How two California researchers are advancing world class science to develop real life solutions

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In our recently launched 5-year Strategic Plan, the California Institute for Regenerative Medicine (CIRM) profiled two researchers who have leveraged CIRM funding to translate basic biological discoveries into potential real-world solutions for devastating diseases.

Dr. Joseph Wu is director of the Stanford Cardiovascular Institute and the recipient of several CIRM awards. Eleven of them to be exact! Over the past 10 years, Dr. Wu’s lab has extensively studied the application of induced pluripotent stem cells (iPSCs) for cardiovascular disease modeling, drug discovery, and regenerative medicine. 

Dr. Wu’s extensive studies and findings have even led to a cancer vaccine technology that is now being developed by Khloris Biosciences, a biotechnology company spun out by his lab. 

Through CIRM funding, Dr. Wu has developed a process to produce cardiomyocytes (cardiac muscle cells) derived from human embryonic stem cells for clinical use and in partnership with the agency. Dr. Wu is also the principal investigator in the first-in-US clinical trial for treating ischemic heart disease. His other CIRM-funded work has also led to the development of cardiomyocytes derived from human induced pluripotent stem cells for potential use as a patch.

Over at UCLA, Dr. Lili Yang and her lab team have generated invariant Natural Killer T cells (iNKT), a special kind of immune system cell with unique features that can more effectively attack tumor cells. 

More recently, using stem cells from donor cord-blood and peripheral blood samples, Dr. Yang and her team of researchers were able to produce up to 300,000 doses of hematopoietic stem cell-engineered iNKT (HSC–iNKT) cells. The hope is that this new therapy could dramatically reduce the cost of producing immune cell products in the future. 

Additionally, Dr. Yang and her team have used iNKT cells to develop both autologous (using the patient’s own cells), and off-the-shelf anti-cancer therapeutics (using donor cells), designed to target blood cell cancers.

The success of her work has led to the creation of a start-up company called Appia Bio. In collaboration with Kite Pharma, Appia Bio is planning on developing and commercializing the promising technology. 

CIRM has been an avid supporter of Dr. Yang and Dr. Wu’s research because they pave the way for development of next-generation therapies. Through our new Strategic Plan, CIRM will continue to fund innovative research like theirs to accelerate world class science to deliver transformative regenerative medicine treatments in an equitable manner to a diverse California and the world.

Visit this page to learn more about CIRM’s new 5-year Strategic Plan and stay tuned as we share updates on our 5-year goals here on The Stem Cellar.

A CIRM-funded therapy for a deadly blood cancer gets approval for Phase 3 clinical trial

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Michael Wang, MD (right) of the Department of Lymphoma & Myeloma at MD Anderson Cancer Center will lead the Phase 3 clinical

Oncternal Therapeutics, Inc. is celebrating an encouraging milestone at the start of the new year following a successful End-of-Phase 2 meeting with the FDA. 

Specifically, the FDA agreed on key elements of the company’s potentially pivotal Phase 3 clinical trial of zilovertamab, which offers potential treatment advantages to patients suffering from relapsed or refractory mantle cell lymphoma (MCL). Zilovertamab (previously called cirmtuzumab because it was developed with CIRM fundingis the company’s investigational anti-ROR1 monoclonal antibody. 

Mantle cell lymphoma is an aggressive form of blood cancer that develops when white blood cells, which are a key component of our immune system and help fight infections, grow out of control. 

The California Institute for Regenerative Medicine (CIRM) funded an earlier-stage trial conducted by Oncternal Therapeutics in collaboration with UC San Diego. 

The Phase 3 clinical trial will be led by Dr. Michael Wang, of the Department of Lymphoma & Myeloma at MD Anderson Cancer Center. The trial will randomize patients with relapsed or refractory MCL who have experienced stable disease or a partial response after receiving four months of oral ibrutinib therapy to receive either blinded zilovertamab or placebo. All patients will continue receiving oral ibrutinib.  

The study (ZILO-301) will be conducted internationally in at least 50 centers experienced in treating MCL, and is expected to begin in the second quarter of 2022.  

The researchers hope the treatment will lead to progression-free survival for patients getting zilovertamab and that this will lead to FDA approval of the therapy. 

The company is also planning to conduct study ZILO-302, an open-label companion study of zilovertamab plus ibrutinib for patients who have progressive disease during the initial four months of ibrutinib monotherapy from Study ZILO-301. 

Read the full release of the study here and be sure to follow the Stem Cellar blog for more updates on the clinical trial.  

Stem Cell Agency Board Invests in Therapy Targeting Deadly Blood Cancers

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Dr. Ezra Cohen, photo courtesy UCSD

Hematologic malignancies are cancers that affect the blood, bone marrow and lymph nodes and include different forms of leukemia and lymphoma. Current treatments can be effective, but in those patients that do not respond, there are few treatment options. Today, the governing Board of the California Institute for Regenerative Medicine (CIRM) approved investing $4.1 million in a therapy aimed at helping patients who have failed standard therapy.

Dr. Ezra Cohen, at the University of California San Diego, and Oncternal Therapeutics are targeting a protein called ROR1 that is found in B cell malignancies, such as leukemias and lymphomas, and solid tumors such as breast, lung and colon. They are using a molecule called a chimeric antigen receptor (CAR) that can enable a patient’s own T cells, an important part of the immune system, to target and kill their cancer cells. These cells are derived from a related approach with an antibody therapy that targets ROR1-binding medication called Cirmtuzumab, also created with CIRM support. This CAR-T product is designed to recognize and kill cancer stem cells that express ROR1.

This is a late-stage preclinical project so the goal is to show they can produce enough high-quality cells to treat patients, as well as complete other regulatory measures needed for them to apply to the US Food and Drug Administration (FDA) for permission to test the therapy in a clinical trial in people.

If given the go-ahead by the FDA the therapy will target patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL) and acute lymphoblastic leukemia (ALL).  

“CAR-T cell therapies represent a transformational advance in the treatment of hematologic malignancies,” says Dr. Maria T. Millan, CIRM’s President and CEO. “This approach addresses the need to develop new therapies for patients whose cancers are resistant to standard chemotherapies, who have few therapeutic options and a very poor chance or recovery.”

One step closer to making ‘off-the-shelf’ immune cell therapy for cancer a reality 

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Immunotherapy is a type of cancer treatment that uses a person’s own immune system to fight cancer. It comes in a variety of forms including targeted antibodies, cancer vaccines, and adoptive cell therapies. While immunotherapies have revolutionized the treatment of aggressive cancers in recent decades, they must be created on a patient-specific basis and as a result can be time consuming to manufacture/process and incredibly costly to patients already bearing the incalculable human cost of suffering from the cruelest disease.

Fortunately, the rapid progress that has led to the present era of cancer immunotherapy is expected to continue as scientists look for ways to improve efficacy and reduce cost. Just this week, a CIRM-funded study published in Cell Reports Medicine revealed a critical step forward in the development of an “off-the-shelf” cancer immunotherapy by researchers at UCLA. “We want cell therapies that can be mass-produced, frozen and shipped to hospitals around the world,” explains Lili Yang, the study’s senior author. 

Lili Yang, the study’s senior author and a member of UCLA’s Broad Stem Cell Research Center

In order to fulfil this ambitious goal, Yang and her colleagues developed a new method for producing large numbers of a specialized T cell known as invariant natural killer T (iNKT) cells. iNKT cells are rare but powerful immune cells that don’t carry the risk of graft-versus-host disease, which occurs when transplanted cells attack a recipient’s body, making them better suited to treat a wide range of patients with various cancers.

Using stem cells from donor cord-blood and peripheral blood samples, the team of researchers discovered that one cord blood donation could produce up to 5,000 doses of the therapy and one peripheral blood donation could produce up to 300,000 doses. The high yield of the resulting cells, called hematopoietic stem cell-engineered iNKT (HSC–iNKT) cells,could dramatically reduce the cost of producing immune cell products in the future. 

In order to test the efficacy of the HSC–iNKT cells, researchers conducted two very important tests. First, they compared its cancer fighting abilities to another set of immune cells called natural killer cells. The results were promising. The HSC–iNKT cells were significantly better at killing several types of tumor cells such as leukemia, melanoma, and lung cancer. Then, the HSC–iNKT cells were frozen and thawed, just as they would be if they were to one day become an off-the-shelf cell therapy. Researchers were once again delighted when they discovered that the HSC–iNKT cells sustained their tumor-killing efficacy.

Next, Yang and her team added a chimeric antigen receptor (CAR) to the HSC–iNKT cells. CAR is a specialized molecule that can enable immune cells to recognize and kill a specific type of cancer. When tested in the lab, researchers found that CAR-equipped HSC–iNKT cells eliminated the specific cancerous tumors they were programmed to destroy. 

This study was made possible in part by three grants from CIRM.

Old therapies inspire new hope for treatment of pediatric brain tumors

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Image courtesy St. Jude Children’s Research Hospital

A recent study led by John Hopkins Medicine has found that combining two ‘old therapies’ can offer a surprising new purpose – fighting Medulloblastoma, the most common malignant brain tumor in children. The fast-growing cancerous tumor originates in the brain or spinal cord and has traditionally been treated with surgery to remove the tumor followed by radiation and chemotherapy. 

The prospective therapy which comprises of copper ions and Disulfiram (DSF-Cu++), paves the way toward a successful treatment that can be used alone or in conjunction with traditional therapy. “Disulfiram, [is] a medication that’s been used for nearly 70 years to treat chronic alcoholism,” explains Betty Tyler, the study’s senior author and associate professor of neurosurgery at Johns Hopkins. “It has great promise being ‘repurposed’ as an anticancer agent, especially when it is complexed with metal ions such as copper.”

The researchers tested the anticancer activity of DSF-Cu++ and, in their attempts to define what it targeted at the molecular level to achieve these effects, were able to highlight four key findings.

First, the team of researchers found that DSF-Cu++ blocks two biological pathways in medulloblastomas that the cancer cells need in order to remove proteins threatening their survival. With these pathways blocked, these proteins accumulate in the tumor and cause the malignant cells to die, leaving them to eventually be removed by the body’s own immune system. 

Second, the researchers discovered that just a few hours of exposure to DSF-Cu++ not only kills medulloblastoma cells but can also effectively reduce the cancer stem cells responsible for their creation. 

The third finding in the study revealed that DSF-CU++ keeps cancer cells from recovering. By impairing the ability of medulloblastoma cells to repair the damage done to their DNA, DSF-CU++ enhances the cell killing power of the treatment.

Lastly, the promising combo of DSF-CU++ demonstrated significant increases in prolonging survival days of mice whose brains were implanted with two subtypes of medulloblastoma. 

A new approach to a deadly childhood cancer

Cancers of the blood, bone marrow and lymph nodes (also called hematologic malignancies) are the most common form of cancer in children and young adults. Current treatments can be effective but can also pose life-threatening health risks to the child. Now researchers at Stanford have developed a new approach and the Board of the California Institute for Regenerative Medicine (CIRM) voted to support that approach in a clinical trial.

The Board approved investing $11,996,634 in the study, which is the Stem Cell Agency’s 76th clinical trial.

The current standard of care for cancers such as acute leukemias and lymphomas is chemotherapy and a bone marrow (also called HSCT) transplant. However, without a perfectly matched donor the risk of the patient’s body rejecting the transplant is higher. Patients may also be at greater risk of graft vs host disease (GVHD), where the donor cells attack the patient’s body. In severe cases GVHD can be life-threatening.

Dr. Maria Grazia Roncarlo: Photo courtesy Stanford

Dr. Maria Grazia Roncarolo and her team at Stanford will test an immunotherapy cell approach using a therapy that is enriched with specialized immune cells called type 1 regulatory T (Tr1) cells. These cells will be infused into the patient following the bone marrow transplant. Both the Tr1 cells and the bone marrow will come from the same donor. The hope is this will help provide the patient’s immune system with these regulatory cells to combat life-threatening graft versus host disease and increase the success of treatment and bone marrow (HSCT) transplant.

“Every year around 500 children receive stem cell transplants in California, and while many children do well, too many experiences a rejection of the transplant or a relapse of the cancer,” says Dr. Maria T. Millan, President and CEO of CIRM. “Finding an improved therapy for these children means a shorter stay in the hospital, less risk of the need for a second transplant, and a greater quality of life for the child and the whole family.”

The CIRM Board has previously approved funding for 12 other clinical trials targeting cancers of the blood. You can read about them here.

Lung cancer, Sherlock Holmes and piano

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Image of lung cancer

When we think of lung cancer we typically tend to think it’s the end result of years of smoking cigarettes. But, according to the Centers for Disease Control and Prevention, between 10 and 20 percent of cases of lung cancer (20,000 to 40,000 cases a year) happen to non-smokers, people who have either never smoked or smoked fewer than 100 cigarettes in their life. Now researchers have found that there are different genetic types of cancer for smokers and non-smokers, and that might mean the need for different kinds of treatment.

A team at the National Cancer Institute did whole genome sequencing on tumors from 232 never-smokers who had lung cancer. In an interview with STATnews, researcher Maria Teresa Landi said they called their research the Sherlock-Lung study, after the famous fictional pipe-smoking detective Sherlock Holmes. “We used a detective approach. By looking at the genome of the tumor, we use the changes in the tumors as a footprint to follow to infer the causes of the disease.”

They also got quite creative in naming the three different genetic subtypes they found. Instead of giving them the usual dry scientific names, they called them piano, mezzo-forte and forte; musical terms for soft, medium and loud.

Half of the tumors in the non-smokers were in the piano group. These were slow growing with few mutations. The median latency period for these (the time between being exposed to something and being diagnosed) was nine years. The mezzo-forte group made up about one third of the cases. Their cancers were more aggressive with a latency of around 14 weeks. The forte group were the most aggressive, and the ones that most closely resembled smokers’ cancer, with a latency period of just one month.

So, what is the role of stem cells in this research? Well, in the study, published in the journal Nature Genetics the team found that the piano subtype seemed to be connected to genes that help regulate stem cells. That complicates things because it means that the standard treatments for lung cancer that work for the mezzo-forte and forte varieties, won’t work for the piano subtype.

“If this is true, it changes a lot of things in the way we should think of tumorigenesis,” Dr. Landi said.

With that in mind, and because early-detection can often be crucial in treating cancer, what can non-smokers do to find out if they are at risk of developing lung cancer? Well, right now there are no easy answers. For example, the U.S. Preventive Services Task Force does not recommend screening for people who have never smoked because regular CT scans could actually increase an otherwise healthy individual’s risk of developing cancer.

National Academy of Medicine honors CIRM Grantees

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As someone who is not always as diligent as he would like to be about sending birthday cards on time, I’m used to sending belated greetings to people. So, I have no shame in sending belated greetings to four CIRM grantees who were inducted into the National Academy of Medicine in 2020.

I say four, but it’s really three and a half. I’ll explain that later.

Being elected to the National Academy of Medicine is, in the NAM’s own modest opinion, “considered one of the highest honors in the fields of health and medicine and recognizes individuals who have demonstrated outstanding professional achievement and commitment to service.”

To be fair, NAM is right. The people elected are among the best and brightest in their field and membership is by election from the other members of NAM, so they are not going to allow any old schmuck into the Academy (which could explain why I am still waiting for my membership).

The CIRM grantees elected last year are:

Dr. Antoni Ribas: Photo courtesy UCLA

Antoni Ribas, MD, PhD, professor of medicine, surgery, and molecular and medical pharmacology, U. C. Los Angeles.

Dr. Ribas is a pioneer in cancer immunology and has devoted his career to developing new treatments for malignant melanoma. When Dr. Ribas first started malignant melanoma was an almost always fatal skin cancer. Today it is one that can be cured.

In a news release Dr. Ribas said it was a privilege to be honored by the Academy: “It speaks to the impact immunotherapy has played in cancer research. When I started treating cases of melanoma that had metastasized to other organs, maybe 1 in 20 responded to treatment. Nobody in their right mind wanted to be a specialist in this field. It was the worst of the worst cancers.”

Looks like he chose his career path wisely.

Dr. Jeffrey Goldberg: Photo courtesy Stanford

Jeffrey Louis Goldberg, MD, PhD, professor and chair of ophthalmology, Stanford University, Palo Alto, Calif.

Dr. Goldberg was honored for his contribution to the understanding of vision loss and ways to reverse it. His lab has developed artificial retinas that transmit images down the optic nerve to the brain through tiny silicon chips implanted in the eye. He has also helped use imaging technology to better improve our ability to detect damage in photoreceptor cells (these are cells in the retina that are responsible for converting light into signals that are sent to the brain and that give us our color vision and night vision)

In a news release he expressed his gratitude saying: “I look forward to serving the goals of the National Academies, and to continuing my collaborative research efforts with my colleagues at the Byers Eye Institute at Stanford and around the world as we further our efforts to combat needless blindness.”

Dr. Mark Anderson; photo courtesy UCSF

Mark S. Anderson, MD, PhD, professor in Diabetes Research, Diabetes Center, U. C. San Francisco.

Dr. Anderson was honored for being a leader in the study of autoimmune diseases such as type 1 diabetes. This focus extends into the lab, where his research examines the genetic control of autoimmune diseases to better understand the mechanisms by which immune tolerance is broken.

Understanding what is happening with the immune system, figuring out why it essentially turns on the body, could one day lead to treatments that can stop that, or even reverse it by boosting immune activity.

Dr. John Dick: Photo courtesy University Health Network, Toronto

Remember at the beginning I said that three and a half CIRM grantees were elected to the Academy, well, Canadian researcher, Dr. John Dick is the half. Why? Well, because the award we funded actually went to UC San Diego’s Dennis Carson but it was part of a Collaborative Funding Partnership Program with Dr. Dick at the University of Toronto. So, we are going to claim him as one of our own.

And he’s a pretty impressive individual to partner with. Dr. Dick is best known for developing a test that led to the discovery of leukemia stem cells. These are cells that can evade surgery, chemotherapy and radiation and which can lead to patients relapsing after treatment. His work helped shape our understanding of cancer and revealed a new strategy for curing it.

CIRM funds clinical trials targeting heart disease, stroke and childhood brain tumors

Gary Steinberg (Jonathan Sprague)

Heart disease and stroke are two of the leading causes of death and disability and for people who have experienced either their treatment options are very limited. Current therapies focus on dealing with the immediate impact of the attack, but there is nothing to deal with the longer-term impact. The CIRM Board hopes to change that by funding promising work for both conditions.

Dr. Gary Steinberg and his team at Stanford were awarded almost $12 million to conduct a clinical trial to test a therapy for motor disabilities caused by chronic ischemic stroke.  While “clot busting” therapies can treat strokes in their acute phase, immediately after they occur, these treatments can only be given within a few hours of the initial injury.  There are no approved therapies to treat chronic stroke, the disabilities that remain in the months and years after the initial brain attack.

Dr. Steinberg will use embryonic stem cells that have been turned into neural stem cells (NSCs), a kind of stem cell that can form different cell types found in the brain.  In a surgical procedure, the team will inject the NSCs directly into the brains of chronic stroke patients.  While the ultimate goal of the therapy is to restore loss of movement in patients, this is just the first step in clinical trials for the therapy.  This first-in-human trial will evaluate the therapy for safety and feasibility and look for signs that it is helping patients.

Another Stanford researcher, Dr. Crystal Mackall, was also awarded almost $12 million to conduct a clinical trial to test a treatment for children and young adults with glioma, a devastating, aggressive brain tumor that occurs primarily in children and young adults and originates in the brain.  Such tumors are uniformly fatal and are the leading cause of childhood brain tumor-related death. Radiation therapy is a current treatment option, but it only extends survival by a few months.

Dr. Crystal Mackall and her team will modify a patient’s own T cells, an immune system cell that can destroy foreign or abnormal cells.  The T cells will be modified with a protein called chimeric antigen receptor (CAR), which will give the newly created CAR-T cells the ability to identify and destroy the brain tumor cells.  The CAR-T cells will be re-introduced back into patients and the therapy will be evaluated for safety and efficacy.

Joseph Wu Stanford

Stanford made it three in a row with the award of almost $7 million to Dr. Joe Wu to test a therapy for left-sided heart failure resulting from a heart attack.  The major issue with this disease is that after a large number of heart muscle cells are killed or damaged by a heart attack, the adult heart has little ability to repair or replace these cells.  Thus, rather than being able to replenish its supply of muscle cells, the heart forms a scar that can ultimately cause it to fail.  

Dr. Wu will use human embryonic stem cells (hESCs) to generate cardiomyocytes (CM), a type of cell that makes up the heart muscle.  The newly created hESC-CMs will then be administered to patients at the site of the heart muscle damage in a first-in-human trial.  This initial trial will evaluate the safety and feasibility of the therapy, and the effect upon heart function will also be examined.  The ultimate aim of this approach is to improve heart function for patients suffering from heart failure.

“We are pleased to add these clinical trials to CIRM’s portfolio,” says Maria T. Millan, M.D., President and CEO of CIRM.  “Because of the reauthorization of CIRM under Proposition 14, we have now directly funded 75 clinical trials.  The three grants approved bring forward regenerative medicine clinical trials for brain tumors, stroke, and heart failure, debilitating and fatal conditions where there are currently no definitive therapies or cures.”

City of Hope researchers discover potential therapy to treat brain tumors

Glioblastoma (GBM) is a common type of aggressive brain tumor that is found in adults.  Survival of this type of brain cancer is poor with just 40% survival in the first-year post diagnosis and 17% in the second year, according to the American Association of Neurological Surgeons.  This disease has taken the life of former U.S. Senator John McCain and Beau Biden, the late son of U.S. President Joe Biden.

In a CIRM supported lab that conducted the study, Dr. Yanhong Shi and her team at City of Hope, a research and treatment center for cancer, have discovered a potential therapy that they have tested that has been shown to suppress GBM tumor growth and extend the lifespan of tumor-bearing mice. 

Dr. Shi and her team first started by looking at PUS7, a gene that is highly expressed in GBM tissue in comparison to normal brain tissue.  Dr. Qi Cui, a scientist in Dr. Shi’s team and the first author of the study, analyzed various databases and found that high levels of PUS7 have also been associated with worse survival in GBM patients.  The team then studied different glioblastoma stem cells (GSCs), which play a vital role in brain tumor growth, and found that shutting off the PUS7 gene prevented GSC growth and self-renewal. 

The City of Hope team then transplanted two kinds of GSCs, some with the PUS7 gene and some with the PUS7 gene turned off, into immunodeficient mice.  What they found was that the mice implanted with the PUS7-lacking GSCs had less tumor growth and survived longer compared to the mice with the control GSCs that had PUS7 gene.

The team then proceeded to look for an inhibitor of PUS7 from a database of thousands of different compounds and drugs approved by the Food and Drug Administration (FDA).  After identifying a promising compound, the researchers tested the potential therapy in mice implanted with GSCs with the PUS7 gene.  What they found was remarkable.  The therapy inhibited the growth of brain tumors in the mice and their survival was significantly prolonged.

“This is one of the most important studies in my lab in recent years and the first paper to show a causal link between PUS7-mediated modification and cancer in general and GBM in particular” says Dr. Shi.  “It will be a milestone study for RNA modification in cancer.”

The full study was published in Nature Cancer.

Dr. Shi has previously worked on several CIRM-funded research projects, such as looking at a potential link between COVID-19 and a gene for Alzheimer’s as well as the development of a therapy for Canavan disease.