Paving the Way

When someone scores a goal in soccer all the attention is lavished on them. Fans chant their name, their teammates pile on top in celebration, their agent starts calling sponsors asking for more money. But there’s often someone else deserving of praise too, that’s the player who provided the assist to make the goal possible in the first place. With that analogy in mind, CIRM just provided a very big assist for a very big goal.

The goal was scored by Jasper Therapeutics. They have just announced data from their Phase 1 clinical trial treating people with Myelodysplastic syndromes (MDS). This is a group of disorders in which immature blood-forming cells in the bone marrow become abnormal and leads to low numbers of normal blood cells, especially red blood cells. In about one in three patients, MDS can progress to acute myeloid leukemia (AML), a rapidly progressing cancer of the bone marrow cells.

The most effective way to treat, and even cure, MDS/AML is with a blood stem cell transplant, but this is often difficult for older patients, because it involves the use of toxic chemotherapy to destroy their existing bone marrow blood stem cells, to make room for the new, healthy ones. Even with a transplant there is often a high rate of relapse, because it’s hard for chemotherapy to kill all the cancer cells.

Jasper has developed a therapy, JSP191, which is a monoclonal antibody, to address this issue. JSP191 helps supplement the current treatment regimen by clearing all the remaining abnormal cells from the bone marrow and preventing relapse. In addition it also means the patients gets smaller doses of chemotherapy with lower levels of toxicity. In this Phase 1 study six patients, between the ages of 65 and 74, were given JSP191 – in combination with low-dose radiation and chemotherapy – prior to getting their transplant. The patients were followed-up at 90 days and five of the six had no detectable levels of MDS/AML, and the sixth patient had reduced levels. None of the patients experienced serious side effects.

Clearly that’s really encouraging news. And while CIRM didn’t fund this clinical trial, it wouldn’t have happened without us paving the way for this research. That’s where the notion of the assist comes in.

CIRM support led to the development of the JSP191 technology at Stanford. Our CIRM funds were used in the preclinical studies that form the scientific basis for using JSP191 in an MDS/AML setting.

Not only that, but this same technique was also used by Stanford’s Dr. Judy Shizuru in a clinical trial for children born with a form of severe combined immunodeficiency, a rare but fatal immune disorder in children. A clinical trial that CIRM funded.

It’s a reminder that therapies developed with one condition in mind can often be adapted to help treat other similar conditions. Jasper is doing just that. It hopes to start clinical trials this year using JSP191 for people getting blood stem cell transplants for severe autoimmune disease, sickle cell disease and Fanconi anemia.

Latest CIRM TRAN1 awards focus on CAR-based cell therapy to treat cancer

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.

TRAN1-12245

Image Description: Hideho Okada, M.D., Ph.D.

$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.

TRAN1-12250

Image Description: Lili Yang, Ph.D.

$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.

TRAN1-12258

Image Description: Cristina Puig-Saus, Ph.D.

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.

New technique maps out diversity and location of cells in tissue or tumor

Image Description: Alex Marson is part of a team of researchers who developed a new technique to map the specialized diversity and spatial location of individual cells within a tissue or tumor. Photo Credit: Anastasiia Sapon

All the cells in your body work together and each can have a different role. Their individual function not only depends on cell type, but can also depend on their specific location and surroundings.

A CIRM supported and collaborative study at the Gladstone Institutes, UC San Francisco (UCSF), and UC Berkeley has developed a more efficient method than ever before to simultaneously map the specialized diversity and spatial location of individual cells within a tissue or a tumor.

The technique is named XYZeq and involves segmenting a tissue into microscopic regions. Within each of these microscopic grids, each cell’s genetic information is analyzed in order to better understand how each particular cell functions relative to its spacial location.

For this study, the team obtained tissue from mice with liver and spleen tumors. A slice of tissue was then placed on a slide that divides the tissue into hundreds of “microwells” the size of a grain of salt. Each cell in the tissue gets tagged with a unique “molecular barcode” that represents the microwell it’s contained in, much like a zip code. The cells are then mixed up and assigned a second barcode to ensure that each cell within a given square can be individually identified, similar to a street address within a zip code. Finally, the genetic information in the form of RNA from each cell is analyzed. Once the results are obtained, both barcodes tell the researchers exactly where in the tissue it came from.

The team found that some cell types located near the liver tumor were not evenly spaced out. They also found immune cells and specific types of stem cells clustered in certain regions of the tumor. Additionally, certain stem cells had different levels of some RNA molecules depending on how far they resided from the tumor.

The researchers aren’t entirely sure what this pattern means, but they believe that it’s possible that signals generated by or near the tumor affect what nearby cells do.

In a press release, Alex Marson, M.D., Ph.D., a senior author of the study, elaborates on what the XYZeq technology could mean for disease modeling.

“I think we’re actually taking a step toward this being the way tissues are analyzed to diagnose, characterize, or study disease; this is the pathology of the future.”

The full results of the study were published in Science Advances.

CIRM Board Approves Clinical Trials for Blood Cancer and Pediatric Brain Tumors

Today the governing Board of the California Institute for Regenerative Medicine (CIRM) awarded $14.4 million for two new clinical trials for blood cancer and pediatric brain tumors.

These awards bring the total number of CIRM-funded clinical trials to 70. 

$6.0 million was awarded to Immune-Onc Therapeutics to conduct a clinical trial for patients with acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML), both of which are types of blood cancer. AML affects approximately 20,000 people in the United States each year and has a 5-year survival rate of about 25 percent. Anywhere from 15-30 percent of CMML cases eventually progress into AML.

Paul Woodard, M.D. and his team will treat AML and CMML patients with an antibody therapy called IO-202 that targets leukemic stem cells.  The antibody works by blocking a signal named LILRB4 whose expression is connected with decreased rates of survival in AML patients.  The goal is to attain complete cancer remissions and prolonged survival.

$8.4 million was also awarded to City of Hope to conduct a clinical trial for children with malignant brain tumors.  Brain tumors are the most common solid tumor of childhood, with roughly 5,000 new diagnoses per year in the United States.

Leo D. Wang, M.D., Ph.D. and his team will treat pediatric patients with aggressive brain tumors using chimeric antigen receptor (CAR) T cell therapy.  The CAR T therapy involves obtaining a patient’s own T cells, which are an immune system cell that can destroy foreign or abnormal cells, and modifying them so that they are able to identify and destroy the brain tumors.  The aim of this approach is to improve patient outcome.

“Funding the most promising therapies for aggressive blood cancer and brain tumors has always aligned with CIRM’s mission,” says Maria T. Millan, M.D., President and CEO of CIRM.  “We are excited to fund these trials as the first of many near-term and future stem cell- and regenerative medicine-based approaches that CIRM will be able to support with bond funds under Proposition 14”.

Saying thanks and farewell to a friend

Tom Howing

In this job you get to meet a lot of remarkable people, none more so than the patients who volunteer to take part in what are giant experiments. They are courageous pioneers, willing to be among the first people to ever try a new therapy, knowing that it may not help them and, potentially, might even harm them.

Tom Howing was one such person. I got to know Tom when we were putting together our 2017 Annual Report. Back in 2015 Tom was diagnosed with Stage 4 cancer that had spread throughout his body. He underwent surgery and chemotherapy. That worked for a while, but then the cancer returned. So, Tom had more surgery and chemotherapy. Again, it worked for a while but when the cancer returned again Tom was running out of options.

That’s when he learned about a clinical trial with a company called Forty Seven Inc. that was testing a new anti-cancer therapy that CIRM was supporting. Tom says he didn’t hesitate.

“When I was diagnosed with cancer I knew I had battle ahead of me. After the cancer came back again they recommended I try this CD47 clinical trial. I said absolutely, let’s give it a spin. I guess one is always a bit concerned whenever you put the adjective “experimental” in front of anything. But I’ve always been a very optimistic and positive person and have great trust and faith in my caregivers.”

Optimistic and positive are great ways to describe Tom. Happily, his optimism was rewarded. The therapy worked.

“Scans and blood tests came back showing that the cancer appears to be held in check. My energy level is fantastic. The treatment that I had is so much less aggressive than chemo, my quality of life is just outstanding.”

But after a year or so Tom had to drop out of the trial. He tried other therapies and they kept the cancer at bay. For a while. But it kept coming back. And eventually Tom ran out of options. And last week, he ran out of time.

Tom was a truly fine man. He was kind, caring, funny, gracious and always grateful for what he had. He talked often about his family and how the stem cell therapy helped him spend not just more time with them, but quality time.

He knew when he signed up for the therapy that there were no guarantees, but he wanted to try, saying that even if it didn’t help him that the researchers might learn something to help others down the line.

“The most important thing I would say is, I want people to know there is always hope and to stay positive.”

Tom ultimately lost his battle with cancer. But he never lost his spirit, his delight in his family and his desire to keep going as long as he could. In typical Tom fashion he preferred to put his concerns aside and cheer others along.

“To all those people who are putting in all the hours at the bench and microscope, it’s important for them to know that they are making a huge impact on the lives of real people and they should celebrate it and revel in it and take great pride in it.”

We consider ourselves fortunate to have known Tom and to have been with him on part of his journey. He touched our lives, as he touched the lives of so many others. Our thoughts and wishes go out to his family and friends. He will be remembered, because we never forget our friends.

A few years ago Tom came and talked to the CIRM Board. Here is the video of that event.

A word from our Chair, several in fact

In 2005, the New Oxford American Dictionary named “podcast” its word of the year. At the time a podcast was something many had heard of but not that many actually tuned in to. My how times have changed. Now there are some two million podcasts to chose from, at least according to the New York Times, and who am I to question them.

Yesterday, in the same New York Times, TV writer Margaret Lyons, wrote about how the pandemic helped turn her from TV to podcasts: “Much in the way I grew to prefer an old-fashioned phone call to a video chat, podcasts, not television, became my go-to medium in quarantine. With their shorter lead times and intimate production values, they felt more immediate and more relevant than ever before.”

I mention this because an old colleague of ours at CIRM, Neil Littman, has just launched his own podcast and the first guest on it was Jonathan Thomas, Chair of the CIRM Board. Their conversation ranged from CIRM’s past to the future of the regenerative field as a whole, with a few interesting diversions along the way. It’s fun listening. And as Margaret Lyons said it might be more immediate and more relevant than ever before.

Charting a course for the future

A new home for stem cell research?

Have you ever been at a party where someone says “hey, I’ve got a good idea” and then before you know it everyone in the room is adding to it with ideas and suggestions of their own and suddenly you find yourself with 27 pages of notes, all of them really great ideas. No, me neither. At least, not until yesterday when we held the first meeting of our Scientific Strategy Advisory Panel.

This is a group that was set up as part of Proposition 14, the ballot initiative that refunded CIRM last November (thanks again everyone who voted for that). The idea was to create a panel of world class scientists and regulatory experts to help guide and advise our Board on how to advance our mission. It’s a pretty impressive group too. You can see who is on the SSAP here.  

The meeting involved some CIRM grantees talking a little about their work but mostly highlighting problems or obstacles they considered key issues for the future of the field as a whole. And that’s where the ideas and suggestions really started flowing hard and fast.

It started out innocently enough with Dr. Amander Clark of UCLA talking about some of the needs for Discovery or basic research. She advocated for a consortium approach (this quickly became a theme for many other experts) with researchers collaborating and sharing data and findings to help move the field along.

She also called for greater diversity in research, including collecting diverse cell samples at the basic research level, so that if a program advanced to later stages the findings would be relevant to a wide cross section of society rather than just a narrow group.

Dr. Clark also said that as well as supporting research into neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, there needed to be a greater emphasis on neurological conditions such as autism, bipolar disorder and other mental health problems.

(CIRM is already committed to both increasing diversity at all levels of research and expanding mental health research so this was welcome confirmation we are on the right track).

Dr. Mike McCun called for CIRM to take a leadership role in funding fetal tissue research, things the federal government can’t or won’t support, saying this could really help in developing an understanding of prenatal diseases.

Dr. Christine Mummery, President of ISSCR, advocated for support for early embryo research to deepen our understanding of early human development and also help with issues of infertility.

Then the ideas started coming really fast:

  • There’s a need for knowledge networks to share information in real-time not months later after results are published.
  • We need standardization across the field to make it easier to compare study results.
  • We need automation to reduce inconsistency in things like feeding and growing cells, manufacturing cells etc.
  • Equitable access to CRISPR gene-editing treatments, particularly for underserved communities and for rare diseases where big pharmaceutical companies are less likely to invest the money needed to develop a treatment.
  • Do a better job of developing combination therapies – involving stem cells and more traditional medications.

One idea that seemed to generate a lot of enthusiasm – perhaps as much due to the name that Patrik Brundin of the Van Andel Institute gave it – was the creation of a CIRM Hotel California, a place where researchers could go to learn new techniques, to share ideas, to collaborate and maybe take a nice cold drink by the pool (OK, I just made that last bit up to see if you were paying attention).

The meeting was remarkable not just for the flood of ideas, but also for its sense of collegiality.  Peter Marks, the director of the Food and Drug Administration’s Center for Biologics Evaluation and Research (FDA-CBER) captured that sense perfectly when he said the point of everyone working together, collaborating, sharing information and data, is to get these projects over the finish line. The more we work together, the more we will succeed.

De-stressing stem cells and the Bonnie & Clyde of stem cells

Dr. John Cashman

The cells in our body are constantly signalling with each other, it’s a critical process by which cells communicate not just with other cells but also with elements within themselves. One of the most important signalling pathways is called Wnt. This plays a key role in early embryonic and later development. But when Wnt signalling goes wrong, it can also help spur the growth of cancer.

Researchers at the Human BioMolecular Research Institute (HBRI) and Stanford University, have reported on a compound that can trigger a cascade of events that create stress and ultimately impact Wnt’s ability to control the ability of cells to repair themselves.

In a news release Dr. Mark Mercola, a co-author of a CIRM-funded study – published in the journal Cell Chemical Biology – says this is important: “because it explains why stressed cells cannot regenerate and heal tissue damage. By blocking the ability to respond to Wnt signaling, cellular stress prevents cells from migrating, replicating and differentiating.”

The researchers discovered a compound PAWI-2 that shows promise in blocking the compound that causes this cascade of problems. Co-author Dr. John Cashman says PAWI-2 could lead to treatments in a wide variety of cancers such as pancreatic, breast, prostate and colon cancer.

“As anti-cancer PAWI-2 drug development progresses, we expect PAWI-2 to be less toxic than current therapeutics for pancreatic cancer, and patients will benefit from improved safety, less side effects and possibly with significant cost-savings.”

Dr. Catriona Jamieson: Photo courtesy Moores Cancer Center, UCSD

Speaking of cancer….

Stem cells have many admirable qualities. However, one of their less admirable ones is their ability to occasionally turn into cancer stem cells. Like regular stem cells these have the ability to renew and replicate themselves over time, but as cancer stem cells they use that ability to help fuel the growth and spread of cancer in the body. Now, researchers at U.C. San Diego are trying to better understand how those regular stem cells become cancer stem cells, so they can stop that process.

In a CIRM-funded study Dr. Catriona Jamieson and her team identified two molecules, APOBEC3C and ADAR1, that play a key role in this process.

In a news release Jamieson said: “APOBEC3C and ADAR1 are like the Bonnie and Clyde of pre-cancer stem cells — they drive the cells into malignancy.”

So they studied blood samples from 54 patients with leukemia and 24 without. They found that in response to inflammation, APOBEC3C promotes the rapid production of pre-leukemia stem cells. That in turn enables ADAR1 to go to work, interfering with gene expression in a way that helps those pre-leukemia stem cells turn into leukemia stem cells.

They also found when they blocked the action of ADAR1 or silenced the gene in patient cells in the laboratory, they were able to stop the formation of leukemia stem cells.

The study is published in the journal Cell Reports.

DNA therapeutic treats blood cancer in mice and begins human clinical trial

The left image represents a microscopic view of the bone marrow of a myeloma-bearing mouse treated with control, and the right image represents the same for a myeloma-bearing mouse treated with ION251, an experimental therapeutic. The red dots represent the IRF4 protein within human myeloma cells, which are much sparser after ION251 treatment. Image credit: UC San Diego Health

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.

Inspiring new documentary about stem cell research

Poster for the documentary “Ending Disease”

2020 has been, to say the very least, a difficult and challenging year for all of us. But while the focus of the world has, understandably, been on the coronavirus there was also some really promising advances in stem cell research. Those advances are captured in a great new documentary called Ending Disease.

The documentary is by Emmy award-winning filmmaker Joe Gantz. In it he follows ten people who are facing life-threatening or life-changing diseases and injuries and who turn to pioneering stem cell therapies for help.

It’s an inspiring documentary, one that reminds you of the real need for new treatments and the tremendous hope and promise of stem cell therapies. Here’s a look at a trailer for Ending Disease.

You can see an exclusive screening of Ending Disease on Friday, January 8th, 2021 at 5:00pm PST.

After the livestream, there will be a live Q&A session where former members of the successful Proposition 14 campaign team – which refunded CIRM with an additional $5.5 billion – will be joined by CIRM’s President and CEO Dr. Maria Millan, talking about what lies ahead for CIRM and the future of stem cell research.

To purchase a ticket, click here. It only costs $12 and 50% of the ticket sales proceeds will go to Americans for Cures to help them continue to advocate for the advancement of stem cell research, and more importantly, for the patients and families to whom stem cell research provides so much hope.

If you need any extra persuading that it’s something you should definitely put on our calendar, here’s a letter from the film maker Joe Gantz.

I am the director of the documentary Ending Disease: The Stem Cell, Anti-Cancer T-Cell, & Antibody Revolution In Medicine, a film that will help inform people about the progress that’s been made in this field and how people with their lives on the line are now able to benefit from these new regenerative therapies. 

I was granted unprecedented access to ten of the first generation of clinical trials using stem cell and regenerative medicine to treat and cure many of the most devastating diseases and conditions including: brain cancer, breast cancer, leukemia and lymphoma, HIV, repairing a broken spinal cord, retinitis pigmentosa and SCID. The results are truly inspiring.

This is personal for me.  After spending four years making this documentary, I was diagnosed with bladder cancer. Upon diagnosis, I immediately felt the same desperation as millions of families who are in search of a medical breakthrough. I understood, on a personal level, what the patients we followed in the film all knew: when you are diagnosed with a disease, there is a narrow window of time in which you can effectively seek a life-saving treatment or cure. If treatment becomes available outside of that window, then it is too late. However, Ending Disease shows that with continued support for regenerative medicine, we can create a near future in which one-time cures and highly mitigating therapies are available to patients for a whole host of diseases.

Best regards,

Joe