Breakthrough image could lead to better therapies

Image of a blood stem cell in its natural environment: Photo courtesy UC Merced

When it comes to using stem cells for therapy you don’t just need to understand what kinds of cell to use, you also need to understand the environment that is best for them. Trying to get stem cells to grow in the wrong environment would be like trying to breed sheep in a pond. It won’t end well.

But for years scientists struggled to understand how to create the right environment, or niche, for these cells. The niche provides a very specific micro-environment for stem cells, protecting them and enabling them to self-renew over long periods of time, helping repair damaged tissues and organs in the body.

But different stem cells need different niches, and those involve both physical and chemical properties, and getting that mixture right has been challenging. That in turn has slowed down our ability to use those cells to develop new therapies.

UC Merced’s Joel Spencer in the lab: Photo courtesy UC Merced

Now UC Merced’s Professor Joel Spencer and his team have developed a way of capturing an image of hematopoietic or blood stem cells (HSCs), inside their niche in the bone marrow. In an article on UC Merced News, he says this could be a big step forward.

“Everyone knew black holes existed, but it took until last year to directly capture an image of one due to the complexity of their environment. It’s analogous with stem cells in the bone marrow. Until now, our understanding of HSCs has been limited by the inability to directly visualize them in their native environment.

“This work brings an advancement that will open doors to understanding how these cells work which may lead to better therapeutics for hematologic disorders including cancer.”

In the past, studying HSCs involved transplanting them into a mouse or other animal that had undergone radiation to kill off its own bone marrow cells. It enabled researchers to track the HSCs but clearly the new environment was very different than the original, natural one. So, Spencer and his team developed new microscopes and imaging techniques to study cells and tissues in their natural environment.  

In the study, published in the journal Nature, Spencer says all this is only possible because of recent technological breakthroughs.

“My lab is seeking to answer biological questions that were impossible until the advancements in technology we have seen in the past couple decades. You need to be able to peer inside an organ, inside a live animal and see what’s happening as it happens.”

Being able to see how these cells behave in their natural environment may help researchers learn how to recreate that environment in the lab, and help them develop new and more effective ways of using those cells to repair damaged tissues and organs.

CIRM Board Meeting Highlights Important Updates to Clinical Trials

Dr. Maria T. Millan, President and CEO of CIRM, presenting the President’s Report

This past Thursday the governing Board of the California Institute for Regenerative Medicine (CIRM) were presented with an update on CIRM’s clinical portfolio, which to date includes 60 clinical trials in various areas including kidney failure, cancer, and other rare diseases.  The full President’s Report gives an update on 15 of these trials, in addition to our landmark Cure Sickle Cell Initiative with the NIH and our various educational programs.

Although we won’t be diving into extensive detail for all of these trials, we wanted to highlight several key updates made in this presentation to demonstrate how our clinical portfolio is maturing, with many of these trials moving towards registration. Classically, registration trials are large Phase 3 trials. Notably, some of the highlighted CIRM trials are small Phase 2 or earlier trials that seek to gain enough safety and efficacy data to support final FDA marketing approval. This is a trend with regenerative medicine programs where trial sizes are often small due to the fact that the affected populations are so small with some of these rare diseases. Despite this, the approaches could allow a so called “large effect size,” meaning the signal of clinical benefit per patient is strong enough to give a read of whether the therapy is working or not. CIRM programs often address rare unmet needs and utilize this approach.

For example, Orchard Therapeutics, which is conducting a phase 2 clinical trial for ADA Severe Combined Immunodeficiency (ADA-SCID), a rare immune disorder caused by a genetic mutation, has shown a long-term recovery of the immune system in 20 patients two years post treatment.  Orchard plans to submit a Biologics License Application (BLA) sometime in 2020, which is the key step necessary to obtain final approval from the Food and Drug Administration (FDA) for a therapy.

“We are thrilled to see encouraging results for this genetically modified cell therapy approach and a path forward for FDA approval,” says Maria T. Millan, MD, President and CEO of CIRM. “CIRM is proud of the role it has played in this program.  We funded the program while it was at UCLA and it is now in partnership with Orchard Therapeutics as it takes the program through this final phase toward FDA marketing approval.  Success in this program is a game changer for patients with ADA-SCID who had no other options and who had no bone marrow transplant donors. It also opens up possibilities for future approaches for this dieaseas as well as the other 6,000 genetic diseases that currently have no treatment.”    

The trial uses a gene therapy approach that takes the patient’s own blood stem cells, introduces a functional version of the ADA gene, and reintroduces these corrected blood stem cells back into the patient. From blood tests, one can readily detect whether the approach is successful from the presence of ADA and from the presence of immune cells that were not previously present. To date, it has been awarded approximately $19 million in CIRM funding.  Additionally, it has received FDA Breakthrough Therapy as well as Orphan Drug Designations, both of which are designed to accelerate  the development of the treatment.

Another trial that was highlighted is Rocket Pharmaceutical’s clinical trial for Leukocyte Adhesion Deficiency-1 (LAD-1), a rare and fatal pediatric disease that affects the body’s ability to combat infections. They have just released initial results from their first patient. This is also a gene therapy approach using the patient’s own blood stem cells. The notable aspect of this trial is that the investigators designed this small phase 1 trial of nine patients to be “registration enabling.”  This means that, if they find compelling data, they intend to bring the experience and data from this trial to the FDA to seek agreement on what would be required to get final marketing approval in order to get this treatment to patients with severe unmet medical needs in the most timely way possible.     

Preliminary results demonstrate early evidence of safety and potential efficacy.  There were visible improvements in multiple disease-related skin lesions after receiving the therapy. They are collecting more data on more patients.  To date, it has received $6.6 million in CIRM funding.

As a unique immuno-oncology approach (using the body’s immune system to battle cancer), CIRM is funding Forty Seven Inc. to conduct a clinical trial for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), both of which are forms of cancer.  They have received Fast Track and Orphan Drug designation from the FDA.

The trial is using an antibody blocking CD47, a “don’t eat me” signal, which allows the body’s own immune cells to seek and destroy cancerous stem cells.  This is combined with chemotherapy to render the cancer stem cells more susceptible to immune destruction.  This trial has received $5 million in CIRM funding thus far.

Other registration phase trials in the CIRM portfolio include the following Phase 3 trials:

Brainstorm Cell Therapeutics, for a fatal debilitating neurodegenerative disease, Amyotrophic Lateral Sclerosis (Lou Gehrig’s disease).  That company has completed enrollment and expects top line results in the final quarter of 2020.

Humacyte, which is testing bioengineered de-cellularized vessels that are implanted to create vascular access that is repopulated by the patients own stem cells to make it more like native vessel.  The company is conducting two Phase 3 trials to compare this bioengineered vessel to synthetic grafts and to the patients’ own vessels for use in hemodialysis, a “life line” for patients with end stage renal disease. Humacyte was the first US FDA Cell Therapy program to receive the Regenerative Medicine Advanced Technologies (RMAT) in March 2017. To date, these trials have been awarded $24 million in CIRM funding.

Medeor Therapeutics has received $11.2M in CIRM funding to conduct a Phase 3 trial in combined blood stem cell and kidney transplantation to induce immunologic tolerance so that the blood stem cells teach the patient’s immune system to recognize the transplanted kidney as its own.  The goal is to remove the need for chronic immunosuppressive medications, that have its own complications. If successful, transplant recipients would not need to “trade one chronic condition for another.”

Rave reviews for new Killer-T Cell study

Anytime you read a news headline that claims a new discovery “may treat all cancer” it’s time to put your skeptic’s hat on. After all, there have been so many over-hyped “discoveries” over the years that later flopped, that it would be natural to question the headline writer. And yet, this time, maybe, this one has some substance behind it.

Andrew Sewell with research fellow Garry Dolton. (Photo Credit: Cardiff University)

Researchers at the University of Cardiff in Wales have discovered a new kind of immune cell, a so-called “killer T-cell”, that appears to be able to target and kill many human cancer cells, such as those found in breast, prostate and lung cancer. At least in the lab.

The immune system is our body’s defense against all sorts of threats, from colds and flu to cancer. But many cancers are able to trick the immune system and evade detection as they spread throughout the body. The researchers found one T-cell receptor (TCR) that appears to be able to identify cancer cells and target them, but leave healthy tissues alone.

In an interview with the BBC, Prof. Andrew Sewell, the lead researcher on the study said: “There’s a chance here to treat every patient. Previously nobody believed this could be possible. It raises the prospect of a ‘one-size-fits-all’ cancer treatment, a single type of T-cell that could be capable of destroying many different types of cancers across the population.”

The study, published in the journal Nature Immunology, suggests the TCR works by using a molecule called MR1 to identify cancerous cells. MR1 is found on every cell in our body but in cancerous cells it appears to give off a different signal, which enables the TCR to identify it as a threat.

When the researchers injected this TCR into mice that had cancer it was able to clear away many of the cells. The researchers admit there is still a long way to go before they know if this approach will work in people, but Sewell says they are encouraged by their early results.

“There are plenty of hurdles to overcome. However, if this testing is successful, then I would hope this new treatment could be in use in patients in a few years’ time.”

CIRM is funding a number of clinical trials that use a similar approach to targeting cancers, taking the patient’s own immune T-cells and, in the lab, “re-educating” to be able to recognize the cancerous cells. Those cells are then returned to the patient where it’s hoped they’ll identify and destroy the cancer. You can read about those here , here, here, here, and here.

It’s official: the state of regenerative medicine is strong

A panel discussion to a packed house at the annual ARM State of the Industry briefing

Calling it a “year of dramatic impact for patients” Janet Lambert, the CEO of the Alliance for Regenerative Medicine (ARM), gave the annual “State of the Industry” briefing today in San Francisco.

The briefing is a traditional kick-off event to mark JP Morgan week in the City, a time when hotel rooms go for $1,000 a night and just reserving a table in the lobby for meetings can set you back hundreds of dollars. Fortunately, the ARM briefing is free. And worth every penny.

Janet Lambert, CEO Alliance for Regenerative Medicine

Lambert ran down the numbers that highlighted how the field is growing and expanding:

  • 987 companies world wide – most of those in the US
  • 1,000 + clinical trials
  • $9.8 billion in revenue/investments

Saying “for many of these patients these therapies don’t just bring improvements, they bring dramatic improvements” Lambert pointed out that when those 1,000 clinical trials are fully enrolled it will mean 60,000 patients getting stem cell and gene therapies. She says it’s estimated that in the coming years around half a million patients in the US alone will get one of those therapies.

More and more of the clinical trials are at advanced stages:

  • 100 Phase 3
  • 591 Phase 2
  • 381 Phase 1

The biggest sector for clinical trials is cancer, but there are also substantial numbers for central nervous system therapies, muscular skeletal and even rare diseases.

Lambert said there are two key issues facing the field in the coming year. One is improving the industry’s manufacturing capability to ensure we are able to produce the cells needed to treat large numbers of patients. As evidence she cited the fact that Pfizer and Novartis are investing hundreds of millions of dollars in in-house manufacturing facilities. 

The second key issue is reimbursement, so that companies can get paid for delivering those treatments to patients.  “There is appetite and interest in this from people around the world, but right now most conversations about reimbursement are taking place one at a time. We haven’t yet evolved to the point where we have standard models to help get products to market and help them be commercially successful.”

The forecast for the year ahead? “Sunny with some clouds. 2019 was a year of significant growth and we enter 2020 with hopes of continued expansion, as we look to grow the impact on patients.” 

Facebook Live: Ask the Stem Cell Team

On December 12th we hosted our latest ‘Facebook Live: Ask the Stem Cell Team’ event. This time around we really did mean team. We had a host of our Science Officers answering questions from friends and supporters of CIRM. We got a lot of questions and didn’t have enough time to address them all. So here’s answers to all the questions.

What are the obstacles to using partial cellular reprogramming to return people’s entire bodies to a youthful state. Paul Hartman.  San Leandro, California

Dr. Kelly Shepard

Dr. Kelly Shepard: Certainly, scientists have observed that various manipulations of cells, including reprogramming, partial reprogramming, de-differentiation and trans-differentiation, can restore or change properties of cells, and in some cases, these changes can reflect a more “youthful” state, such as having longer telomeres, better proliferative capacity, etc. However, some of these same rejuvenating properties, outside of their normal context, could be harmful or deadly, for example if a cell began to grow and divide when or where it shouldn’t, similar to cancer. For this reason, I believe the biggest obstacles to making this approach a reality are twofold: 1)  our current, limited understanding of the nature of partially reprogrammed cells; and 2) our inability to control the fate of those cells that have been partially reprogrammed, especially if they are inside a living organism.  Despite the challenges, I think there will be step wise advances where these types of approaches will be applied, starting with specific tissues. For example, CIRM has recently funded an approach that uses reprogramming to make “rejuvenated” versions of T cells for fighting lung cancer.  There is also a lot of interest in using such approaches to restore the reparative capacity of aged muscle. Perhaps some successes in these more limited areas will be the basis for expanding to a broader use.

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STROKE

What’s going on with Stanford’s stem cell trials for stroke? I remember the first trial went really well In 2016 have not heard anything about since? Elvis Arnold

Dr. Lila Collins

Dr. Lila Collins: Hi Elvis, this is an evolving story.  I believe you are referring to SanBio’s phase 1/2a stroke trial, for which Stanford was a site. This trial looked at the safety and feasibility of SanBio’s donor or allogeneic stem cell product in chronic stroke patients who still had motor deficits from their strokes, even after completing physical therapy when natural recovery has stabilized.  As you note, some of the treated subjects had promising motor recoveries. 

SanBio has since completed a larger, randomized phase 2b trial in stroke, and they have released the high-level results in a press release.  While the trial did not meet its primary endpoint of improving motor deficits in chronic stroke, SanBio conducted a very similar randomized trial in patients with stable motor deficits from chronic traumatic brain injury (TBI).  In this trial, SanBio saw positive results on motor recovery with their product.  In fact, this product is planned to move towards a conditional approval in Japan and has achieved expedited regulatory status in the US, termed RMAT, in TBI which means it could be available more quickly to patients if all goes well.  SanBio plans to continue to investigate their product in stroke, so I would stay tuned as the work unfolds. 

Also, since you mentioned Stanford, I should note that Dr Gary Steinberg, who was a clinical investigator in the SanBio trial you mentioned, will soon be conducting a trial with a different product that he is developing, neural progenitor cells, in chronic stroke.  The therapy looks promising in preclinical models and we are hopeful it will perform well for patients in the clinic.

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I am a stroke survivor will stem cell treatment able to restore my motor skills? Ruperto

Dr. Lila Collins:

Hi Ruperto. Restoring motor loss after stroke is a very active area of research.  I’ll touch upon a few ongoing stem cell trials.  I’d just like to please advise that you watch my colleague’s comments on stem cell clinics (these can be found towards the end of the blog) to be sure that any clinical research in which you participate is as safe as possible and regulated by FDA.

Back to stroke, I mentioned SanBio’s ongoing work to address motor skill loss in chronic stroke earlier.  UK based Reneuron is also conducting a phase 2 trial, using a neural progenitor cell as a candidate therapy to help recover persistent motor disability after stroke (chronic).  Dr Gary Steinberg at Stanford is also planning to conduct a clinical trial of a human embryonic stem cell-derived neuronal progenitor cell in stroke.

There is also promising work being sponsored by Athersys in acute stroke. Athersys published results from their randomized, double blinded placebo controlled Ph2 trial of their Multistem product in patients who had suffered a stroke within 24-48 hours.  After intravenous delivery, the cells improved a composite measure of stroke recovery, including motor recovery.  Rather than acting directly on the brain, Multistem seems to work by traveling to the spleen and reducing the inflammatory response to a stroke that can make the injury worse.

Athersys is currently recruiting a phase 3 trial of its Multistem product in acute stroke (within 1.5 days of the stroke).  The trial has an accelerated FDA designation, called RMAT and a special protocol assessment.  This means that if the trial is conducted as planned and it reaches the results agreed to with the FDA, the therapy could be cleared for marketing.  Results from this trial should be available in about two years. 

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Questions from several hemorrhagic stroke survivors who say most clinical trials are for people with ischemic strokes. Could stem cells help hemorrhagic stroke patients as well?

Dr. Lila Collins:

Regarding hemorrhagic stroke, you are correct the bulk of cell therapies for stroke target ischemic stroke, perhaps because this accounts for the vast bulk of strokes, about 85%.

That said, hemorrhagic strokes are not rare and tend to be more deadly.  These strokes are caused by bleeding into or around the brain which damages neurons.  They can even increase pressure in the skull causing further damage.  Because of this the immediate steps treating these strokes are aimed at addressing the initial bleeding insult and the blood in the brain.

While most therapies in development target ischemic stroke, successful therapies developed to repair neuronal damage or even some day replace lost neurons, could be beneficial after hemorrhagic stroke as well.

We are aware of a clinical trial targeting acute hemorrhagic stroke that is being run by the Mayo clinic in Jacksonville Florida.

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I had an Ischemic stroke in 2014, and my vision was also affected. Can stem cells possibly help with my vision issues. James Russell

Dr. Lila Collins:

Hi James. Vision loss from stroke is complex and the type of loss depends upon where the stroke occurred (in the actual eye, the optic nerve or to the other parts of the brain controlling they eye or interpreting vision).  The results could be:

  1. Visual loss from damage to the retina
  2. You could have a normal eye with damage to the area of the brain that controls the eye’s movement
  3. You could have damage to the part of the brain that interprets vision.

You can see that to address these various issues, we’d need different cell replacement approaches to repair the retina or the parts of the brain that were damaged. 

Replacing lost neurons is an active effort that at the moment is still in the research stages.  As you can imagine, this is complex because the neurons have to make just the right connections to be useful. 

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VISION

Is there any stem cell therapy for optical nerve damage? Deanna Rice

Dr. Ingrid Caras

Dr. Ingrid Caras: There is currently no proven stem cell therapy to treat optical nerve damage, even though there are shady stem cell clinics offering treatments.  However, there are some encouraging early gene therapy studies in mice using a virus called AAV to deliver growth factors that trigger regeneration of the damaged nerve. These studies suggest that it may be possible to restore at least some visual function in people blinded by optic nerve damage from glaucoma

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I read an article about ReNeuron’s retinitis pigmentosa clinical trial update.  In the article, it states: “The company’s treatment is a subretinal injection of human retinal progenitors — cells which have almost fully developed into photoreceptors, the light-sensing retinal cells that make vision possible.” My question is: If they can inject hRPC, why not fully developed photoreceptors? Leonard

Dr. Kelly Shepard: There is evidence from other studies, including from other tissue types such as blood, pancreas, heart and liver, that fully developed (mature) cell types tend not to engraft as well upon transplantation, that is the cells do not establish themselves and survive long term in their new environment. In contrast, it has been observed that cells in a slightly less “mature” state, such as those in the progenitor stage, are much more likely to establish themselves in a tissue, and then differentiate into more mature cell types over time. This question gets at the crux of a key issue for many new therapies, i.e. what is the best cell type to use, and the best timing to use it.

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My question for the “Ask the Stem Cell Team” event is: When will jCyte publish their Phase IIb clinical trial results. Chris Allen

Dr. Ingrid Caras: The results will be available sometime in 2020.

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I understand the hRPC cells are primarily neurotropic (rescue/halt cell death); however, the literature also says hRPC can become new photoreceptors.  My questions are: Approximately what percentage develop into functioning photoreceptors? And what percentage of the injected hRPC are currently surviving? Leonard Furber, an RP Patient

Dr. Kelly Shepard: While we can address these questions in the lab and in animal models, until there is a clinical trial, it is not possible to truly recreate the environment and stresses that the cells will undergo once they are transplanted into a human, into the site where they are expected to survive and function. Thus, the true answer to this question may not be known until after clinical trials are performed and the results can be evaluated. Even then, it is not always possible to monitor the fate of cells after transplantation without removing tissues to analyze (which may not be feasible), or without being able to transplant labeled cells that can be readily traced.

Dr. Ingrid Caras – Although the cells have been shown to be capable of developing into photoreceptors, we don’t know if this actually happens when the cells are injected into a patient’s eye.   The data so far suggest that the cells work predominantly by secreting growth factors that rescue damaged retinal cells or even reverse the damage. So one possible outcome is that the cells slow or prevent further deterioration of vision. But an additional possibility is that damaged retinal cells that are still alive but are not functioning properly may become healthy and functional again which could result in an improvement in vision.

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DIABETES

What advances have been made using stem cells for the treatment of Type 2 Diabetes? Mary Rizzo

Dr. Ross Okamura

Dr. Ross Okamura: Type 2 Diabetes (T2D) is a disease where the body is unable to maintain normal glucose levels due to either resistance to insulin-regulated control of blood sugar or insufficient insulin production from pancreatic beta cells.  The onset of disease has been associated with lifestyle influenced factors including body mass, stress, sleep apnea and physical activity, but it also appears to have a genetic component based upon its higher prevalence in certain populations. 

Type 1 Diabetes (T1D) differs from T2D in that in T1D patients the pancreatic beta cells have been destroyed by the body’s immune system and the requirement for insulin therapy is absolute upon disease onset rather than gradually developing over time as in many T2D cases.  Currently the only curative approach to alleviate the heavy burden of disease management in T1D has been donor pancreas or islet transplantation. However, the supply of donor tissue is small relative to the number of diabetic patients.  Donor islet and pancreas transplants also require immune suppressive drugs to prevent allogenic immune rejection and the use of these drugs carry additional health concerns.  However, for some patients with T1D, especially those who may develop potentially fatal hypoglycemia, immune suppression is worth the risk.

To address the issue of supply, there has been significant activity in stem cell research to produce insulin secreting beta cells from pluripotent stem cells and recent clinical data from Viacyte’s CIRM funded trial indicates that implanted allogeneic human stem cell derived cells in T1D patients can produce circulating c-peptide, a biomarker for insulin.  While the trial is not designed specifically to cure insulin-dependent T2D patients, the ability to produce and successfully engraft stem cell-derived beta cells would be able to help all insulin-dependent diabetic patients.

It’s also worth noting that there is a sound scientific reason to clinically test a patient-derived pluripotent stem cell-based insulin-producing cells in insulin-dependent T2D diabetic patients; the cells in this case could be evaluated for their ability to cure diabetes in the absence of needing to prevent both allogeneic and autoimmune responses.

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SPINAL CORD INJURY

Is there any news on clinical trials for spinal cord injury? Le Ly

Kevin McCormack: The clinical trial CIRM was funding, with Asterias (now part of a bigger company called Lineage Cell Therapeutics, is now completed and the results were quite encouraging. In a news release from November of 2019 Brian Culley, CEO of Lineage Cell Therapeutics, described the results this way.

“We remain extremely excited about the potential for OPC1 (the name of the therapy used) to provide enhanced motor recovery to patients with spinal cord injuries. We are not aware of any other investigative therapy for SCI (spinal cord injury) which has reported as encouraging clinical outcomes as OPC1, particularly with continued improvement beyond 1 year. Overall gains in motor function for the population assessed to date have continued, with Year 2 assessments measuring the same or higher than at Year 1. For example, 5 out of 6 Cohort 2 patients have recovered two or more motor levels on at least one side as of their Year 2 visit whereas 4 of 6 patients in this group had recovered two motor levels as of their Year 1 visit. To put these improvements into perspective, a one motor level gain means the ability to move one’s arm, which contributes to the ability to feed and clothe oneself or lift and transfer oneself from a wheelchair. These are tremendously meaningful improvements to quality of life and independence. Just as importantly, the overall safety of OPC1 has remained excellent and has been maintained 2 years following administration, as measured by MRI’s in patients who have had their Year 2 follow-up visits to date. We look forward to providing further updates on clinical data from SCiStar as patients continue to come in for their scheduled follow up visits.”

Lineage Cell Therapeutics plans to meet with the FDA in 2020 to discuss possible next steps for this therapy.

In the meantime the only other clinical trial I know that is still recruiting is one run by a company called Neuralstem. Here is a link to information about that trial on the www.clinicaltrials.gov website.

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ALS

Now that the Brainstorm ALS trial is finished looking for new patients do you have any idea how it’s going and when can we expect to see results? Angela Harrison Johnson

Dr. Ingrid Caras: The treated patients have to be followed for a period of time to assess how the therapy is working and then the data will need to be analyzed.  So we will not expect to see the results probably for another year or two.

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AUTISM

Are there treatments for autism or fragile x using stem cells? Magda Sedarous

Dr. Kelly Shepard: Autism and disorders on the autism spectrum represent a collection of many different disorders that share some common features, yet have different causes and manifestations, much of which we still do not understand. Knowing the origin of a disorder and how it affects cells and systems is the first step to developing new therapies. CIRM held a workshop on Autism in 2009 to brainstorm potential ways that stem cell research could have an impact. A major recommendation was to exploit stem cells and new technological advances to create cells and tissues, such as neurons, in the lab from autistic individuals that could then be studied in great detail.  CIRM followed this recommendation and funded several early-stage awards to investigate the basis of autism, including Rett Syndrome, Fragile X, Timothy Syndrome, and other spectrum disorders. While these newer investigations have not yet led to therapies that can be tested in humans, this remains an active area of investigation. Outside of CIRM funding, we are aware of more mature studies exploring the effects of umbilical cord blood or other specific stem cell types in treating autism, such as an ongoing clinical trial conducted at Duke University.

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PARKINSON’S DISEASE

What is happening with Parkinson’s research? Hanifa Gaphoor

Dr. Kent Fitzgerald

Dr. Kent Fitzgerald: Parkinson’s disease certainly has a significant amount of ongoing work in the regenerative medicine and stem cell research. 

The nature of cell loss in the brain, specifically the dopaminergic cells responsible for regulating the movement, has long been considered a good candidate for cell replacement therapy.  

This is largely due to the hypothesis that restoring function to these cells would reverse Parkinson’s symptoms. This makes a lot of sense as front line therapy for the disease for many years has been dopamine replacement through L-dopa pills etc.  Unfortunately, over time replacing dopamine through a pill loses its benefit, whereas replacing or fixing the cells themselves should be a more permanent fix. 

Because a specific population of cells in one part of the brain are lost in the disease, multiple labs and clinicians have sought to replace or augment these cells by transplantation of “new” functional cells able to restore function to the area an theoretically restore voluntary motor control to patients with Parkinson’s disease. 

Early clinical research showed some promise, however also yielded mixed results, using fetal tissue transplanted into the brains of Parkinson’s patients.   As it turns out, the cell types required to restore movement and avoid side effects are somewhat nuanced.  The field has moved away from fetal tissue and is currently pursuing the use of multiple stem cell types that are driven to what is believed to be the correct subtype of cell to repopulate the lost cells in the patient. 

One project CIRM sponsored in this area with Jeanne Loring sought to develop a cell replacement therapy using stem cells from the patients themselves that have been reprogrammed into the kinds of cell damaged by Parkinson’s.  This type of approach may ultimately avoid issues with the cells avoiding rejection by the immune system as can be seen with other types of transplants (i.e. liver, kidney, heart etc).

Still, others are using cutting edge gene therapy technology, like the clinical phase project CIRM is sponsoring with Krystof Bankiewicz to investigate the delivery of a gene (GDNF) to the brain that may help to restore the activity of neurons in the Parkinson’s brain that are no longer working as they should. 

The bulk of the work in the field of PD at the present remains centered on replacing or restoring the dopamine producing population of cells in the brain that are affected in disease.   

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HUNTINGTON’S DISEASE

Any plans for Huntington’s? Nikhat Kuchiki

Dr. Lisa Kadyk

Dr. Lisa Kadyk: The good news is that there are now several new therapeutic approaches to Huntington’s Disease that are at various stages of preclinical and clinical development, including some that are CIRM funded.   One CIRM-funded program led by Dr. Leslie Thompson at UC Irvine is developing a cell-based therapeutic that consists of neural stem cells that have been manufactured from embryonic stem cells.   When these cells are injected into the brain of a mouse that has a Huntington’s Disease mutation, the cells engraft and begin to differentiate into new neurons.  Improvements are seen in the behavioral and electrophysiological deficits in these mutant mice, suggesting that similar improvements might be seen in people with the disease.   Currently, CIRM is funding Dr. Thompson and her team to carry out rigorous safety studies in animals using these cells, in preparation for submitting an application to the FDA to test the therapy in human patients in a clinical trial.   

There are other, non-cell-based therapies also being tested in clinical trials now, using  anti-sense oligonucleotides (Ionis, Takeda) to lower the expression of the Huntington protein.  Another HTT-lowering approach is similar – but uses miRNAs to lower HTT levels (UniQure, Voyager)

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TRAUMATIC BRAIN INJURY (TBI)

My 2.5 year old son recently suffered a hypoxic brain injury resulting in motor and speech disabilities. There are several clinical trials underway for TBI in adults. My questions are:

  • Will the results be scalable to pediatric use and how long do you think it would take before it is available to children?
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  • I’m wondering why the current trials have chosen to go the route of intracranial injections as opposed to something slightly less invasive like an intrathecal injection?
  • Is there a time window period in which stem cells should be administered by, after which the administration is deemed not effective?

Dr. Kelly Shepard:  TBI and other injuries of the nervous system are characterized by a lot of inflammation at the time of injury, which is thought to interfere with the healing process- and thus some approaches are intended to be delivered after that inflammation subsides. However, we are aware of approaches that intend to deliver a therapy to a chronic injury, or one that has occurred  previously. Thus, the answer to this question may depend on how the intended therapy is supposed to work. For example, is the idea to grow new neurons, or is it to promote the survival of neurons of other cells that were spared by the injury? Is the therapy intended to address a specific symptom, such as seizures? Is the therapy intended to “fill a gap” left behind after inflammation subsides, which might not restore all function but might ameliorate certain symptoms.? There is still a lot we don’t understand about the brain and the highly sophisticated network of connections that cannot be reversed by only replacing neurons, or only reducing inflammation, etc. However, if trials are well designed, they should yield useful information even if the therapy is not as effective as hoped, and this information will pave the way to newer approaches and our technology and understanding evolves.

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We have had a doctor recommending administering just the growth factors derived from MSC stem cells. Does the science work that way? Is it possible to isolate the growth factors and boost the endogenous growth factors by injecting allogenic growth factors?

Dr. Stephen Lin

Dr. Stephen Lin:  Several groups have published studies on the therapeutic effects in non-human animal models of using nutrient media from MSC cultures that contain secreted factors, or extracellular vesicles from cells called exosomes that carry protein or nucleic acid factors.  Scientifically it is possible to isolate the factors that are responsible for the therapeutic effect, although to date no specific factor or combination of factors have been identified to mimic the effects of the undefined mixtures in the media and exosomes.  At present no regulatory approved clinical therapy has been developed using this approach. 

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PREDATORY STEM CELL CLINICS

What practical measures are being taken to address unethical practitioners whose bad surgeries are giving stem cell advances a bad reputation and are making forward research difficult? Kathy Jean Schultz

Dr. Geoff Lomax

Dr. Geoff Lomax: Terrific question! I have been doing quite a bit research into the history of this issue of unethical practitioners and I found an 1842 reference to “quack medicines.” Clearly this is nothing new. In that day, the author appealed to make society “acquainted with the facts.”

In California, we have taken steps to (1) acquaint patients with the facts about stem cell treatments and (2) advance FDA authorized treatments for unmet medical needs.

  • First, CIRM work with Senator Hernandez in 2017 to write a law the requires provides to disclose to patient that a stem cell therapy has not been approved by the Food and Drug administration.
  • We continue to work with the State Legislature and Medical Board of California to build on policies that require accurate disclosure of the facts to patients.
  • Second, our clinical trial network the — Alpha Stem Cell Clinics – have supported over 100 FDA-authorized clinical trials to advance responsible clinical research for unmet medical needs.

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I’m curious if adipose stem cell being used at clinics at various places in the country is helpful or beneficial? Cheri Hicks

Adipose tissue has been widely used particularly in plastic and reconstructive surgery. Many practitioners suggest adipose cells are beneficial in this context. With regard to regenerative medicine and / or the ability to treat disease and injury, I am not aware of any large randomized clinical trials that demonstrate the safety and efficacy of adipose-derived stem cells used in accordance with FDA guidelines.

I went to a “Luncheon about Stem Cell Injections”. It sounded promising. I went thru with it and got the injections because I was desperate from my knee pain. The price of stem cell injections was $3500 per knee injection. All went well. I have had no complications, but haven’t noticed any real major improvement, and here I am a year later. My questions are:

 1) I wonder on where the typical injection cells are coming from?

  2) I wonder what is the actual cost of the cells?

3) What kind of results are people getting from all these “pop up” clinics or established clinics that are adding this to there list of offerings?

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Dr. Geoff Lomax: You raise a number of questions and point here; they are all very good and it’s is hard to give a comprehensive response to each one, but here is my reaction:

  • There are many practitioners in the field of orthopedics who sincerely believe in the potential of cell-based treatments to treat injury / pain
  • Most of the evidence presented is case reports that individuals have benefited
  • The challenge we face is not know the exact type of injury and cell treatments used.
  • Well controlled clinical trials would really help us understand for what cells (or cell products) and for what injury would be helpful
  • Prices of $3000 to $5000 are not uncommon, and like other forms of private medicine there is often a considerable mark-up in relation to cost of goods.
  • You are correct that there have not been reports of serious injury for knee injections
  • However the effectiveness is not clear while simultaneously millions of people have been aided by knee replacements.

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Do stem cells have benefits for patients going through chemotherapy and radiation therapy? Ruperto

Dr. Kelly Shepard: The idea that a stem cell therapy could help address effects of chemotherapy or radiation is being and has been pursued by several investigators over the years, including some with CIRM support. Towards the earlier stages, people are looking at the ability of different stem cell-derived neural cell preparations to replace or restore function of certain brain cells that are damaged by the effects of chemotherapy or radiation. In a completely different type of approach, a group at City of Hope is exploring whether a bone marrow transplant with specially modified stem cells can provide a protective effect against the chemotherapy that is used to treat a form of brain cancer, glioblastoma. This study is in the final stage of development that, if all goes well, culminates with application to the FDA to allow initiation of a clinical trial to test in people.

Dr. Ingrid Caras: That’s an interesting and valid question.  There is a Phase 1 trial ongoing that is evaluating a novel type of stem/progenitor cell from the umbilical cord of healthy deliveries.  In animal studies, these cells have been shown to reduce the toxic effects of chemotherapy and radiation and to speed up recovery. These cells are now being tested in a First-in-human clinical trial in patients who are undergoing high-dose chemotherapy to treat their disease.

There is a researcher at Stanford, Michelle Monje, who is investigating that the role of damage to stem cells in the cognitive problems that sometimes arise after chemo- and radiation therapy (“chemobrain”).  It appears that damage to stem cells in the brain, especially those responsible for producing oligodendrocytes, contributes to chemobrain.  In CIRM-funded work, Dr. Monje has identified small molecules that may help prevent or ameliorate the symptoms of chemobrain.

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Is it possible to use a technique developed to fight one disease to also fight another? For instance, the bubble baby disease, which has cured (I think) more than 50 children, may also help fight sickle cell anemia?  Don Reed.

Dr. Lisa Kadyk: Hi Don. Yes, the same general technique can often be applied to more than one disease, although it needs to be “customized” for each disease.   In the example you cite, the technique is an “autologous gene-modified bone marrow transplant” – meaning the cells come from the patient themselves.  This technique is relevant for single gene mutations that cause diseases of the blood (hematopoietic) system.  For example, in the case of “bubble baby” diseases, a single mutation can cause failure of immune cell development, leaving the child unable to fight infections, hence the need to have them live in a sterile “bubble”.   To cure that disease, blood stem cells, which normally reside in the bone marrow, are collected from the patient and then a normal version of the defective gene is introduced into the cells, where it is incorporated into the chromosomes.   Then, the corrected stem cells are transplanted back into the patient’s body, where they can repopulate the blood system with cells expressing the normal copy of the gene, thus curing the disease.  

A similar approach could be used to treat sickle cell disease, since it is also caused by a single gene mutation in a gene (beta hemoglobin) that is expressed in blood cells.  The same technique would be used as I described for bubble baby disease but would differ in the gene that is introduced into the patient’s blood stem cells. 

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Is there any concern that CIRM’s lack of support in basic research will hamper the amount of new approaches that can reach clinical stages? Jason

Dr. Kelly Shepard: CIRM always has and continues to believe that basic research is vital to the field of regenerative medicine. Over the past 10 years CIRM has invested $904 million in “discovery stage/basic research”, and about $215 million in training grants that supported graduate students, post docs, clinical fellows, undergraduate, masters and high school students performing basic stem cell research. In the past couple of years, with only a limited amount of funds remaining, CIRM made a decision to invest most of the remaining funds into later stage projects, to support them through the difficult transition from bench to bedside. However, even now, CIRM continues to sponsor some basic research through its Bridges and SPARK Training Grant programs, where undergraduate, masters and even high school students are conducting stem cell research in world class stem cell laboratories, many of which are the same laboratories that were supported through CIRM basic research grants over the past 10 years. While basic stem cell research continues to receive a substantial level of support from the NIH ($1.8 billion in 2018, comprehensively on stem cell projects) and other funders, CIRM believes continued support for basic research, especially in key areas of stem cell research and vital opportunities, will always be important for discovering and developing new treatments.

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What is the future of the use of crispr cas9 in clinical trials in california/globally. Art Venegas

Dr. Kelly Shepard: CRISPR/Cas9 is a powerful gene editing tool. In only a few years, CRISPR/Cas9 technology has taken the field by storm and there are already a few CRISPR/Cas9 based treatments being tested in clinical trials in the US. There are also several new treatments that are at the IND enabling stage of development, which is the final testing stage required by the FDA before a clinical trial can begin. Most of these clinical trials involving CRISPR go through an “ex vivo” approach, taking cells from the patient with a disease causing gene, correcting the gene in the laboratory using CRISPR, and reintroducing the cells carrying the corrected gene back into the patient for treatment.  Sickle cell disease is a prime example of a therapy being developed using this strategy and CIRM funds two projects that are preparing for clinical trials with this approach.  CRISPR is also being used to develop the next generation of cancer T-cell therapies (e.g. CAR-T), where T-cells – a vital part of our immune system – are modified to target and destroy cancer cell populations.  Using CRISPR to edit cells directly in patients “in vivo” (inside the body) is far less common currently but is also being developed.  It is important to note that any FDA sanctioned “in vivo” CRISPR clinical trial in people will only modify organ-specific cells where the benefits cannot be passed on to subsequent generations. There is a ban on funding for what are called germ line cells, where any changes could be passed down to future generations.

CIRM is currently supporting multiple CRISPR/Cas9 gene editing projects in California from the discovery or most basic stage of research, through the later stages before applying to test the technique in people in a clinical trial.

While the field is new – if early safety signals from the pioneering trials are good, we might expect a number of new CRISPR-based approaches to enter clinical testing over the next few years. The first of these will will likely be in the areas of bone marrow transplant to correct certain blood/immune or  metabolic diseases, and cancer immunotherapies, as these types of approaches are the best studied and furthest along in the pipeline.

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Explain the differences between gene therapy and stem cell therapy? Renee Konkol

Dr. Stephen Lin:  Gene therapy is the direct modification of cells in a patient to treat a disease.  Most gene therapies use modified, harmless viruses to deliver the gene into the patient.  Gene therapy has recently seen many success in the clinic, with the first FDA approved therapy for a gene induced form of blindness in 2017 and other approvals for genetic forms of smooth muscle atrophy and amyloidosis. 

Stem cell therapy is the introduction of stem cells into patients to treat a disease, usually with the purpose of replacing damaged or defective cells that contribute to the disease.  Stem cell therapies can be derived from pluripotent cells that have the potential to turn into any cell in the body and are directed towards a specific organ lineage for the therapy.  Stem cell therapies can also be derived from other cells, called progenitors, that have the ability to turn into a limited number of other cells in the body. for example hematopoietic or blood stem cells (HSCs), which are found in bone marrow, can turn into other cells of the blood system including B-cells and T-cells: while mesenchymal stem cells (MSCs), which are usually found in fat tissue, can turn into bone, cartilage, and fat cells.  The source of these cells can be from the patient’s own body (autologous) or from another person (allogeneic).

Gene therapy is often used in combination with cell therapies when cells are taken from the patient and, in the lab, modified genetically to correct the mutation or to insert a correct form of the defective gene, before being returned to patients.  Often referred to as “ex vivo gene therapy” – because the changes are made outside the patient’s body – these therapies include Chimeric Antigen Receptor T (CAR-T) cells for cancer therapy and gene modified HSCs to treat blood disorders such as severe combined immunodeficiency and sickle cell disease. This is an exciting area that has significantly improved and even cured many people already.

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Currently, how can the outcome of CIRM stem cell medicine projects and clinical trials be soundly interpreted when their stem cell-specific doses are not known? James L. Sherley, M.D., Ph.D., Director. Asymmetrex, LLC

Dr. Stephen Lin:  Stem cell therapies that receive approval to conduct clinical trials must submit a package of data to the FDA that includes studies that demonstrate their effectiveness, usually in animal models of the disease that the cell therapy is targeting.  Those studies have data on the dose of the cell therapy that creates the therapeutic effect, which is used to estimate cell doses for the clinical trial.  CIRM funds discovery and translational stage awards to conduct these types of studies to prepare cell therapies for clinical trials.  The clinical trial is also often designed to test multiple doses of the cell therapy to determine the one that has the best therapeutic effect.   Dosing can be very challenging with cell therapies because of issues including survival, engraftment, and immune rejection, but CIRM supports studies designed to provide data to give the best estimate possible.

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Is there any research on using stem cells to increase the length of long bones in people?” For example, injecting stem cells into the growth plates to see if the cells can be used to lengthen limbs. Sajid

Dr. Kelly Shepard: There is quite a lot of ongoing research seeking ways to repair bones with stem cell based approaches, which is not the same but somewhat related. Much of this is geared towards repairing the types of bone injuries that do not heal well naturally on their own (large gaps, dead bone lesions, degenerative bone conditions). Also, a lot of this research involves engineering bone tissues in the lab and introducing the engineered tissue into a bone lesion that need be repaired. What occurs naturally at the growth plate is a complex interaction between many different cell types, much of which we do not fully understand. We do not fully understand how to use the cells that are used to engineer bone tissue in the lab. However, a group at Stanford, with some CIRM support, recently discovered a “skeletal stem cell” that exists naturally at the ends of human bones and at sites of fracture.  These are quite different than MSCs and offer a new path to be explored for repairing and generating bone. 

Journalism Pioneer and Founder of Latino Cancer Institute Joins Stem Cell Agency Board

Ysabel Duron

Ysabel Duron, a pioneering award-winning Latina journalist, and a leading figure in cancer education in the Latino community in the US, has been appointed to the governing Board of the California Institute for Regenerative Medicine.  

State Controller Betty Yee made the appointment saying: “Ms. Duron’s personal perspective as a (cancer) survivor and her commitment to equity will serve the institute’s mission well.”

Ms. Duron was a journalist and TV news anchor for more than 43 years winning numerous awards, including two EMMYS. She has been inducted into the Hall of Fame of the National Association of Hispanic Journalists and given the Living Legacy Award by the Chicana/Latina Foundation.

As a journalist she covered her own battle against Hodgkin’s Lymphoma, using her reporting to help raise awareness about the disease and the health disparities involved in treating it in communities of color.

In 2003, as a result of her own experience, she founded Latinas Contra Cancer, a non-profit organization that advocates for and serves the Latino community. She is now the President of the Latino Cancer Institute, a national network of Latino cancer service agencies addressing the community’s cancer disparities. 

“As a veteran journalist, I like to think I am as curious as a scientist, I just frame the question differently,” says Ms. Duron. “Usually I am looking for the best return for the public health! This appointment gives me a new learning opportunity to understand a very complex issue, and, make it bite size so the public, patients and advocates will understand how these scientific revelations will impact lives in the short term and the long run. As a steward of taxpayer dollars, I also want to make sure there is equity for communities across California, and that the research serves all of us”

We are delighted to welcome Ysabel to the Board,” says Jonathan Thomas, CIRM Board Chair. “She has a well-deserved reputation as a champion for patients and an activist committed to breaking down barriers that prevent people in the Latino community accessing quality care. She will add a powerful voice to our Board.”

Ms. Duron replaces Sherry Lansing as the CIRM Board patient advocate for cancer.

“It is impossible to overstate Sherry’s importance and contributions to CIRM over her long tenure on the Board,” says Thomas. “Sherry was one of the original Board Members and a towering presence who played a central role in the formulative years of the Agency, including co-chairing the Standards Working Group, which set the ethical guidelines for the future research CIRM would enable.  Since that time, she has been a commanding voice of reason and an unrelenting positive force on behalf of all patients. She will be sorely missed.”  

An off-the-shelf cancer killer

iPS Cell: Photo from the lab of Kathrin Plath at UCLA

One of the hottest areas in cancer research right now is the use of CAR-T treatments. These use the patient’s own re-engineered immune system cells to target and kill the tumor. But the thing that makes it so appealing – using the patient’s own cells – also makes it really complicated and expensive. Creating a custom-made therapy from each patient’s own cells takes time and costs a lot of money. But now a new approach could change that.

Fate Therapeutics has developed an off-the-shelf therapy (thanks to CIRM funding) that could, theoretically, be stored at hospitals and clinics around the country and used whenever it’s needed for anyone who needs it.

At this year’s meeting of the American Society of Hematology (ASH) Fate announced that the first patient treated with this new approach seems to be doing very well. The patient had acute myeloid leukemia and wasn’t responding to conventional treatments. However, following treatment with Fate’s FT516 the patient responded quickly and – according to STAT News’ Adam Feuerstein – was able to leave the hospital and spend Thanksgiving with his family.

Equally impressive is that 42 days after being treated with FT516, the man showed no signs of leukemia in either his bone marrow or blood.

FT516 is designed to provide a one-two combination attack on cancer. It’s made up of the wonderfully named natural killer (NK) cells, which are a critical part of our immune system defenses against cancer. These NK cells are created by using the iPSC process and have been genetically modified to express a protein that boosts their cancer-killing abilities.

Because these cells are manufactured they can, if effective, be produced in large numbers and stored for whenever needed. That would not only dramatically reduce costs but also make them more widely available when they are needed.

This is only one patient and the follow-up is still relatively short. Even so, the results are encouraging and certainly give hope that Fate is on to something big. We’ll be keeping track and let you know how things progress.

Four CIRM Funded Trials Release Results at 2019 ASH Meeting

With more than 17,000 members from nearly 100 countries, the American Society of Hematology (ASH) is an organization composed of clinicians and scientists around the world working to conquer various blood diseases. Currently, they are having their 61st Annual ASH Meeting to highlight some of the exciting work going on in the field. Four of our CIRM funded trials have released promising results at this conference and we wanted to take the opportunity to highlight them below.

Sangamo Therapeutics

Sangamo Therapeutics is conducting a CIRM-funded clinical trial for beta-thalassemia, a severe form of anemia caused by mutations in the hemoglobin gene. The therapy Sangamo is testing takes a patient’s own blood stem cells and, using a gene-editing technology called zinc finger nuclease (ZFN), provides a functional copy of the hemoglobin gene. These modified cells are then given back to the patient. The company announced preliminary results from their first three patients treated. in the clinical trials at the ASH 2019 Conference as well.

Some of the highlights are the following:

  • The first three patients experienced prompt hematopoietic reconstitution, meaning that their supply of blood stem cells was restored.
  • The first three patients experienced no clonal hematopoiesis, meaning that the blood stem cells did not create cells with mutations in the DNA
  • Additional study results are expected in late 2020 once enrollment is complete and all six patients have longer follow-up

You can read more detailed results regarding the first three patients in the press release.

Forty Seven, Inc.

In another CIRM funded trial, Forty Seven, Inc. is testing a treatment for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The treatment involves an antibody called magrolimab in combination with the chemotherapy drug azacitidine. Cancer cells express a signal that send a “don’t eat me” message to white blood cells that are part of the immune system designed to “eat” and destroy unhealthy cells. Magrolimab works by blocking the signal, enabling the body’s own immune system to detect these evasive cancer cells. The goal is to use both magrolimab and azacitidine to make the cancer stem cells vulnerable to being attacked and destroyed by the immune system.

Of the 46 patients evaluated, 24 patients had untreated higher-risk MDS and 22 patients had untreated AML. None of the patients were eligible for treatment with chemotherapy.

In higher-risk MDS, the overall response rate (ORR), which is the proportion of patients in a trial whose tumor is destroyed or significantly reduced by a treatment, was 92%.

Within this group of patients with an ORR, the following was observed:

  • 12 patients (50%) achieved a complete response (CR), meaning that they experienced a disappearance of all signs of cancer in response to treatment.
  • Two patients (8%) achieved hematologic (blood) improvement. 
  • Additionally, two patients (8%) achieved stable disease, meaning the cancer is neither increasing nor decreasing in extent or severity.

In untreated AML, the ORR was 64% and the following was observed within this group patients with an ORR:

  • Nine patients (41%) achieved a CR
  • Three patients (14%) achieved a CR with an incomplete blood count recovery (CRi)
  • One patient (5%) achieved a morphologic leukemia-free state (MLFS), which is defined as the disappearance of all cells with morphologic characteristics of leukemia, accompanied by bone marrow recovery, in response to treatment.
  • Seven patients (32%) achieved stable disease (SD)

The median time to response among MDS and AML patients treated with the combination was 1.9 months.

More details regarding these results are available via the news release.

Oncternal Therapeutics

Onceternal Therapeutics, which is conducting a CIRM-funded trial for a treatment for lymphoma and leukemia, presented results at the 2019 ASH Meeting. The treatment involves an antibody called cirmtuzumab (named after yours truly) being used with a cancer fighting drug called ibrutinib. The antibody recognizes and attaches to a protein on the surface of cancer stem cells. This attachment disables the protein, which slows the growth of the leukemia and makes it more vulnerable to anti-cancer drugs.

Some of the results presented are summarized as follows:

  • Twenty-nine of the 34 patients achieved a response, for an overall best objective response rate of 85%.
  • One patient achieved a complete response (CR) and remained in remission six months after completion of the trial and discontinuation of all anti-CLL therapy. In addition, three patients met radiographic and hematologic response criteria for Clinical CR.
  • Five patients had stable disease.
  • The total clinical benefit rate was 100%.
  • None of the patients died or saw their disease progress.
  • Patients achieved responses rapidly, with 68% of patients achieving a clinical response by three months on the combination therapy.
  • The rise in leukemic cell counts that is typically seen in the first six months with ibrutinib by itself was blunted with the addition of cirmtuzumab, and leukemic cell counts returned toward baseline and normal levels rapidly.

You can read more about these results in the official press release.

Rocket Pharmaceuticals

Last, but not least, Rocket Pharmaceuticals presented results at the 2019 ASH Conference related to a CIRM-funded trial for Leukocyte Adhesion Deficiency-I (LAD-I), a rare pediatric disease caused by a mutation in a specific gene that affects the body’s ability to combat infections. As a result, there is low expression of neutrophil (CD18). The company is testing a treatment that uses a patient’s own blood stem cells and inserts a functional version of the gene.  These modified stem cells are then reintroduced back into the patient. The goal is to establish functional immune cells, enabling the body to combat infections.  

Here are some of the highlights from the presentation:

  • Initial results from the first pediatric patient treated demonstrate early evidence of safety and potential effectiveness. 
  • The patient exhibited early signs of engraftment
  •  The patient also displayed visible improvement of multiple disease-related skin lesions after receiving therapy
  •  No safety issues related to administration have been identified

More detailed results on this trial are available via the news release.

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.

CIRM Board Awards $15.8 Million to Four Translational Research Projects

Last week, the CIRM Board approved $32.92 million in awards directed towards four new clinical trials in vision related diseases and Parkinson’s Disease.

In addition to these awards, the Board also approved investing $15.80 million in four awards in the Translational Research program. The goal of this program is to help promising projects complete the testing needed to begin talking to the US Food and Drug Administration (FDA) about holding a clinical trial.

Before we go into more specific details of each one of these awards, here is a table summarizing these four new projects:

ApplicationTitleInstitutionAward Amount
TRAN1 11536Ex Vivo Gene Editing of Human Hematopoietic Stem Cells for the Treatment of X-Linked Hyper IgM Syndrome  UCLA $4,896,628
TRAN1 11555BCMA/CS1 Bispecific CAR-T Cell Therapy to Prevent Antigen Escape in Multiple Myeloma  UCLA $3,176,805
TRAN1 11544 Neural Stem cell-mediated oncolytic immunotherapy for ovarian cancer  City of Hope $2,873,262
TRAN1 11611Development of a human stem cell-derived inhibitory neuron therapeutic for the treatment of chronic focal epilepsyNeurona Therapeutics$4,848,750
Dr. Caroline Kuo, UCLA

$4.89 million was awarded to Dr. Caroline Kuo at UCLA to pursue a gene therapy approach for X-Linked Hyper IgM Syndrome (X-HIM).

X-HIM is a hereditary immune disorder observed predominantly in males in which there are abnormal levels of different types of antibodies in the body.  Antibodies are also known as Immunoglobulin (Ig) and they combat infections by attaching to germs and other foreign substances, marking them for destruction.  In infants with X-HIM, there are normal or high levels of antibody IgM but low levels of antibodies IgG, IgA, and IgE.  The low level of these antibodies make it difficult to fight off infection, resulting in frequent pneumonia, sinus infections, ear infections, and parasitic infections.  Additionally, these infants have an increased risk of cancerous growths. 

The gene therapy approach Dr. Kuo is continuing to develop involves using CRISPR/Cas9 technology to modify human blood stem cells with a functional version of the gene necessary for normal levels of antibody production.  The ultimate goal would be to take a patient’s own blood stem cells, modify them with the corrected gene, and reintroduce them back into the patient.

CIRM has previously funded Dr. Kuo’s earlier work related to developing this gene therapy approach for XHIM.

Dr. Yvonne Chen, UCLA

$3.17 million was awarded to Dr. Yvonne Chen at UCLA to develop a CAR-T cell therapy for multiple myeloma (MM).

MM is a type of blood cancer that forms in the plasma cell, a type of white blood cell that is found in the bone marrow.  An estimated 32,110 people in the United States will be diagnosed with MM in 2019 alone.  Several treatment options are available to patients with MM, but there is no curative therapy.

The therapy that Dr. Chen is developing will consist of a genetically-modified version of the patient’s own T cells, which are an immune system cell that can destroy foreign or abnormal cells.  The T cells will be modified with a protein called a chimeric antigen receptor (CAR) that will recognize BCMA and CS1, two different markers found on the surface of MM cells.  These modified T cells (CAR-T cells) are then infused into the patient, where they are expected to detect and destroy BCMA and CS1 expressing MM cells.

Dr. Chen is using CAR-T cells that can detect two different markers in a separate clinical trial that you can read about in a previous blog post.

Dr. Karen Aboody, City of Hope

$2.87 million was awarded to Dr. Karen Aboody at City of Hope to develop an immunotherapy delivered via neural stem cells (NSCs) for treatment of ovarian cancer.

Ovarian cancer affects approximately 22,000 women per year in the United States alone.  Most ovarian cancer patients eventually develop resistance to chemotherapy, leading to cancer progression and death, highlighting the need for treatment of recurring ovarian cancer.

The therapy that Dr. Aboody is developing will use an established line of NSCs to deliver a virus that specifically targets these tumor cells.  Once the virus has entered the tumor cell, it will continuously replicate until the cell is destroyed.  The additional copies of the virus will then go on to target neighboring tumor cells.  This process could potentially stimulate the body’s own immune response to fight off the cancer cells as well.

Dr. Cory Nicholas, Neurona Therapeutics

$4.85 million was awarded to Dr. Cory Nicholas at Neurona Therapeutics to develop a treatment for epilepsy.

Epilepsy affects more than 3 million people in the United States with about 150,000 newly diagnosed cases in the US every year. It results in persistent, difficult to manage, or uncontrollable seizures that can be disabling and significantly impair quality of life. Unfortunately, anti-epileptic drugs fail to manage the disease in a large portion of people with epilepsy. Approximately one-third of epilepsy patients are considered to be drug-resistant, meaning that they do not adequately respond to at least two anti-epileptic drugs.

The therapy that Dr. Nicholas is developing will derive interneurons from human embryonic stem cells (hESCs). These newly derived interneurons would then be delivered to the brain via injection whereby the new cells are able to help regulate aberrant brain activity and potentially eliminate or significantly reduce the occurrence of seizures.

CIRM has previously funded the early stage development of this approach via a comprehensive grant and discovery grant.