Earlier this week the CIRM ICOC Board awarded $14.5 million to fund three translational stage research projects (TRAN1), whose goal is to support early development activities necessary for advancement to a clinical study or broad end use of a potential therapy. Although all three projects have their distinct area of focus, they all utilize CAR-based cell therapy to treat a certain type of cancer. This approach involves obtaining T cells, which are an immune system cell that can destroy foreign or abnormal cells, and modifying them with a chimeric antigen receptor (CAR). This enables the newly created CAR-engineered cells to identify specific tumor signals and destroy the cancer. In the sections below we will take a deeper look at each one of these recently approved projects.
$2,663,144 was awarded to the University of California, San Francisco (UCSF) to develop specialized CAR-T cells that are able to recognize and destroy tumor cells in glioblastoma, an aggressive type of cancer that occurs in the brain and spinal cord. The specialized CAR-T cells have been created such that they are able to detect two specific signals expressed in glioblastoma. Hideho Okada, M.D., Ph.D. and his team at UCSF will test the therapy in mice with human glioblastoma grafts. They will be looking at preclinical safety and if the CAR-T cell therapy is able to produce a desired or intended result.
$5,949,651 was awarded to the University of California, Los Angeles (UCLA) to develop specialized CAR-engineered cells from human blood stem cells to treat multiple myeloma, a type of blood cancer. Lili Yang, Ph.D. and her team have developed a method using human blood stem cells to create invariant natural killer T (iNKT) cells, a special kind of T cell with unique features that can more effectively attack tumor cells using multiple mechanisms and migrate to and infiltrate tumor sites. After being modified with CAR, the newly created CAR-iNKT cells are able to target a specific signal present in multiple myeloma. The team will test the therapy in mice with human multiple myeloma. They will be looking at preclinical safety and if the CAR-iNKT cells are able to produce a desired or intended result.
Another $5,904,462 was awarded to UCLA to develop specialized CAR-T cells to treat melanoma, a form of skin cancer. Cristina Puig-Saus, Ph.D. and her team will use naïve/memory progenitor T cells (TNM), a subset of T cells enriched with stem cells and memory T cells, an immune cell that remains long after an infection has been eliminated. After modification with CAR, the newly created CAR-TNM cells will target a specific signal present in melanoma. The team will test the therapy in mice with human melanoma. They will be looking at preclinical safety and if the CAR-TNM cells are able to produce a desired or intended result.
Multiple myeloma is the second most common blood cancer in the United States, with more than 32,000 new cases predicted in 2020. Unfortunately, many patients with this type of blood cancer eventually develop resistance to multiple types of treatments. This phenomenon is partially due to the fact that cancer stem cells, which have the ability to evade traditional therapies and then self-renew, help drive the disease.
It is for this reason that a team of researchers, at the UC San Diego School of Medicine and Ionis Pharmaceuticals, are developing a therapy that can destroy these malignant stem cells, thereby preventing the cancer from coming back. With support from CIRM, the team developed an approach that interacts with IRF4, a gene that allows myeloma stem cells and tumor cells to grow and survive chemotherapy and radiation. They have engineered an oligonucleotide, a short DNA molecule, to prevent IRF4 from functioning. The therapy, known as ION251, lowered disease burden, reduced the amount of myeloma stem cells, and increased survival when tested in mice bearing human myeloma. These results have enabled the team to start a Phase I clinical trial to see if this approach is safe and effective in people with myeloma.
To study the disease and test ION251, the team transplanted human myeloma cells into mice that lack an immune system and thus won’t reject human cells. Ten mice received the ION251 treatment and an additional ten mice received a control treatment. After receiving the ION251 therapy, the treated mice had significantly fewer myeloma cells after two to six weeks of treatment. Additionally, 70 to 100 percent of the treated mice survived, whereas none of the untreated control mice did.
In a news release from UC San Diego Health, Dr. Leslie Crews, co-senior author and assistant professor at the UCSD School of Medicine, elaborated on the promising results from the mouse study.
“The results of these preclinical studies were so striking that half the microscopy images we took to compare bone marrow samples between treated and untreated mice kept coming back blank — in the treated mice, we couldn’t find any myeloma cells left for us to study. It makes the science more difficult, but it gives me hope for patients.”
The Phase I clinical trial to assess the safety of ION251, sponsored by Ionis Pharmaceuticals, is now recruiting participants at Moores Cancer Center at UC San Diego Health and elsewhere. More information on this can be viewed by clicking the link here.
The full results of this study were published in the journal Cell Stem Cell.
Bryon Jenkin’s is one of the people we profiled in our recent 18 Month Report. The theme of the report is “Perseverance” and Byron certainly epitomizes that. This is his story.
A former Navy flight officer and accomplished athlete Byron Jenkins learned in June 2013 that he had multiple myeloma, an incurable blood cancer, and that it was eating through his bones. After five years of, chemotherapy, radiation, immunotherapy, and experimental procedures, he found himself bed ridden, exhausted, barely able to move. Byron says: “I was alive, but I wasn’t living.”
As the treatments lost their ability to hold the cancer at bay, Byron’s wife, family and close friends had made preparations for his seemingly inevitable demise.
Then Byron took part in a CIRM-funded CAR-T clinical trial for a treatment developed by Poseida Therapeutics. The team used Byron’s own immune system cells, re-engineered in the lab, to recognize the cancer and to fight back. Within two weeks Byron was feeling so much better he was able to stop taking all of his medications. “I haven’t taken so much as an aspirin since then.”
Two years later he is once again able to enjoy a full, active life with his family; biking, hiking and skiing with his wife and kids. He is back working full-time and only checks in with his oncologist once in a while.
Byron says despite his ordeal he never lost faith, that the love of his family helped give him the strength to continue to fight. “Hope kept me going through this long arduous process. This is the first treatment to give me a continued normal life. CAR-T was the answer to my prayers.”
What are the latest advances in stem cell research targeting cancer? Can stem cells help people battling COVID-19 or even help develop a vaccine to stop the virus? What are researchers and the scientific community doing to help address the unmet medical needs of underserved communities? Those are just a few of the topics being discussed at the Annual CIRM Alpha Stem Cell Clinic Network Symposium on Thursday, October 8th from 9am to 1.30pm PDT.
Like pretty nearly everything these days the symposium is going to be a virtual event, so you can watch it from the comfort of your own home on a phone or laptop. And it’s free.
The CIRM Alpha Clinics are a network of leading medical centers here in California. They specialize in delivering stem cell and gene therapies to patients. So, while many conferences look at the promise of stem cell therapies, here we deal with the reality; what’s in the clinic, what’s working, what do we need to do to help get these therapies to patients in need?
It’s a relatively short meeting, with short presentations, but that doesn’t mean it will be short on content. Some of the best stem cell researchers in the U.S. are taking part so you’ll learn an awful lot in a short time.
We’ll hear what’s being done to find therapies for
Rare diseases that affect children
Type 1 diabetes
We’ll discuss how to create a patient navigation system that can address social and economic determinants that impact patient participation? And we’ll look at ways that the Alpha Clinic Network can partner with community care givers around California to increase patient access to the latest therapies.
It’s going to be a fascinating day. And did I mention it’s free!
Every so often you hear a story and your first reaction is “oh, I have to share this with someone, anyone, everyone.” That’s what happened to me the other day.
I was talking with Kristin MacDonald, an amazing woman, a fierce patient advocate and someone who took part in a CIRM-funded clinical trial to treat retinitis pigmentosa (RP). The disease had destroyed Kristin’s vision and she was hoping the therapy, pioneered by jCyte, would help her. Kristin, being a bit of a pioneer herself, was the first person to test the therapy in the U.S.
Anyway, Kristin was doing a Zoom presentation and wanted to look her best so she asked a friend to come over and do her hair and makeup. The woman she asked, was Rosie Barrero, another patient in that RP clinical trial. Not so very long ago Rosie was legally blind. Now, here she was helping do her friend’s hair and makeup. And doing it beautifully too.
That’s when you know the treatment works. At least for Rosie.
There are many other stories to be heard – from patients and patient advocates, from researchers who develop therapies to the doctors who deliver them. – at our CIRM 2020 Grantee Meeting on next Monday September 14th Tuesday & September 15th.
It’s two full days of presentations and discussions on everything from heart disease and cancer, to COVID-19, Alzheimer’s, Parkinson’s and spina bifida. Here’s a link to the Eventbrite page where you can find out more about the event and also register to be part of it.
Like pretty much everything these days it’s a virtual event so you’ll be able to join in from the comfort of your kitchen, living room, even the backyard.
And it’s free!
You can join us for all two days or just one session on one day. The choice is yours. And feel free to tell your friends or anyone else you think might be interested.
The governing Board of the California Institute for Regenerative Medicine (CIRM) yesterday invested $32.92 million to fund the Stem Cell Agency’s first clinical trial in Parkinson’s disease (PD), and to support three clinical trials targeting different forms of vision loss.
This brings the total number of clinical trials funded by CIRM to 60.
The PD trial will be carried out by Dr. Krystof Bankiewicz at Brain Neurotherapy Bio, Inc. He is using a gene therapy approach to promote the production of a protein called GDNF, which is best known for its ability to protect dopaminergic neurons, the kind of cell damaged by Parkinson’s. The approach seeks to increase dopamine production in the brain, alleviating PD symptoms and potentially slowing down the disease progress.
David Higgins, PhD, a CIRM Board member and patient advocate for Parkinson’s says there is a real need for new approaches to treating the disease. In the US alone, approximately 60,000 people are diagnosed with PD each year and it is expected that almost one million people will be living with the disease by 2020.
“Parkinson’s Disease is a serious unmet medical need and, for reasons we don’t fully understand, its prevalence is increasing. There’s always more outstanding research to fund than there is money to fund it. The GDNF approach represents one ‘class’ of potential therapies for Parkinson’s Disease and has the potential to address issues that are even broader than this specific therapy alone.”
The Board also approved funding for two clinical trials targeting retinitis pigmentosa (RP), a blinding eye disease that affects approximately 150,000 individuals in the US and 1.5 million people around the world. It is caused by the destruction of light-sensing cells in the back of the eye known as photoreceptors. This leads to gradual vision loss and eventually blindness. There are currently no effective treatments for RP.
Dr. Henry Klassen and his team at jCyte are injecting human retinal progenitor cells (hRPCs), into the vitreous cavity, a gel-filled space located in between the front and back part of the eye. The proposed mechanism of action is that hRPCs secrete neurotrophic factors that preserve, protect and even reactivate the photoreceptors, reversing the course of the disease.
CIRM has supported early development of Dr. Klassen’s approach as well as preclinical studies and two previous clinical trials. The US Food and Drug Administration (FDA) has granted jCyte Regenerative Medicine Advanced Therapy (RMAT) designation based on the early clinical data for this severe unmet medical need, thus making the program eligible for expedited review and approval.
The other project targeting RP is led by Dr. Clive Svendsen from the Cedars-Sinai Regenerative Medicine Institute. In this approach, human neural progenitor cells (hNPCs) are transplanted to the back of the eye of RP patients. The goal is that the transplanted hNPCs will integrate and create a protective layer of cells that prevent destruction of the adjacent photoreceptors.
The third trial focused on vision destroying diseases is led by Dr. Sophie Deng at the University of California Los Angeles (UCLA). Dr. Deng’s clinical trial addresses blinding corneal disease by targeting limbal stem cell deficiency (LSCD). Under healthy conditions, limbal stem cells (LSCs) continuously regenerate the cornea, the clear front surface of the eye that refracts light entering the eye and is responsible for the majority of the optical power. Without adequate limbal cells , inflammation, scarring, eye pain, loss of corneal clarity and gradual vision loss can occur. Dr. Deng’s team will expand the patient’s own remaining LSCs for transplantation and will use novel diagnostic methods to assess the severity of LSCD and patient responses to treatment. This clinical trial builds upon previous CIRM-funded work, which includes early translational and late stage preclinical projects.
“CIRM funds and accelerates promising early stage research, through development and to clinical trials,” says Maria T. Millan, MD, President and CEO of CIRM. “Programs, such as those funded today, that were novel stem cell or gene therapy approaches addressing a small number of patients, often have difficulty attracting early investment and funding. CIRM’s role is to de-risk these novel regenerative medicine approaches that are based on rigorous science and have the potential to address unmet medical needs. By de-risking programs, CIRM has enabled our portfolio programs to gain significant downstream industry funding and partnership.”
CIRM Board also awarded $5.53 million to Dr. Rosa Bacchetta at Stanford to complete work necessary to conduct a clinical trial for IPEX syndrome, a rare disease caused by mutations in the FOXP3 gene. Immune cells called regulatory T Cells normally function to protect tissues from damage but in patients with IPEX syndrome, lack of functional Tregs render the body’s own tissues and organs to autoimmune attack that could be fatal in early childhood. Current treatment options include a bone marrow transplant which is limited by available donors and graft versus host disease and immune suppressive drugs that are only partially effective. Dr. Rosa Bacchetta and her team at Stanford will use gene therapy to insert a normal version of the FOXP3 gene into the patient’s own T Cells to restore the normal function of regulatory T Cells.
The CIRM 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.
The TRAN1 Awards are summarized in the table below:
Ex Vivo Gene Editing of Human Hematopoietic Stem Cells for the Treatment of X-Linked Hyper IgM Syndrome
BCMA/CS1 Bispecific CAR-T Cell Therapy to Prevent Antigen Escape in Multiple Myeloma
Neural Stem cell-mediated oncolytic immunotherapy for ovarian cancer
City of Hope
Development of a human stem cell-derived inhibitory neuron therapeutic for the treatment of chronic focal epilepsy
Within all of our bodies there is a special type of “super” immune cell that holds enormous potential. Unlike regular immune cells that can only attack one cancer at a time, these “super” immune cells have the ability to target many types of cancers at once. These specialized cells are known as invariant natural killer T cells or iNKT cells for short. Unfortunately, there are relatively few of these cells normally present in the body.
However, in a CIRM-funded study, Dr. Lily Yang and her team of researchers at UCLA have found a way to produce iNKT cells from human blood stem cells. They were then able to test these iNKT cells on mice with both human bone marrow and human cancers. These mice either had multiple melanoma, a type of blood cancer, or melanoma, a solid tumor cancer. The researchers then studied what happened to mice’s immune system, cancers, and engineered iNKT cells after they had integrated into the bone marrow.
The results were remarkable. The team found that the blood stem cells now differentiated normally into iNKT cells, producing iNKT cells for the rest of the animal’s life, which was generally about a year. Mice without the engineered stem cell transplants had undetectable levels of iNKT cells while those that received the engineered cells had iNKT cells make up as much as 60% of the total immune system cells. The team also found that the engineered iNKT cells were able to suppress tumor growth in both multiple myeloma and melanoma.
Dr. Yang, in a press release by UCLA health, discussed the significance of the results in this animal model and the enormous potential this could have for cancer patients.
“What’s really exciting is that we can give this treatment just once and it increases the number of iNKT cells to levels that can fight cancer for the lifetime of the animals.” said Yang.
In the same press release, Dr. Yang continued to highlight the study’s importance by saying that,
“One advantage of this approach is that it’s a one-time cell therapy that can provide patients with a lifelong supply of iNKT cells.”
Researchers mentioned that they could control total iNKT cell make up in the immune system depending on how they engineered the blood stem cells. However, more research is needed to determine how these engineered iNKT cells might be useful for treating cancer in humans and evaluating any long-term side effects associated with an increased number of these cells.
The full results of this study were published in the journal Cell Stem Cell.
Battling cancer is always a balancing act. The methods we use – surgery, chemotherapy and radiation – can help remove the tumors but they often come at a price to the patient. In cases where the cancer has spread to the bone the treatments have a limited impact on the disease, but their toxicity can cause devastating problems for the patient. Now, in a CIRM-supported study, researchers at UC Irvine (UCI) have developed a method they say may be able to change that.
Bone metastasis –
where cancer starts in one part of the body, say the breast, but spreads to the
bones – is one of the most common complications of cancer. It can often result
in severe pain, increased risk of fractures and compression
of the spine. Tackling them is difficult because some cancer cells can
alter the environment around bone, accelerating the destruction of healthy bone
cells, and that in turn creates growth factors that stimulate the growth of the
cancer. It is a vicious cycle where one problem fuels the other.
Now researchers at
UCI have developed a method where they combine engineered mesenchymal stem cells (taken from the bone marrow) with
targeting agents. These act like a drug delivery device, offloading
different agents that simultaneously attack the cancer but protect the bone.
In a news release Weian Zhao, lead author of the study, said:
“What’s powerful about this
strategy is that we deliver a combination of both anti-tumor and anti-bone
resorption agents so we can effectively block the vicious circle between
cancers and their bone niche. This is a safe and almost nontoxic treatment
compared to chemotherapy, which often leaves patients with lifelong issues.”
published in the journal EBioMedicine,
has already been shown to be effective in mice. Next, they hope to be able to
do the safety tests to enable them to apply to the Food and Drug Administration
for permission to test it in people.
The team say if this
approach proves effective it might also be used to help treat other bone-related
diseases such as osteoporosis and multiple myeloma.
It’s not often you read the word “sensational” in a news release about stem cells. But this week researchers at the University of Copenhagen released findings that are overturning long-held ideas about the development of cells in our stomachs. So perhaps calling it “sensational” is not too big a stretch.
In the past it was believed that the development of immature cells in our stomachs, before a baby is born, was predetermined, that the cells had some kind of innate sense of what they were going to become and when. Turns out that’s not the case. The researchers say it’s the cells’ environment that determines what they will become and that all cells in the fetus’ gut have the potential to turn into stem cells.
In the “sensational” news
release lead author, Kim Jensen, says this
finding could help in the development of new therapies.
“We used to believe that a cell’s
potential for becoming a stem cell was predetermined, but our new results show
that all immature cells have the same probability for becoming stem cells in
the fully developed organ. In principle, it is simply a matter of being in the
right place at the right time. Here signals from the cells’ surroundings
determine their fate. If we are able to identify the signals that are necessary
for the immature cell to develop into a stem cell, it will be easier for us to
manipulate cells in the wanted direction’.
It’s long been known that some lizards and other mammals can
regrow severed limbs, but it hasn’t been clear how. Now scientists at the
University of Cambridge in the UK have figured out what’s going on.
genomics the scientists were able to track which genes are turned on and
off at particular times, allowing them to watch what happens inside the tail of
the African clawed frog tadpole as it regenerates the damaged limb.
They found that the response was orchestrated by a group of
skin cells they called Regeneration-Organizing
Cells, or ROCs. Can Aztekin, one of the lead authors of the study in the
journal Science, says seeing how ROCs work could lead
to new ideas on how to stimulate similar regeneration in other mammals.
“It’s an astonishing process to
watch unfold. After tail amputation, ROCs migrate from the body to the wound
and secrete a cocktail of growth factors that coordinate the response of tissue
precursor cells. These cells then work together to regenerate a tail of the
right size, pattern and cell composition.”
Orphan Drug Designation for CIRM-funded
Poseida Therapeutics got some good news recently about their CIRM-funded therapy for multiple myeloma. The US Food and Drug Administration (FDA) granted them orphan drug designation.
drug designation is given to therapies targeting rare diseases or disorders
that affect fewer than 200,000 people in the U.S. It means the company may be
eligible for grant funding toward clinical trial costs, tax
advantages, FDA user-fee benefits and seven years of market
exclusivity in the United States following marketing approval by
is seeking to destroy these cancerous myeloma cells with an immunotherapy
approach that uses the patient’s own engineered immune system T cells to seek
and destroy the myeloma cells.”
CEO, Eric Ostertag, said the designation is an important milestone for the
company therapy which “has
demonstrated outstanding potency, with strikingly low rates of toxicity in our
phase 1 clinical trial. In fact, the FDA has approved fully outpatient dosing
in our Phase 2 trial starting in the second quarter of 2019.”
Every day at CIRM we get calls from people looking for a stem cell therapy to help them fight a life-threatening or life-altering disease or condition. One of the most common calls is about osteoarthritis, a painful condition where the cartilage that helps cushion our joints is worn away, leaving bone to rub on bone. People call asking if we have something, anything, that might be able to help them. Now we do.
At yesterday’s CIRM Board meeting the Independent Citizens’ Oversight Committee or ICOC (the formal title of the Board) awarded almost $8.5 million to the California Institute for Biomedical Research (CALIBR) to test a drug that appears to help the body regenerate cartilage. In preclinical tests the drug, KA34, stimulated mesenchymal stem cells to turn into chondrocytes, the kind of cell found in healthy cartilage. It’s hoped these new cells will replace those killed off by osteoarthritis and repair the damage.
This is a Phase 1 clinical trial where the goal is primarily to make sure this approach is safe in patients. If the treatment also shows hints it’s working – and of course we hope it will – that’s a bonus which will need to be confirmed in later stage, and larger, clinical trials.
From a purely selfish perspective, it will be nice for us to be able to tell callers that we do have a clinical trial underway and are hopeful it could lead to an effective treatment. Right now the only alternatives for many patients are powerful opioids and pain killers, surgery, or turning to clinics that offer unproven stem cell therapies.
Targeting immune system cancer
The CIRM Board also awarded Poseida Therapeutics $19.8 million to target multiple myeloma, using the patient’s own genetically re-engineered stem cells. Multiple myeloma is caused when plasma cells, which are a type of white blood cell found in the bone marrow and are a key part of our immune system, turn cancerous and grow out of control.
As Dr. Maria Millan, CIRM’s President & CEO, said in a news release:
“Multiple myeloma disproportionately affects people over the age of 65 and African Americans, and it leads to progressive bone destruction, severe anemia, infectious complications and kidney and heart damage from abnormal proteins produced by the malignant plasma cells. Less than half of patients with multiple myeloma live beyond 5 years. Poseida’s technology is seeking to destroy these cancerous myeloma cells with an immunotherapy approach that uses the patient’s own engineered immune system T cells to seek and destroy the myeloma cells.”
In a news release from Poseida, CEO Dr. Eric Ostertag, said the therapy – called P-BCMA-101 – holds a lot of promise:
“P-BCMA-101 is elegantly designed with several key characteristics, including an exceptionally high concentration of stem cell memory T cells which has the potential to significantly improve durability of response to treatment.”
The third clinical trial funded by the Board yesterday also uses T cells. Researchers at Children’s Hospital of Los Angeles were awarded $4.8 million for a Phase 1 clinical trial targeting potentially deadly infections in people who have a weakened immune system.
Viruses such as cytomegalovirus, Epstein-Barr, and adenovirus are commonly found in all of us, but our bodies are usually able to easily fight them off. However, patients with weakened immune systems resulting from chemotherapy, bone marrow or cord blood transplant often lack that ability to combat these viruses and it can prove fatal.
The researchers are taking T cells from healthy donors that have been genetically matched to the patient’s immune system and engineered to fight these viruses. The cells are then transplanted into the patient and will hopefully help boost their immune system’s ability to fight the virus and provide long-term protection.
Whenever you can tell someone who calls you, desperately looking for help, that you have something that might be able to help them, you can hear the relief on the other end of the line. Of course, we explain that these are only early-stage clinical trials and that we don’t know if they’ll work. But for someone who up until that point felt they had no options and, often, no hope, it’s welcome and encouraging news that progress is being made.