontrollable production of abnormal white blood cells. Another condition, known as myelodysplastic syndromes (MDS), are a group of cancers in which immature blood cells in the bone marrow do not mature and therefore do not become healthy blood cells.

For diseases that originate in the bone marrow, one treatment involves introducing healthy HSCs from a donor or gene therapy. However, before this type of treatment can take place, all of the problematic HSCs must be eliminated from the patient’s body. This process, known as pre-treatment, involves a combination of chemotherapy and radiation, which can be extremely toxic and life threatening. There are some patients whose condition has progressed to the point where their bodies are not strong enough to withstand pre-treatment. Additionally, there are long-term side effects that chemotherapy and radiation can have on infant children that are discussed in a previous blog about pediatric brain cancer.

Could there be a targeted, non-toxic approach to eliminating unwanted HSCs that can be used in combination with stem cell therapies? Researchers at Stanford say yes and have very promising results to back up their claim.

Dr. Judith Shizuru and her team at Stanford University have developed an antibody that can eliminate problematic blood forming stem cells safely and efficiently. The antibody is able to identify a protein on HSCs and bind to it. Once it is bound, the protein is unable to function, effectively removing the problematic blood forming stem cells.

Dr. Shizuru is the senior author of a study published online on February 11th, 2019 in Blood that was conducted in mice and focused on MDS. The results were very promising, demonstrating that the antibody successfully depleted human MDS cells and aided transplantation of normal human HSCs in the MDS mouse model.

This proof of concept holds promise for MDS as well as other disease conditions. In a public release from Stanford Medicine, Dr. Shizuru is quoted as saying, “A treatment that specifically targets only blood-forming stem cells would allow us to potentially cure people with diseases as varied as sickle cell disease, thalassemia, autoimmune disorders and other blood disorders…We are very hopeful that this body of research is going to have a positive impact on patients by allowing better depletion of diseased cells and engraftment of healthy cells.”

The research mentioned was partially funded by us at CIRM. Additionally, we recently awarded a $3.7 million dollar grant to use the same antibody in a human clinical trial for the so-called “bubble baby disease”, which is also known as severe combined immunodeficiency (SCID). You can read more about that award on a previous blog post linked here.

71 for Proposition 71

Proposition 71 is the state ballot initiative that created California’s Stem Cell Agency. This month, the Agency reached another milestone when the 71st clinical trial was initiated in the CIRM Alpha Stem Cell Clinics (ASCC) Network. The ASCC Network deploys specialized teams of doctors, nurses and laboratory technicians to conduct stem cell clinical trials at leading California Medical Centers.

StateClinics_Image_CMYK

These teams work with academic and industry partners to support patient-centered for over 40 distinct diseases including:

  • Amyotrophic Lateral Sclerosis (ALS)
  • Brain Injury & Stroke
  • Cancer at Multiple Sites
  • Diabetes Type 1
  • Eye Disease / Blindness Heart Failure
  • HIV / AIDS
  • Kidney Failure
  • Severe Combined Immunodeficiency (SCID)
  • Sickle Cell Anemia
  • Spinal Cord Injury

These clinical trials have treated over 400 patients and counting. The Alpha Stem Cell Clinics are part of CIRM’s Strategic Infrastructure. The Strategic Infrastructure program which was developed to support the growth of stem cell / regenerative medicine in California. A comprehensive update of CIRM’s Infrastructure Program was provided to our Board, the ICOC.

CIRM’s infrastructure catalyzes stem cell / regenerative medicine by providing resources to all qualified researchers and organizations requiring specialized expertise. For example, the Alpha Clinics Network is supporting clinical trials from around the world.

Many of these trials are sponsored by commercial companies that have no CIRM funding. To date, the ASCC Network has over $27 million in contracts with outside sponsors. These contracts serve to leverage CIRMs investment and provide the Network’s medical centers with a diverse portfolio of clinical trials to address patients’’ unmet medical needs.

Alpha Clinics – Key Performance Metrics

  • 70+ Clinical Trials
  • 400+ Patients Treated
  • 40+ Disease Indications
  • Over $27 million in contracts with commercial sponsors

The CIRM Alpha Stem Cell Clinics and broader Infrastructure Programs are supporting stem cell research and regenerative medicine at every level, from laboratory research to product manufacturing to delivery to patients. This infrastructure has emerged to make California the world leader in regenerative medicine. It all started because California’s residents supported a ballot measure and today we have 71 clinical trials for 71.

 

 

New hope for stem cell therapy in patients with leukemia

LeukemiaWhiteBloodCell

Leukemia white blood cell

Of the many different kinds of cancer that affect humans, leukemia is the most common in young people. As with many types cancer, doctors mostly turn to chemotherapy to treat patients. Chemotherapy, however, comes with its own share of issues, primarily severe side effects and the constant threat of disease recurrence.

Stem cell therapy treatment has emerged as a potential cure for some types of cancer, with leukemia patients being among the first groups of patients to receive this type of treatment. While exciting because of the possibility of a complete cure, stem cell therapy comes with its own challenges. Let’s take a closer look.

Leukemia is characterized by abnormal white blood cells (also known as the many different types of cells that make up our immune system) that are produced at high levels. Stem cell therapy is such an appealing treatment option because it involves replacing the patient’s aberrant blood stem cells with healthy ones from a donor, which provides the possibility of complete and permanent remission for the patient.

Unfortunately, in approximately half of patients who receive this therapy, the donor cells (which turn into immune cells), can also destroy the patients healthy tissue (i.e. liver, skin etc…), because the transplanted blood stem cells recognize patient’s tissue as foreign. While doctors try to lessen this type of response (also known as graft versus host disease (GVHD)), by suppressing the patient’s immune system, this procedure lessens the effectiveness of the stem cell therapy itself.

Now scientists at the University of Zurich have made an important discovery – published in the journal Science Translational Medicine – that could mitigate this potentially fatal response in patients. They found that a molecule called GM-CSF, is a critical mediator of the severity of GVHD. Using a mouse model, they showed that if the donor cells were unable to produce GM-CSF, then mice fared significantly better both in terms of less damage to tissues normally affected by GVHD, such as the skin, and overall survival.

While exciting, the scientists were concerned about narrowing in on this molecule as a potential target to lessen GVHD, because GM-CSF, an important molecule in the immune system, might also be important for ensuring that the donor immune cells do their jobs properly. Reassuringly, the researchers found that blocking GM-CSF’s function had no effect on the ability of the donor cells to exert their anti-cancer effect. This was surprising because previously the ability of donor cells to cause GVHD, versus protect patients from the development of cancer was thought to occur via the same biological mechanisms.

Most excitingly, however, was that finding that high levels of GM-CSF are also observed in patient samples, and that the levels of GM-CSF correlate to the severity of GVHD. Dr. Burkhard Becher and his colleagues, the authors of this study, now want to run a clinical trial to determine whether blocking GM-CSF blocks GVHD in humans like it does in mice. In a press release, Dr. Becher states the importance of these findings:

“If we can stop the graft-versus-host response while preserving the anti-cancer effect, this procedure can be employed much more successfully and with fewer risks to the patient. This therapeutic strategy holds particular promise for patients with the poorest prognosis and highest risk of fatality.”

How CIRM support helped a promising approach to type 1 diabetes get vital financial backing

Death-Vallery-011

The “Valley of Death” sounds like a scary place from “Lord of the Rings” or “Game of Thrones” that our heroes have to navigate to reach safety. The reality is not that different. It’s the space that young companies have to navigate from having a good idea to getting financial backing, so they can move their projects towards the clinic. At the other side of the Valley are deep-pocket investors, waiting to see what makes it through before deciding if they want to support them.

It’s a Catch 22 situation. Without financing companies can’t make it through the Valley; but they need to get through before the folks with money will considering investing. As a result many companies languish or even fail to make it through the Valley of Death. Without that financial support promising therapies are lost before they even get a chance to show their potential.

CIRM was created, in part, to help those great ideas get through the Valley. That’s why it is so gratifying to hear the news today from ViaCyte – that is developing a promising approach to treating type 1 diabetes – that they have secured $80 million in additional financing.

The money comes from Bain Capital Life Sciences, TPG and RA Capital Management and several other investors. It’s important because it is a kind of vote of confidence in ViaCyte, suggesting these deep-pocket investors believe the company’s approach has real potential.

In a news release Adam Koppel, a Managing Director at Bain, said:

“ViaCyte is the clear leader in beta cell replacement, and we are excited about the lasting impact that it’s stem cell-derived therapies can potentially have on improving treatment and quality of life for people living with insulin-requiring diabetes. We look forward to partnering with ViaCyte’s management team to accelerate the development of ViaCyte’s transformative cell therapies to help patients.”

CIRM has been a big supporter of ViaCyte for several years, investing more than $70 million to help them develop a cell therapy that can be implanted under the skin that is capable of delivering insulin to people with type 1 diabetes when needed. The fact that these investors are now stepping up to help it progress suggests we are not alone in thinking this project has tremendous promise.

But ViaCyte is far from the only company that has benefitted from CIRM’s early and consistent support. This year alone CIRM-funded companies have raised more than $1.0 billion in funding from outside investors; a clear sign of validation not just for the companies and their therapies, but also for CIRM and its judgement.

This includes:

  • Humacyte raising $225 million for its program to help people battling kidney failure
  • Forty Seven Inc. raising $113 million from an Initial Public Offering for its programs targeting different forms of cancer
  • Nohla Therapeutics raising $56 million for its program treating acute myeloid leukemia

We have shown there is a path through the Valley of Death. We are hoping to lead many more companies through that in the coming years, so they can bring their therapies to people who really need them, the patients.

 

 

 

CIRM-supported study shows promise in fighting acute myeloid leukemia

Chemotherapy

Chemotherapy

For years chemotherapy has been a mainstay in the war against cancer. While it can be very effective it can also come with some nasty side effects. Since chemo works by killing rapidly growing cells, it not only hits the cancer cells, but can also hit other rapidly growing cells too, including those in our hair roots, which is why many people undergoing chemo lose their hair.

So, the key to a truly effective anti-cancer therapy is one that does as much damage as possible to the cancer cells, and as little as possible to all the healthy cells in the body. A therapy being developed by Cellerant Therapeutics seems to have found that sweet spot in a new therapy targeting acute myeloid leukemia (AML).

AML starts in the bone marrow and quickly moves into the blood, where it can spread to other parts of the body. It is the second most common form of leukemia and claims around 10,000 lives in the US every year. Chemotherapy is the main weapon used against AML but it can also cause nausea, hair loss and other complications and in most cases has limited effectiveness because, over time, the leukemia cells get used to it.

Cellerant 2013In a study published in the journal Blood Advances, Cellerant researchers explain the limitations of existing treatments.

“The current standard of care for acute myeloid leukemia (AML) is largely ineffective with very high relapse rates and low survival rates, mostly due to the inability to eliminate a rare population of leukemic stem cells (LSCs) that initiate tumor growth and are resistant to standard chemotherapy.”

Cellerant has developed a therapy called CLT030 which targets CLL1, a marker found on the surface of leukemia cells but not on normal blood stem cells. Preclinical studies in mice show CLT030 is able to zero in on this surface marker and attack the leukemia but do little damage to blood or other surrounding cells.

In a news release, Ram Mandalam, President and CEO of Cellerant, said this is encouraging news:

“AML remains a significant unmet medical need, and our therapy, CLT030, that can target leukemic stem cells precisely while minimally affecting normal hematopoietic stem cells could improve outcomes while avoiding much of the toxicities associated with conventional chemotherapy and other targeted therapeutics.”

Mandalam says they are now doing the late-stage preclinical testing to be able to apply to the Food and Drug Administration for permission to start a clinical trial. CIRM is funding this stage of the research.