Super charging killer cells to fight leukemia

Colorized scanning electron micrograph of a natural killer cell.
Photo credit: National Institute of Allergy and Infectious Diseases

Racing car drivers are forever tinkering with their cars, trying to streamline them and soup up their engines because while fast is good, faster is better. Researchers do the same things with potential anti-cancer therapies, tinkering with them to make them safer and more readily available to patients while also boosting their ability to fight cancer.

That’s what researchers at the University of California San Diego (UCSD), in a CIRM-funded study, have done. They’ve taken immune system cells – with the already impressive name of ‘natural killer’ (NK) cells – and made them even deadlier to cancers.

These natural killer (NK) cells are considered one of our immune system’s frontline weapons against outside threats to our health, things like viruses and cancer. But sometimes the cancers manage to evade the NKs and spread throughout the body or, in the case of leukemia, throughout the blood.

Lots of researchers are looking at ways of taking a patient’s own NK cells and, in the lab boosting their ability to fight these cancers. However, using a patient’s own cells is both time consuming and very, very expensive.

Dan Kaufman MD

Dr. Dan Kaufman and his team at UCSD decided it would be better to try and develop an off-the-shelf approach, a therapy that could be mass produced from a single batch of NK cells and made available to anyone in need.

Using the iPSC method (which turns tissues like skin or blood into embryonic stem cell-like cells, capable of becoming any other cell in the body) they created a line of NK cells. Then they removed a gene called CISH which slows down the activities of cytokines, acting as a kind of brake or restraint on the immune system.

In a news release, Dr. Kaufman says removing CISH had a dramatic effect, boosting the power of the NK cells.

“We found that CISH-deleted iPSC-derived NK cells were able to effectively cure mice that harbor human leukemia cells, whereas mice treated with the unmodified NK cells died from the leukemia.”

Dr. Kaufman says the next step is to try and develop this approach for testing in people, to see if it can help people whose disease is not responding to conventional therapies.

“Importantly, iPSCs provide a stable platform for gene modification and since NK cells can be used as allogeneic cells (cells that come from donors) that do not need to be matched to individual patients, we can create a line of appropriately modified iPSC-derived NK cells suitable for treating hundreds or thousands of patients as a standardized, ‘off-the-shelf’ therapy.”

The study is published in the journal Cell Stem Cell.

Human immune cells made using pluripotent stem cells in world first

Dr. Andrew Elfanty (left) and Dr. Ed Stanley (right), Murdoch Children’s Research Institute in Melbourne, Australia

Our immune system is the first line of defense our bodies use to fight off infections and disease. One crucial component of this defense mechanism are lymphocytes, which are specialized cells that give rise to various kinds of immune cells, such as a T cell, designed to attack and destroy harmful foreign bodies. Problems in how certain immune cells are formed can lead to diseases such as leukemia and other immune system related disorders.

But how exactly do immune cells form early on in the body?

Dr. Andrew Elfanty and Dr. Ed Stanley at Murdoch Children’s Research Institute in Australia have reproduced and visualized a method in the laboratory used to create human immune cells from pluripotent stem cells, a kind of stem cell that can make virtually any kind of cell in the body. Not only can this unlock a better understanding of leukemia and other immune related diseases, it could potentially lead to a patient’s own skin cells being used to produce new cells for cancer immunotherapy or to test autoimmune disease therapies.

Dr. Elefanty and Dr. Stanley used genetic engineering and a unique way of growing stem cells to make this discovery.

As observed in this video, the team was able to engineer pluripotent stem cells to glow green when they expressed a specific protein found in early immune cells. These cells can be seen migrating along blood vessels outlined in red. These cells go on to populate the thymus, which as we discussed in an earlier blog, is an organ that is crucial in developing functional T cells.

In a press release from Murdoch Children’s Research Institute, Dr. Stanley talks about the important role these early immune cells might play.

“We think these early cells might be important for the correct maturation of the thymus, the organ that acts as a nursery for T-cells”

In addition to this, the team also isolated the green, glowing pluripotent stem cells and showed that they could be used for multiple immune cell types, including those necessary for shaping the development of the immune system as a whole.

In the same press release, Dr. Elefanty discusses the future direction that their research could lead to.

“Although a clinical application is likely still years away, we can use this new knowledge to test ideas about how diseases like childhood leukemia and type 1 diabetes develop. Understanding more about the steps these cells go through, and how we can more efficiently nudge them down a desired pathway, is going to be crucial to that process.”

The full results to this study were published in Nature Cell Biology.

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.

UCLA Conducts CAR-T Cell Clinical Trial for Patients with Recurring and Non-Responsive Cancers

Dr. Sarah Larson (left) and Dr. Yvonne Chen (right)

There have been many advances made towards the treatment of various cancers, such as deadly forms of leukemia and lymphoma, that were once considered a death sentence and thought to be incurable. Unfortunately, there are still people who do not respond to treatment or eventually relapse and see the cancer return. However, researchers at UCLA are attempting to fine-tune some of these approaches to help people with these recurring and non-treatment responding cancers.

Diagram describing CAR-T cell therapy

Dr. Sarah Larson and Dr. Yvonne Chen at UCLA are conducting a clinical trial that involves genetically-modifying a patient’s own T cells, which are an immune system cell that can destroy foreign or abnormal cells. The T-cells are modified with a protein called a chimeric antigen receptor (CAR), which identifies and destroys the cancer by detecting a specific protein, referred to as an antigen, on the cancer cells. These genetically modified T-cells are referred to as CAR-T cells and are re-introduced back into the patient as part of the therapy.

Previous CAR-T cells developed can only recognize one specific protein. For example, one FDA-approved CAR-T cell therapy is able to recognize a protein called CD19, which is found in B-cell lymphoma and leukemia. However, over time, the cancer cells can lose the CD19 antigen, making the CAR-T cell ineffective and can result in a reoccurrence of the cancer.

In a news release by UCLA, Dr. Larson describes the limitations of this design:

“One of the reasons CAR T cell therapy can stop working in patients is because the cancer cells escape from therapy by losing the antigen CD19, which is what the CAR T cells are engineered to target.”

But Dr. Larson and Dr. Chen are using a CAR-T cell that is able to recognize not one by two proteins simultaneously. In addition to recognizing CD19, their CAR-T cell is also able to recognize a protein called CD20, which is also found in B-cell lymphoma and leukemia. This is called a bispecific CAR-T cell because of it’s ability to identify two protein targets simultaneously.

In the same UCLA news release, Dr. Larson hopes that this approach will be more effective:

“One way to keep the CAR T cells working is to have more than one antigen to target. So by using both CD19 and CD20, the thought is that it will be more effective and prevent the loss of the antigen, which is known as antigen escape, one of the common mechanisms of resistance.”

Before the clinical trial, Dr. Chen and her team at UCLA conducted preclinical studies that showed how using bispecific CAR-T cells provided a much better defense compared to single target CAR-T cells against tumors in mice.

In the same UCLA news release, Dr. Chen elaborate on the results of her preclinical studies:

“Based on these results, we’re quite optimistic that the bispecific CAR can achieve therapeutic improvement over the single-input CD19 CAR that’s currently available.”

This first-in-humans study will evaluate the therapy in patients with non-Hodgkin’s B-cell lymphoma or chronic lymphocytic leukemia that has come back or has not responded to treatment. The goal is to determine a safe therapeutic dose.

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.

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.

Newly developed biosensor can target leukemic stem cells

Dr. Michael Milyavsky (left) and his research student Muhammad Yassin (right). Image courtesy of Tel Aviv University.

Every three minutes, one person in the United States is diagnosed with a blood cancer, which amounts to over 175,000 people every year. Every nine minutes, one person in the United States dies from a blood cancer, which is over 58,000 people every year. These eye opening statistics from the Leukemia & Lymphoma Society demonstrate why almost one in ten cancer deaths in 2018 were blood cancer related.

For those unfamiliar with the term, a blood cancer is any type of cancer that begins in blood forming tissue, such as those found in the bone marrow. One example of a blood cancer is leukemia, which results in the production of abnormal blood cells. Chemotherapy and radiation are used to wipe out these cells, but the blood cancer can sometimes return, something known as a relapse.

What enables the return of a blood cancer such as leukemia ? The answer lies in the properties of cancer stem cells, which have the ability to multiply and proliferate and can resist the effects of certain types of chemotherapy and radiation. Researchers at Tel Aviv University are looking to decrease the rate of relapse in blood cancer by targeting a specific type of cancer stem cell known as a leukemic stem cell, which are often found to be the most malignant.

Dr. Michael Milyavsky and his team at Tel Aviv University have developed a biosensor that is able to isolate, label, and target specific genes found in luekemic stem cells. Their findings were published on January 31, 2019 in Leukemia.

In a press release Dr. Milyavsky said:

“The major reason for the dismal survival rate in blood cancers is the inherent resistance of leukemic stem cells to therapy, but only a minor fraction of leukemic cells have high regenerative potential, and it is this regeneration that results in disease relapse. A lack of tools to specifically isolate leukemic stem cells has precluded the comprehensive study and specific targeting of these stem cells until now.”

In addition to isolating and labeling leukemic stem cells, Dr. Milyavsky and his team were able to demonstrate that the leukemic stem cells labeled by their biosensor were sensitive to an inexpensive cancer drug, highlighting the potential this technology has in creating more patient-specific treatment options.

In the article, Dr. Milyavsky said:

” Using this sensor, we can perform personalized medicine oriented to drug screens by barcoding a patient’s own leukemia cells to find the best combination of drugs that will be able to target both leukemia in bulk as well as leukemia stem cells inside it.”

The researchers are now investigating genes that are active in leukemic stem cells in the hope finding other druggable targets.

CIRM has funded two clinical trials that also use a more targeted approach for cancer treatment. One of these trials uses an antibody to treat chronic lymphocytic leukemia (CLL) and the other trial uses a different antibody to treat acute myeloid leukemia (AML).

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.

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.”