Harnessing the body’s immune system to tackle cancer

Often on the Stem Cellar we write about work that is in a clinical trial. But getting research to that stage takes years and years of dedicated work. Over the next few months, we are profiling some of the scientists we fund who are doing Discovery (early stage) and Translational (pre-clinical) research, to highlight the importance of this work in developing the treatments that could ultimately save lives. 

This second profile in the series is by Ross Okamura, Ph.D., a science officer in CIRM’s Discovery & Translation Program.

Your immune system is your body’s main protection against disease; harnessing this powerful defense system to target a given disorder is known as immunotherapy.  There are different types of immunotherapies that have been developed over the years. These include vaccines to help generate antibodies against viruses, drugs to direct immune cell function and most recently, the engineering of immune cells to fight cancer.

Understanding How Immunotherapies Work

One of the more recent immunotherapy approaches to fight cancer that has seen rapid development is equipping a subset of immune cells (T cells) with a chimeric antigen receptor (CAR). In brief, CAR T ceIls are first removed from the patient and then engineered to recognize a specific feature of the targeted cancer cells.  This direct targeting of T cells to the cancer allows for an effective anti-cancer therapy made from your own immune system.

Simplified explanation of how CAR T cell therapies fight cancer. (Memorial Sloan Kettering)

For the first time this fall, two therapeutics employing CAR T cells targeting different types of blood cancers were approved for use by the US Food and Drug Administration (FDA) based on remarkable results found during the clinical trials. Specifically, Kymriah (developed by Novartis) was approved for treatment of acute lymphoblastic leukemia and Yescarta (developed by Kite Pharma) was approved for treatment of non-Hodgkin lymphoma.

There are drawbacks to the CAR T approach, however. Revving up the immune system to attack tumors can cause dangerous side effects. When CAR T cells enter the body, they trigger the release of proteins called cytokines, which join in the attack on the tumors. But this can also create what’s referred to as a cytokine storm or cytokine release syndrome (CRS), which can lead to a range of responses, from a mild fever to multi-organ failure and death. Balancing treatments to resolve CRS after it’s detected while still maintaining the treatment’s cancer-killing abilities is a significant challenge that remains to be overcome.  A second issue is that cancer cells can evade the immune system by no longer producing the target that the CAR-T therapy was designed to recognize. When this happens, the patient subsequently experiences a cancer relapse that is no longer treatable by the same cell therapy.

Natural Killer (NK) T cells represent another type of anti-cancer immunotherapy that is also being tested in clinical trials. NK cells are part of the innate immune system responsible for defending your body against both infection and tumor formation.  NK cells target stressed cells by releasing cell-penetrating proteins that poke holes in the cells leading to induced cell death.  As an immunotherapy, NK cells have the potential to avoid both the issues of CRS and cancer cell immune evasion as they release a more limited array of cytokines and do not rely on a specific single target to recognize tumors.  NK cells instead selectively target tumor cells due to the presence of stress-induced proteins on the cancer cells. In addition, the cancer cells lack other proteins that would normally send out a “I’m a healthy cell you can ignore me” message to NK cells. Without that message, NK cells target and kill those cancer cells.

Developing new immunotherapies against cancer

Dan Kaufman, UCSD

Dr. Dan Kaufman of the University of California at San Diego is a physician-scientist whose research group developed a method to produce functional NK cells from human pluripotent stem cells (PSC).  In order to overcome a major hurdle in the use of NK cells as an anti-cancer therapeutic, Dr. Kaufman is exploring using stem cells as a limitless source to produce a scalable, standardized, off-the-shelf product that could treat thousands of patients.  CIRM is currently funding Dr. Kaufman’s work under both a Discovery Quest award and a just recently funded Translational research award in order to try to advance this candidate approach.

In the CIRM Translational award, Dr. Kaufman is looking to cure acute myelogenous leukemia (AML) which in the US has a 5-year survival rate of 27% (National Cancer Institute, 2017) and is estimated to kill over 10,000 individuals this year (American Cancer Society, 2017).  He has previously shown that his stem cell-derived NK cells can kill human cancer cells in a dish and in mouse models, and his goals are to perform preliminary safety studies and to develop a process to scale his production of NK cells to support a clinical trial in people.  Since NK cells don’t require the patient and the donor to be a genetic match to be effective, a bank of PSC-derived NK cells derived from a single donor could potentially treat thousands of patients.

Looking forward, CIRM is also providing Discovery funding to Dr. Kaufman to explore ways to improve his existing approach against leukemia as well as expand the potential of his stem cell-derived NK cell therapeutic by engineering his cells to directly target solid tumors like ovarian cancer.

The field of pluripotent stem cell-based immunotherapies is full of game-changing potential and important innovations like Dr. Kaufman’s are still in the early stages.  CIRM recognizes the importance of supporting early stage research and is currently investing $27.9 million to fund 8 active Discovery and Translation awards in the cancer immunotherapy area.

Advertisements

Scientists find switch that targets immunotherapies to solid tumors

Cancer immunotherapies harness the power of the patient’s own immune system to fight cancer. One type of immunotherapy, called adoptive T cell therapy, uses immune cells called CD8+ Killer T cells to target and destroy tumors. These T cells are made in the spleen and lymph nodes and they can migrate to different locations in the body through a part of our circulatory system known as the lymphatic system.

CD8+ T cells can also leave the circulation and travel into the body’s tissues to fight infection and cancer. Scientists from the Scripps Research Institute and UC San Diego are interested in learning how these killer T cells do just that in hopes of developing better immunotherapies that can specifically target solid tumors.

In a study published last week in the journal Nature, the teams discovered that a gene called Runx3 acts as a switch that programs CD8+ T cells to set up shop within tissues outside of the circulatory system, giving them access to solid tumors.

“Runx3 works on chromosomes inside killer T cells to program genes in a way that enables the T cells to accumulate in a solid tumor,” said Matthew Pipkin, co-senior author and Associate Professor at The Scripps Research Institute.

Study authors Adam Getzler, Dapeng Wang and Matthew Pipkin of The Scripps Research Institute collaborated with scientists at the University of California, San Diego.

They discovered Runx3 by comparing what genes were expressed in CD8+ T cells found in the lymphatic system to CD8+ T cells that were found in tissues outside of the circulation. They then screened thousands of potential factors for their ability to influence CD8+ T cells to infiltrate solid tumors.

“We found a distinct pattern,” Pipkin said. “The screens showed that Runx3 is one at the top of a list of regulators essential for T cells to reside in non-lymphoid tissues.”

The team then set out to prove that Runx3 was a key factor in getting CD8+ T cells to localize at the site of solid tumors. To do this, they took T cells that either overexpressed Runx3 or did not express Runx3 in these cells. The T cells were then transplanted into mice with melanoma through a process known as adoptive cell transfer. Overexpression of Runx3 in T cells not only reduced tumor size but also extended lifespan in the mice. On the other hand, removing Runx3 expression had a negative impact on their survival rate.

This research, which was supported in part by CIRM funding, offers a new strategy for developing better cancer immunotherapies for solid tumors.

Pipkin concluded in a Scripps Research Institutes News Release,

“Knowing that modulating Runx3 activity in T cells influences their ability to reside in solid tumors opens new opportunities for improving cancer immunotherapy. We could probably use Runx3 to reprogram adoptively transferred cells to help drive them to amass in solid tumors.”

CIRM-Funded Research Makes Multiple Headlines this Week

When it rains it pours.

This week, multiple CIRM-funded studies appeared in the news, highlighting the exciting progress our Agency is making towards funding innovative stem cell research and promoting the development of promising stem cell therapies for patients.

Below are highlights.


Fate Therapeutics Partners with UC San Diego to Develop Cancer Immunotherapy

Last week, Dr. Dan Kaufman and his team at UC San Diego, received a $5.15 million therapeutic translational research award from CIRM to advance the clinical development of a stem cell-derived immunotherapy for acute myelogenous leukemia (AML), a rare form of blood cancer.

Today, it was announced that the UCSD team is entering into a research collaboration with a San Diego biopharmaceutical company Fate Therapeutics to develop a related immunotherapy for blood cancers. The therapy consists of immune cells called chimeric antigen receptor-targeted natural killer (CAR NK) cells that can target tumor cells and stop their growth. Fate Therapeutics has developed an induced pluripotent stem cell (iPSC) platform to develop and optimize CAR NK cell therapies targeting various cancers.

According to an article by GenBio, this new partnership is already bearing fruit.

“In preclinical studies using an ovarian cancer xenograft model, Dr. Kaufman and Fate Therapeutics had shown that a single dose of CAR-targeted NK cells derived from iPSCs engineered with the CAR construct significantly inhibited tumor growth and increased survival compared to NK cells containing a CAR construct commonly used for T-cell immunotherapy.”

 


City of Hope Brain Cancer Trial Featured as a Key Trial to Watch in 2018

Xconomy posted a series this week forecasting Key Clinical Data to look out for next year. Today’s part two of the series mentioned a recent CIRM-funded trial for glioblastoma, an aggressive, deadly brain cancer.

Christine Brown and her team at the City of Hope are developing a CAR-T cell therapy that programs a patient’s own immune cells to specifically target and kill cancer cells, including cancer stem cells, in the brain. You can read more about this therapy and the Phase 1 trial on our website.

Alex Lash, Xconomy’s National Biotech Editor, argued that good results for this trial would be a “huge step forward for CAR-T”.

Alex Lash

“While CAR-T has proven its mettle in certain blood cancers, one of the biggest medical questions in biotech is whether the killer cells can also eat up solid tumors, which make up the majority of cancer cases. Glioblastoma—an aggressive and usually incurable brain cancer—is a doozy of a solid tumor.”


ViaCyte Receives Innovative New Product Award for Type 1 Diabetes

Last week, San Diego-based ViaCyte was awarded the “Most Innovative New Product Award” by CONNECT, a start-up accelerator focused on innovation, for its PEC-Direct product candidate. The product is a cell-based therapy that’s currently being tested in a CIRM-funded clinical trial for patients with high-risk type 1 diabetes.

In a company news release published today, ViaCyte’s CEO Paul Laikind commented on what the award signifies,

Paul Laikind

“This award acknowledges how ViaCyte has continually broken new ground in stem cell research, medical device engineering, and cell therapy scaling and manufacturing. With breakthrough technology, clinical stage product candidates, an extensive intellectual property estate, and a strong and dedicated team, ViaCyte has all the pieces to advance a transformative new life-saving approach that could help hundreds of thousands of people with high-risk type 1 diabetes around the world.”

Hey, what’s the big idea? CIRM Board is putting up more than $16.4 million to find out

Higgins

David Higgins, CIRM Board member and Patient Advocate for Parkinson’s disease; Photo courtesy San Diego Union Tribune

When you have a life-changing, life-threatening disease, medical research never moves as quickly as you want to find a new treatment. Sometimes, as in the case of Parkinson’s disease, it doesn’t seem to move at all.

At our Board meeting last week David Higgins, our Board member and Patient Advocate for Parkinson’s disease, made that point as he championed one project that is taking a new approach to finding treatments for the condition. As he said in a news release:

“I’m a fourth generation Parkinson’s patient and I’m taking the same medicines that my grandmother took. They work but not for everyone and not for long. People with Parkinson’s need new treatment options and we need them now. That’s why this project is worth supporting. It has the potential to identify some promising candidates that might one day lead to new treatments.”

The project is from Zenobia Therapeutics. They were awarded $150,000 as part of our Discovery Inception program, which targets great new ideas that could have a big impact on the field of stem cell research but need some funding to help test those ideas and see if they work.

Zenobia’s idea is to generate induced pluripotent stem cells (iPSCs) that have been turned into dopaminergic neurons – the kind of brain cell that is dysfunctional in Parkinson’s disease. These iPSCs will then be used to screen hundreds of different compounds to see if any hold potential as a therapy for Parkinson’s disease. Being able to test compounds against real human brain cells, as opposed to animal models, could increase the odds of finding something effective.

Discovering a new way

The Zenobia project was one of 14 programs approved for the Discovery Inception award. You can see the others on our news release. They cover a broad array of ideas targeting a wide range of diseases from generating human airway stem cells for new approaches to respiratory disease treatments, to developing a novel drug that targets cancer stem cells.

Dr. Maria Millan, CIRM’s President and CEO, said the Stem Cell Agency supports this kind of work because we never know where the next great idea is going to come from:

“This research is critically important in advancing our knowledge of stem cells and are the foundation for future therapeutic candidates and treatments. Exploring and testing new ideas increases the chances of finding treatments for patients with unmet medical needs. Without CIRM’s support many of these projects might never get off the ground. That’s why our ability to fund research, particularly at the earliest stage, is so important to the field as a whole.”

The CIRM Board also agreed to invest $13.4 million in three projects at the Translation stage. These are programs that have shown promise in early stage research and need funding to do the work to advance to the next level of development.

  • $5.56 million to Anthony Oro at Stanford to test a stem cell therapy to help people with a form of Epidermolysis bullosa, a painful, blistering skin disease that leaves patients with wounds that won’t heal.
  • $5.15 million to Dan Kaufman at UC San Diego to produce natural killer (NK) cells from embryonic stem cells and see if they can help people with acute myelogenous leukemia (AML) who are not responding to treatment.
  • $2.7 million to Catriona Jamieson at UC San Diego to test a novel therapeutic approach targeting cancer stem cells in AML. These cells are believed to be the cause of the high relapse rate in AML and other cancers.

At CIRM we are trying to create a pipeline of projects, ones that hold out the promise of one day being able to help patients in need. That’s why we fund research from the earliest Discovery level, through Translation and ultimately, we hope into clinical trials.

The writer Victor Hugo once said:

“There is one thing stronger than all the armies in the world, and that is an idea whose time has come.”

We are in the business of finding those ideas whose time has come, and then doing all we can to help them get there.

 

 

 

Stem cell stories that caught our eye: the tale of a tail that grows back and Zika’s devious Trojan Horse

The tale of a tail that grows back (Kevin McCormack)

Ask people what they know about geckos and the odds are they’ll tell you geckos have English accents and sell car insurance. Which tells you a lot more about the power of advertising than it does about the level of knowledge about lizards. Which is a shame, because the gecko has some amazing qualities, not the least of which is its ability to re-grow its tail. Now some researchers have discovered how it regenerates its tail, and what they’ve learned could one day help people with spinal cord injuries.

Geckos often detach a bit of their tail when being pursued by a predator, then grow a new one over the course of 30 days. Researchers at the University of Guelph in Canada found that the lizards use a combination of stem cells and proteins to do that.

They found that geckos have stem cells in their tail called radial glias. Normally these cells are dormant but that changes when the lizard loses its tail. As Matthew Vickaryous, lead author of the study, said in a news release:

“But when the tail comes off everything temporarily changes. The cells make different proteins and begin proliferating more in response to the injury. Ultimately, they make a brand new spinal cord. Once the injury is healed and the spinal cord is restored, the cells return to a resting state.”

Vickaryous hopes that understanding how the gecko can repair what is essentially an injury to its spinal cord, we’ll be better able to develop ways to help people with the same kind of injury.

The study is published in the Journal of Comparative Neurology.

Zika virus uses Trojan Horse strategy to infect developing brain
In April 2015, the World Health Organization declared that infection by Zika virus and its connection to severe birth defects was an international public health emergency. The main concern has been the virus’ link to microcephaly, a condition in which abnormal brain development causes a smaller than normal head size at birth. Microcephaly leads to number of problems in these infants including developmental delays, seizures, hearing loss and difficulty swallowing.

A false color micrograph shows microglia cells (green) infected by the Zika virus (blue). Image Muotri lab/UCSD

Since that time, researchers have been racing to better understand how Zika infection affects brain development with the hope of finding treatment strategies. Now, a CIRM-funded study in Human Molecular Genetics reports important new insights about how Zika virus may be transmitted from infected pregnant women to their unborn babies.

The UCSD researchers behind the study chose to focus on microglia cells. In a press release, team leader Alysson Muotri explained their rationale for targeting these cells:

“During embryogenesis — the early stages of prenatal development — cells called microglia form in the yolk sac and then disperse throughout the central nervous system (CNS) of the developing child. Considering the timing of [Zika] transmission, we hypothesized that microglia might be serving as a Trojan horse to transport the virus during invasion of the CNS.”

In the developing brain, microglia continually travel throughout the brain and clear away dead or infected cells. Smuggling itself aboard microglia would give Zika a devious way to slip through the body’s defenses and infect other brain cells. And that’s exactly what Dr. Muotri’s team found.

Using human induced pluripotent stem cells (iPSCs), they generated brain stem cells – the kind found in the developing brain – and in lab dish infected them with Zika virus. When iPSC-derived microglia were added to the infected neural stem cells, the microglia gobbled them up and destroyed them, just as they would do in the brain. But when those microglia were placed next to uninfected brain stem cells, the Zika virus was easily transmitted to those cells. Muotri summed up the results this way:

“Our findings show that the Zika virus can infect these early microglia, sneaking into the brain where they transmit the virus to other brain cells, resulting in the devastating neurological damage we see in some newborns.”

The team went on to show that an FDA-approved drug to treat hepatitis – a liver disease often caused by viral infection – was effective at decreasing the infection of brain stem cells by Zika-carrying microglia. Since these studies were done in petri dishes, more research will be required to confirm that the microglia are a true drug target for stopping the devastating impact of Zika on newborns.

CIRM stories that caught our eye: UCSD team stops neuromuscular disease in mice, ALS trial enrolls 1st patients and Q&A with CIRM Prez

Ordinarily, we end each week at the Stem Cellar with a few stem cell stories that caught our eye. But, for the past couple of weeks we’ve been busy churning out stories related to our Month of CIRM blog series, which we hope you’ve found enlightening. To round out the series, we present this “caught our eye” blog of CIRM-specific stories from the last half of October.

Stopping neurodegenerative disorder with blood stem cells. (Karen Ring)

CIRM-funded scientists at the UC San Diego School of Medicine may have found a way to treat a progressive neuromuscular disorder called Fredreich’s ataxia (FA). Their research was published last week in the journal Science Translational Medicine.

FA is a genetic disease that attacks the nervous tissue in the spinal cord leading to the loss of sensory nerve cells that control muscle movement. Early on, patients with FA experience muscle weakness and loss of coordination. As the disease progresses, FA can cause scoliosis (curved spine), heart disease and diabetes. 1 in 50,000 Americans are afflicted with FA, and there is currently no effective treatment or cure for this disease.

cherqui

In this reconstituted schematic, blood stem cells transplanted in a mouse model of Friedreich’s ataxia differentiate into microglial cells (red) and transfer mitochondrial protein (green) to neurons (blue), preventing neurodegeneration. Image courtesy of Stephanie Cherqui, UC San Diego School of Medicine.

UCSD scientists, led by CIRM grantee Dr. Stephanie Cherqui, found in a previous study that transplanting blood stem and progenitor cells was an effective treatment for preventing another genetic disease called cystinosis in mice. Cherqui’s cystinosis research is currently being funded by a CIRM late stage preclinical grant.

In this new study, the UCSD team was curious to find out whether a similar stem cell approach could also be an effective treatment for FA. The researchers used an FA transgenic mouse model that was engineered to harbor two different human mutations in a gene called FXN, which produces a mitochondrial protein called frataxin. Mutations in FXN result in reduced expression of frataxin, which eventually leads to the symptoms experienced by FA patients.

When they transplanted healthy blood stem and progenitor cells (HSPCs) from normal mice into FA mice, the cells developed into immune cells called microglia and macrophages. They found the microglia in the brain and spinal cord and the macrophages in the spinal cord, heart and muscle tissue of FA mice that received the transplant. These normal immune cells produced healthy frataxin protein, which was transferred to disease-affected nerve and muscle cells in FA mice.

Cherqui explained their study’s findings in a UC San Diego Health news release:

“Transplantation of wildtype mouse HSPCs essentially rescued FA-impacted cells. Frataxin expression was restored. Mitochondrial function in the brains of the transgenic mice normalized, as did in the heart. There was also decreased skeletal muscle atrophy.”

In the news release, Cherqui’s team acknowledged that the FA mouse model they used does not perfectly mimic disease progression in humans. In future studies, the team will test their method on other mouse models of FA to ultimately determine whether blood stem cell transplants will be an effective treatment option for FA patients.

Brainstorm’s CIRM funded clinical trial for ALS enrolls its first patients
“We have been conducting ALS clinical trials for more than two decades at California Pacific Medical Center (CPMC) and this is, by far, the most exciting trial in which we have been involved to date.”

Those encouraging words were spoken by Dr. Robert Miller, director of CPMC’s Forbes Norris ALS Research Center in an October 16th news release posted by Brainstorm Cell Therapeutics. The company announced in the release that they had enrolled the first patients in their CIRM-funded, stem cell-based clinical trial for the treatment of amyotrophic lateral sclerosis (ALS).

BrainStorm

Also known as Lou Gehrig’s disease, ALS is a cruel, devastating disease that gradually destroys motor neurons, the cells in the brain or spinal cord that instruct muscles to move. People with the disease lose the ability to move their muscles and, over time, the muscles atrophy leading to paralysis. Most people with ALS die within 3 to 5 years from the onset of symptoms and there is no effective therapy for the disease.

Brainstorm’s therapy product, called NurOwn®, is made from mesenchymal stem cells that are taken from the patient’s own bone marrow. These stem cells are then modified to boost their production and release of factors, which are known to help support and protect the motor neurons destroyed by the disease. Because the cells are derived directly from the patient, no immunosuppressive drugs are necessary, which avoids potentially dangerous side effects. The trial aims to enroll 200 patients and is a follow up of a very promising phase 2 trial. CIRM’s $16 million grant to the Israeli company which also has headquarters in the United States will support clinical studies at multiple centers in California. And Abla Creasey, CIRM’s Senior Director of Strategic Infrastructure points out in the press release, the Agency support of this trial goes beyond this single grant:

“Brainstorm will conduct this trial at multiple sites in California, including our Alpha Clinics Network and will also manufacture its product in California using CIRM-funded infrastructure.”

An initial analysis of the effectiveness of NurOwn® in this phase 3 trial is expected in 2019.

CIRM President Maria Millan reflects on her career, CIRM’s successes and the outlook for stem cell biology 

MariaMillan-085_600px

Maria T. Millan, M.D., CIRM President and CEO

RegMedNet a networking website that provides content related to the regenerative medicine community, published an interview this morning with Maria Millan, M.D., CIRM’s new President and CEO. The interview covers the impressive accomplishments that Dr. Millan had achieved before coming to CIRM, with details that even some of us CIRM team members may not have been aware of. In addition to describing her pre-CIRM career, Dr. Millan also describes the Agency’s successes during her term as Vice President of CIRM’s Therapeutics group and she gives her take on future of Agency and the stem cell biology field in general over the next five years and beyond. File this article under “must read”.

The Alpha Stem Cell Clinics: Innovation for Breakthrough Stem Cell Treatments

During this third week of the Month of CIRM, we are focusing on CIRM’s Infrastructure programs which are all focused on helping to accelerate stem cell treatments to patients with unmet medical needs.

So here is the question of the day: What is the world’s largest network of medical centers dedicated to providing stem cell treatments to patients?

The answer is the CIRM Alpha Stem Cell Clinics Network.

The CIRM Alpha Stem Cell Clinics Network consists of leading medical institutions throughout California.

The ASCC Network consists of six leading medical centers throughout California. In 2015, the Network was launched in southern California at the City of Hope, UC Irvine, UC Los Angeles, and UC San Diego. In September 2017, CIRM awarded funding to UC Davis and UC San Francisco to enable the Network to better serve patients throughout the state. Forty stem cell clinical trials have been conducted within the Network with hundreds of patients being treat for a variety of conditions, including:

  • Cancers of the blood, brain, lung and other sites
  • Organ diseases of the heart and kidney
  • Pediatric diseases
  • Traumatic injury to the brain and spine

A complete list of clinical trials may be found on our website.

The Alpha Clinics at UC Los Angeles and San Francisco are working collaboratively on breakthrough treatments for serious childhood diseases. This video highlights a CIRM-funded clinical trial at the UCLA Alpha Clinic that is designed to restore the immune system of patients with life-threatening immune deficiencies. A similar breakthrough treatment is also being used at the UCLA Alpha Clinic to treat sickle cell disease. A video describing this treatment is below.

Why do we need a specialized Network for stem cell clinical trials?

Stem cell treatments are unique in many ways. First, they consist of cells or cell products that frequently require specialized processing. For example, the breakthrough treatments for children, described above, requires the bone marrow to be genetically modified to correct defects. This “gene therapy” is performed in the Alpha Clinic laboratories, which are specifically designed to implement cutting edge gene therapy techniques on the patient’s stem cells.

Many of the cancer clinical trials also take the patient’s own cells and then process them in a laboratory. This processing is designed to enhance the patient’s ability to fight cancer using their own immune cells. Each Alpha Clinic has specialized laboratories to process cells, and the sites at City of Hope and UC Davis have world-class facilities for stem cell manufacturing. The City of Hope and Davis facilities produce high quality therapeutic products for commercial and academic clinical trial sponsors. Because of this ability, the Network has become a prime location internationally for clinical trials requiring processing and manufacturing services.

Another unique feature of the Network is its partnership with CIRM, whose mission is to accelerate stem cell treatments for patients with unmet medical needs. Often, this means developing treatments for rare diseases in which the patient population is comparatively small. For example, there about 40-100 immune deficient children born each year in the United States. We are funding clinical trials to help treat those children. The Network is also treating rare brain and blood cancers.

To find patients that may benefit from these treatments, the Network has developed the capacity to confidentially query over 20 million California patient records. If a good match is found, there is a procedure in place, that is reviewed by an ethics committee, where the patient’s doctor can be notified of the trial and pass that information to the patient. For patients that are interested in learning more, each Alpha Clinic has a Patient Care Coordinator with the job of coordinating the process of educating patients about the trial and assisting them if they choose to participate.

How Can I Learn More?

If you are a patient or a family member and would like to learn more about the CIRM Alpha Clinics, click here. There is contact information for each clinic so you can learn more about specific trials, or you can visit our Alpha Clinics Trials page for a complete list of trials ongoing in the Network.

If you are a patient or a trial sponsor interested in learning more about the services offered through our Alpha Clinics Network, visit our website.

Building California’s stem cell research community, from the ground up

For week three of the Month of CIRM, our topic is infrastructure. What is infrastructure? Read on for a big picture overview and then we’ll fill in the details over the course of the week.

When CIRM was created in 2001, our goal was to grow the stem cell research field in California. But to do that, we first had to build some actual buildings. Since then, our infrastructure programs have taken on many different forms, but all have been focused on a single mission – helping accelerate stem cell research to patients with unmet medical needs.
CIRM_Infrastucture-program-iconScreen Shot 2017-10-16 at 10.58.38 AM

In the early 2000’s, stem cell scientists faced a quandary. President George W. Bush had placed limits on how federal funds could be used for embryonic stem cell research. His policy allowed funding of research involving some existing embryonic stem cell lines, but banned research that developed or conducted research on new stem lines.

Many researchers felt the existing lines were not the best quality and could only use them in a limited capacity. But because they were dependent on the government to fund their work, had no alternative but to comply. Scientists who chose to use non-approved lines were unable to use their federally funded labs for stem cell work.

The creation of CIRM changed that. In 2008, CIRM launched its Major Facilities Grant Program. The program had two major goals:

1) To accommodate the growing numbers of stem cell researchers coming in California as a result of CIRM’s grants and funding.

2) To provide new research space that didn’t have to comply with the federal restrictions on stem cell research.

Over the next few years, the program invested $271million to help build 12 new research facilities around California from Sacramento to San Diego. The institutions used CIRM’s funding to leverage and attract an additional $543 million in funds from private donors and institutions to construct and furnish the buildings.

These world-class laboratories gave scientists the research space they needed to work with any kind of stem cell they wanted and develop new potential therapies. It also enabled the institutions to bring together under one roof, all the stem cell researchers, who previously had been scattered across each campus.

One other important benefit was the work these buildings provided for thousands of construction workers at a time of record unemployment in the industry. Here’s a video about the 12 facilities we helped build:

But building physical facilities was just our first foray into developing infrastructure. We were far from finished.

In the early days of stem cell research, many scientists used cells from different sources, created using different methods. This meant it was often hard to compare results from one study to another. So, in 2013 CIRM created an iPSC Repository, a kind of high tech stem cell bank. The repository collected tissue samples from people who have different diseases, turned those samples into high quality stem cell lines – the kind known as induced pluripotent stem cells (iPSC) – and then made those samples available to researchers around the world. This not only gave researchers a powerful resource to use in developing a deeper understanding of different diseases, but because the scientists were all using the same cell lines that meant their findings could be compared to each other.

That same year we also launched a plan to create a new, statewide network of clinics that specialize in using stem cells to treat patients. The goal of the Alpha Stem Cell Clinics Network is to support and accelerate clinical trials for programs funded by the agency, academic researchers or industry. We felt that because stem cell therapies are a completely new way of treating diseases and disorders, we needed a completely new way of delivering treatments in a safe and effective manner.

The network began with three clinics – UC San Diego, UCLA/UC Irvine, and City of Hope – but at our last Board meeting was expanded to five with the addition of UC Davis and UCSF Benioff Children’s Hospital Oakland. This network will help the clinics streamline challenging processes such as enrolling patients, managing regulatory procedures and sharing data and will speed the testing and distribution of experimental stem cell therapies. We will be posting a more detailed blog about how our Alpha Clinics are pushing innovative stem cell treatments tomorrow.

As the field advanced we knew that we had to find a new way to help researchers move their research out of the lab and into clinical trials where they could be tested in people. Many researchers were really good at the science, but had little experience in navigating the complex procedures needed to get the green light from the US Food and Drug Administration (FDA) to test their work in a clinical trial.

So, our Agency created the Translating (TC) and Accelerating Centers (AC). The idea was that the TC would help researchers do all the preclinical testing necessary to apply for permission from the FDA to start a clinical trial. Then the AC would help the researchers set up the trial and actually run it.

In the end, one company, Quintiles IMS, won both awards so we combined the two entities into one, The Stem Cell Center, a kind of one-stop-shopping home to help researchers move the most promising treatments into people.

That’s not the whole story of course – I didn’t even mention the Genomics Initiative – but it’s hard to cram 13 years of history into a short blog. And we’re not done yet. We are always looking for new ways to improve what we do and how we do it. We are a work in progress, and we are determined to make as much progress as possible in the years to come.

CIRM-Funded Clinical Trials Targeting Cancers

Welcome to the Month of CIRM!

As we mentioned in last Thursday’s blog, during the month of October we’ll be looking back at what CIRM has done since the agency was created by the people of California back in 2004. To start things off, we’ll be focusing on CIRM-funded clinical trials this week. Supporting clinical trials through our funding and partnership is a critical cornerstone to achieving our mission: to accelerate stem cell treatments to patients with unmet medical needs.

Over the next four days, we will post infographics that summarize CIRM-funded trials focused on therapies for cancer, neurologic disorders, heart and metabolic disease, and blood disorders. Today, we review the nine CIRM-funded clinical trial projects that target cancer. The therapeutic strategies are as varied as the types of cancers the researchers are trying to eradicate. But the common element is developing cutting edge methods to outsmart the cancer cell’s ability to evade standard treatment.

For more details about all CIRM-funded clinical trials, visit our clinical trials page and read our clinical trials brochure which provides brief overviews of each trial.

Stem Cell Stories That Caught our Eye: Insights into a healthy brain, targeting mutant cancers and commercializing cell therapies

Here’s your weekly roundup of interesting stem cell stories!

Partnership for a healthy brain. To differentiate or not to differentiate. That is the question the stem cells in our tissues and organs face.

In the case of the brain, neural precursor cells can either remain in a stem cell state or they can differentiate into mature brain cells called neurons and astrocytes. Scientists are interested in understanding how the brain maintains the balance between these different cell states in order to understand how disruption to this balance are associated with psychiatric and neurodegenerative diseases.

Scientists from the Salk Institute, led by Genetics Professor Rusty Gage, published a study this week in Cell Stem Cell that sheds light on how this imbalance can cause brain disease. They found that a partnership between two proteins determines whether a neural precursor develops into a neuron or an astrocyte.

One of these proteins is called Nup153. It’s a protein that’s part of the nuclear pore complex, which sits on the surface of the nuclear membrane and controls the entry and exit of various proteins and molecules. In collaboration with another Salk team under the leadership of Martin Hetzer, Gage discovered that Nup153 was expressed at different levels depending on the cell type. Neural precursors had high levels of Nup153 protein, immature neurons had what they defined as an intermediate level while astrocytes had the lowest level.

When they blocked the function of Nup153, neural precursors differentiated, which led them to conclude that the levels of Nup153 can influence the fate of neural precursor cells. The teams also discovered that Nup153 interacts with the transcription factor Sox2 and that the levels of Sox2 in the different cell types was similar to the levels of Nup153.

A fluorescent microscopy image shows Nup153 (red) in pore complexes encircling and associating with Sox2 (green) in a precursor cell nucleus. Credit: Salk Institute/Waitt Center

In a Salk News release, first author on the study, Tomohisa Toda, explained how their findings shed light on basic cellular processes:

“The fact that we were able to connect transcription factors, which are mobile switches, to the pore complex, which is a very stable structure, offers a clue as to how cells maintain their identity through regulated gene expression.”

Gage’s team will next study how this partnership between the nuclear pore complex and transcription factors can influence the function of neurons in hopes of gaining more understanding of how an imbalance in these interactions can lead to neurological diseases.

“Increasingly, we are learning that diseases like schizophrenia, depression and Alzheimer’s all have a cellular basis. So we are eager to understand how specific brain cells develop, what keeps them healthy and why advancing age or other factors can lead to disease.”

Tomohisa Toda and Rusty Gage. Credit: Salk Institute

Targeting KRAS Mutant Cancer.

CIRM-funded scientists at UC San Diego School of Medicine have developed a new strategy to target cancers that are caused by a mutation in the KRAS gene. Their findings were published in the journal Cancer Discovery.

The KRAS protein is essential for normal signaling processes in tissues, but mutant versions of this protein can cause cancer. According to a UC San Diego Health news release about the study, “there are currently no effective treatments for the 95 percent of pancreatic cancers and up to 30 percent of non-small cell lung cancers with KRAS mutations.”

To address this need, the team identified a biomarker called αvb3 that is associated with cancers dependent on the KRAS mutation. They observed that a protein called Galectin-3 binds to αvb3, which is an integrin receptor on the surface of cancer cells, to promote mutant KRAS’s cancer-causing ability.

This realization offered the team a path towards potential treatments. By inhibiting Galectin-3 with a drug called GCS-100, the scientists would make KRAS-addicted cancers go cold turkey. Senior author on the study, David Cheresh, explained,

“This may be among the first approaches to successfully target KRAS mutant cancers. Previously, we didn’t understand why only certain KRAS-initiated cancers would remain addicted to the mutation. Now we understand that expression of integrin αvb3 creates the addiction to KRAS. And it’s those addicted cancers that we feel will be most susceptible to targeting this pathway using Galectin-3 inhibitors.”

Cheresh concluded that this novel approach could pave the way for a personalized medicine approach for KRAS-addicted cancers.

“KRAS mutations impact a large number of patients with cancer. If a patient has a KRAS mutant cancer, and the cancer is also positive for αvb3, then the patient could be a candidate for a therapeutic that targets this pathway. Our work suggests a personalized medicine approach to identify and exploit KRAS addicted tumors, providing a new opportunity to halt the progression of tumors that currently have no viable targeted therapeutic options.”

Commercializing cell therapy.

Our friends at RegMedNet made an infographic that illustrates how cell therapies have developed over time and how these therapies are advancing towards commercialization.

The infographic states, “The cell therapy industry is rapidly evolving, with new techniques, technology and applications being developed all the time. After some high-profile failures, all eyes are on regulating existing therapies to ensure patient safety is paramount. Legislators, regulators and other stakeholders around the world are navigating a difficult line between hope, hype and the scientific evidence.”

Check out their timeline below and visit the RegMedNet website for more news and information about the regenerative medicine field.