leukemia

Investing in CAR T-cell therapy to treat cancer

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Photo credit: UC Regents 

The California Institute for Regenerative Medicine (CIRM) is investing $4 million to support Dr. William Murphy and UC Davis researchers to develop and test a chimeric antigen receptor (CAR) T-cell therapy to treat various B-cell malignancies, ranging from lymphomas to leukemias. 

In this Q&A—courtesy of UC Davis Health—Dr. Murphy discusses the importance of T-cell therapy and its implications for developing cancer treatments. His work is a collaboration between CIRM, the nonprofit organization Caring Cross, and UC Davis Health. 

What are B-cell malignancies? 

B-cells are a type of white blood cells that make antibodies. They are key to the body’s immune system. When healthy B-cells change into fast-growing cancer cells that don’t die, they cause B-cell malignancies. 

This can affect people at different ages. They may show up in children as B-cell acute lymphoblastic leukemia (B-ALL), an aggressive blood and bone marrow cancer. In adults, they make up about 85% of non-Hodgkin lymphoma (NHL), a cancer that starts in B lymphocytes. In the elderly, B-cell malignancies may come as multiple myeloma, a cancer of the plasma cells. 

There are different lines of treatments for B-cell lymphoma and leukemia, including immunotherapy using chimeric antigen receptor (CAR) T cells. These cells have revolutionized cancer treatment since they have been shown to work, and cure, when nothing else can. 

What is chimeric antigen receptor (CAR) T-cell therapy? 

Chimeric antigen receptor (CAR) T-cell therapy uses the body’s own defenses to fight disease. It is a new and exciting form of immunotherapy that works by modifying the receptors of immune cells (T cells) involving antibodies to target specific cancers, such as leukemias and lymphomas. 

CAR T cells are being used to treat some blood cancers with long-term success. The U.S. Food and Drug Administration (FDA) first approved CAR T-cell therapy in 2017. Their use is growing rapidly and being applied to other tumor types. Yet, this therapy is extremely expensive, even with insurance. It’s also a very intensive procedure and it takes time to generate the CAR T cells from the patient. 

While it could be considered a game changer, one of the issues with this therapy is the case relapse rate. The big holy grail in cancer therapy is how to prevent tumors from evading or escaping the immune attack. Around 60% of patients who get CAR therapy see their cancer return. If we can get the relapse rate down to negligible, that would be a tremendous advance. 

How do you intend to use CAR products to reduce cancer relapse? 

In CAR therapy, we take the immune T cells from a patient and use gene therapy to give a new receptor to signal and direct the T cell. The receptor usually has an antibody that recognizes a particular tumor antigen. Current FDA-approved CAR T therapies only target one tumor antigen. 

CARs have had tremendous success. However, there is significant patient relapse because the tumor adapts and may lose that one antigen that we are targeting, allowing it to escape the treatment. Our strategy is to target multiple antigens to reduce the potential for relapse since the tumor cannot adapt that quickly. 

We are also proposing a novel vector that will carry a CAR product, known as DuoCAR, that targets three antigens at the same time. As long as the tumor has one of the three antigens, then there’s little chance for the tumor to escape all three antibodies. This is similar to when you think about HIV treatment with the triple-drug therapy, where one alone is not sufficient. 

The hope is that the 60 to 70% of the population who would have relapsed if they had the original CAR T cell treatment, would have a home run with our kind of treatment or product. 

So, is this treatment for cancer patients who have relapsed? 

We see this product as a new frontline therapy and not just for patients who relapse. What the patient has to go through in order for CAR T therapy to work is very strenuous. So, yes, if there are relapsed patients, they can be given DuoCAR, but we’re also hoping this will become the new standard of care, replacing the other CARs in the future for everyone. 

To read the full Q&A, click here. 

How CIRM contributed to City of Hope study helping man with HIV into long-term remission

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The news that a stem cell transplant at City of Hope helped a man with HIV go into long-term remission made banner headlines around the world. As it should. It’s a huge achievement, particularly as the 66-year-old man had been living with HIV since 1988.

What wasn’t reported was that work supported by the California Institute for Regenerative Medicine played a role in making that happen.

The Stem Cell Transplant

First the news. In addition to living with HIV the man was diagnosed with acute leukemia. Doctors at City of Hope found a donor who was not only a perfect match to help battle the patient’s leukemia, but the donor also had a rare genetic mutation that meant they were resistant to most strains of HIV.

In transplanting blood stem cells from the donor to the patient they were able to send both his leukemia and HIV into remission. The patient stopped taking all his antiretroviral medications 17 months ago and today has no detectable levels of HIV.

In a news release  City of Hope hematologist Ahmed Aribi, M.D., said the patient didn’t experience any serious complications after the procedure.

“This patient had a high risk for relapsing from AML [acute myeloid leukemia], making his remission even more remarkable and highlighting how City of Hope provides excellent care treating complicated cases of AML and other blood cancers.”

It’s a remarkable achievement and is only the fifth time that a patient with both HIV and leukemia has been put into remission after a transplant from an HIV-resistant donor.

CIRM’s Contribution

So, what does that have to do with CIRM? Well, CIRM’s Alpha Clinics Network helped City of Hope get this case approved by an Institutional Review Board (IRB) and also helped in collecting and shipping the donor blood. In addition, part of the Alpha Clinics team at University of California San Diego helped with the reservoir analysis of blood and gut biopsies to check for any remaining signs of HIV.

It’s a reminder that this kind of achievement is a team effort and CIRM is very good at creating and supporting teams. The Alpha Clinics Network is a perfect example. We created it because there was a need for a network of world-class medical facilities with the experience and expertise to deliver a whole new kind of therapy. The Network has been remarkably successful in doing that with more than 200 clinical trials, taking care of more than 1,000 patients, and treating more than 40 different diseases.

This year our Board approved expanding the number of these clinics to better serve the people of California.

While the role of the Alpha Clinics Network in helping this one patient may seem relatively small, it was also an important one. And we are certainly not stopping here. We have invested more than $79 million in 19 different projects targeting HIV/AIDS, include four clinical trials.

We are in this for the long term and results like the man who had HIV and is now in remission are a sign we are heading in the right direction.

Stem Cell Agency Board Invests in 19 Discovery Research Programs Targeting Cancers, Heart Disease and Other Disorders

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Dr. Judy Shizuru, Stanford University

While stem cell and gene therapy research has advanced dramatically in recent years, there are still many unknowns and many questions remaining about how best to use these approaches in developing therapies. That’s why the governing Board of the California Institute for Regenerative Medicine (CIRM) today approved investing almost $25 million in 19 projects in early stage or Discovery research.

The awards are from CIRM’s DISC2 Quest program, which supports  the discovery of promising new stem cell-based and gene therapy technologies that could be translated to enable broad use and ultimately, improve patient care.

“Every therapy that helps save lives or change lives begins with a researcher asking a simple question, “What if?”, says Dr. Maria T. Millan, the President and CEO of CIRM. “Our Quest awards reflect the need to keep supporting early stage research, to gain a deeper understanding of stem cells work and how we can best tap into that potential to advance the field.”

Dr. Judy Shizuru at Stanford University was awarded $1.34 million to develop a safer, less-toxic form of bone marrow or hematopoietic stem cell transplant (HCT). HCT is the only proven cure for many forms of blood disorders that affect people of all ages, sexes, and races worldwide. However, current methods involve the use of chemotherapy or radiation to destroy the patient’s own unhealthy blood stem cells and make room for the new, healthy ones. This approach is toxic and complex and can only be performed by specialized teams in major medical centers, making access particularly difficult for poor and underserved communities.

Dr. Shizuru proposes developing an antibody that can direct the patient’s own immune cells to kill diseased blood stem cells. This would make stem cell transplant safer and more effective for the treatment of many life-threatening blood disorders, and more accessible for people in rural or remote parts of the country.

Lili Yang UCLA Broad Stem Cell Research Center: Photo courtesy Reed Hutchinson PhotoGraphics

Dr. Lili Yang at UCLA was awarded $1.4 million to develop an off-the-shelf cell therapy for ovarian cancer, which causes more deaths than any other cancer of the female reproductive system.

Dr. Yang is using immune system cells, called invariant natural killer T cells (iNKT) to attack cancer cells. However, these iNKT cells are only found in small numbers in the blood so current approaches involve taking those cells from the patient and, in the lab, modifying them to increase their numbers and strength before transplanting them back into the patient. This is both time consuming and expensive, and the patient’s own iNKT cells may have been damaged by the cancer, reducing the likelihood of success.

In this new study Dr. Yang will use healthy donor cord blood cells and, through genetic engineering, turn them into the specific form of iNKT cell therapy targeting ovarian cancer. This DISC2 award will support the development of these cells and do the necessary testing and studies to advance it to the translational stage.

Timothy Hoey and Tenaya Therapeutics Inc. have been awarded $1.2 million to test a gene therapy approach to replace heart cells damaged by a heart attack.

Heart disease is the leading cause of death in the U.S. with the highest incidence among African Americans. It’s caused by damage or death of functional heart muscle cells, usually due to heart attack. Because these heart muscle cells are unable to regenerate the damage is permanent. Dr. Hoey’s team is developing a gene therapy that can be injected into patients and turn their cardiac fibroblasts, cells that can contribute to scar tissue, into functioning heart muscle cells, replacing those damaged by the heart attack.

The full list of DISC2 Quest awards is:

APPLICATION NUMBERTITLE OF PROGRAMPRINCIPAL INVESTIGATORAMOUNT
  DISC2-13400  Targeted Immunotherapy-Based Blood Stem Cell Transplantation    Judy Shizuru, Stanford Universtiy  $1,341,910    
  DISC2-13505  Combating Ovarian Cancer Using Stem Cell-Engineered Off-The-Shelf CAR-iNKT Cells    Lili Yang, UCLA  $1,404,000
  DISC2-13515  A treatment for Rett syndrome using glial-restricted
neural progenitor cells  		  Alysson Muotri, UC San Diego  $1,402,240    
  DISC2-13454  Targeting pancreatic cancer stem cells with DDR1 antibodies.    Michael Karin, UC San Diego  $1,425,600  
  DISC2-13483  Enabling non-genetic activity-driven maturation of iPSC-derived neurons    Alex Savtchenko, Nanotools Bioscience  $675,000
  DISC2-13405  Hematopoietic Stem Cell Gene Therapy for Alpha
Thalassemia  		  Don Kohn, UCLA    $1,323,007  
    DISC2-13507  CAR T cells targeting abnormal N-glycans for the
treatment of refractory/metastatic solid cancers  		  Michael Demetriou, UC Irvine  $1,414,800  
  DISC2-13463  Drug Development of Inhibitors of Inflammation Using
Human iPSC-Derived Microglia (hiMG)  		  Stuart Lipton, Scripps Research Inst.  $1,658,123  
  DISC2-13390  Cardiac Reprogramming Gene Therapy for Post-Myocardial Infarction Heart Failure    Timothy Hoey, Tenaya Therapeutics  $1,215,000  
  DISC2-13417  AAV-dCas9 Epigenetic Editing for CDKL5 Deficiency Disorder    Kyle Fink, UC Davis  $1,429,378  
  DISC2-13415  Defining the Optimal Gene Therapy Approach of
Human Hematopoietic Stem Cells for the Treatment of
Dedicator of Cytokinesis 8 (DOCK8) Deficiency  		  Caroline Kuo, UCLA  $1,386,232  
  DISC2-13498  Bioengineering human stem cell-derived beta cell
organoids to monitor cell health in real time and improve therapeutic outcomes in patients  		  Katy Digovich, Minutia, Inc.  $1,198,550  
  DISC2-13469  Novel antisense therapy to treat genetic forms of
neurodevelopmental disease.  		  Joseph Gleeson, UC San Diego  $1,180,654  
  DISC2-13428  Therapeutics to overcome the differentiation roadblock in Myelodysplastic Syndrome (MDS)    Michael Bollong, Scripps Research Inst.  $1,244,160  
  DISC2-13456  Novel methods to eliminate cancer stem cells    Dinesh Rao, UCLA  $1,384,347  
  DISC2-13441  A new precision medicine based iPSC-derived model to study personalized intestinal fibrosis treatments in
pediatric patients with Crohn’s diseas  		  Robert Barrett Cedars-Sinai  $776,340
  DISC2-13512  Modified RNA-Based Gene Therapy for Cardiac
Regeneration Through Cardiomyocyte Proliferation		  Deepak Srivastava, Gladstone Institutes  $1,565,784
  DISC2-13510  An hematopoietic stem-cell-based approach to treat HIV employing CAR-T cells and anti-HIV broadly
neutralizing antibodies  		  Brian Lawson, The Scintillon Institute  $1,143,600  
  DISC2-13475  Developing gene therapy for dominant optic atrophy using human pluripotent stem cell-derived retinal organoid disease model    Xian-Jie Yang, UCLA  $1,345,691  

CIRM-supported therapy for blood cancers gets FDA fast track

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People often complain about how long it can take to turn a scientific discovery into an approved therapy for patients. And they’re right. It can take years, decades even. But for Immune-Onc Therapeutics the path to FDA approval may just have been shortened.

Back in April of 2021 the California Institute for Regenerative Medicine (CIRM) approved investing $6 million in Immune-Onc to conduct a clinical trial for patients with acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML). AML and CMML are both 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.

Dr. Paul Woodard and his team are treating patients with an antibody therapy called IO-202 that targets leukemic stem cells.  The antibody works by blocking a signal named LILRB4 which is associated with decreased rates of survival in AML patients.  The goal is to attain complete cancer remissions and prolonged survival.

Well, they must be doing something right because they just received Fast Track designation from the US Food and Drug Administration (FDA) for IO-202. Getting this designation is a big deal because its goal is to speed up the development and review of drugs to treat serious conditions and fill an unmet medical need to get important new medicines to patients earlier.

Getting a Fast Track designation means the team at Immune-Onc may be:

  • Eligible for more written communications and even face-to-face meetings with the FDA to discuss the development plan of IO-202
  • Eligible for Accelerated Approval and Priority Review if relevant criteria are met, which may result in faster approval.

In a press release Dr. Woodard said this was great news.  “We are pleased that the FDA has granted IO-202 Fast Track designation in recognition of its potential to improve outcomes for people with relapsed or refractory AML. We look forward to working closely with the FDA to accelerate the clinical development of IO-202, which is currently being evaluated as a monotherapy and in combination with other agents in a Phase 1 dose escalation and expansion trial in patients with AML with monocytic differentiation and in chronic myelomonocytic leukemia (CMML).”

The FDA also granted IO-202 Orphan Drug Designation for treatment of AML in 2020. That’s defined as a therapy that’s intended for the treatment, prevention or diagnosis of a rare disease or condition, affecting less than 200,000 persons in the US.

Getting Orphan Drug Designation qualifies Immune-Onc for incentives including tax credits for clinical trials and the potential for seven years of market exclusivity if and when it is fully approved by the FDA.

Two Early-Stage Research Programs Targeting Cartilage Damage Get Funding from Stem Cell Agency

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Darryl D’Lima: Scripps Health

Every year millions of Americans suffer damage to their cartilage, either in their knee or other joints, that can eventually lead to osteoarthritis, pain and immobility. Today the governing Board of the California Institute for Regenerative Medicine (CIRM) approved two projects targeting repair of damaged cartilage.

The projects were among 17 approved by CIRM as part of the DISC2 Quest Discovery Program. The program promotes the discovery of promising new stem cell-based and gene therapy technologies that could be translated to enable broad use and ultimately, improve patient care.

Dr. Darryl D’Lima and his team at Scripps Health were awarded $1,620,645 to find a way to repair a torn meniscus. Every year around 750,000 Americans experience a tear in their meniscus, the cartilage cushion that prevents the bones in the knee grinding against each other. These injuries accelerate the early development of osteoarthritis, for which there is no effective treatment other than total joint replacement, which is a major operation. There are significant socioeconomic benefits to preventing disabling osteoarthritis. The reductions in healthcare costs are also likely to be significant.

The team will use stem cells to produce meniscal cells in the lab. Those are then seeded onto a scaffold made from collagen fibers to create tissue that resembles the knee meniscus. The goal is to show that, when placed in the knee joint, this can help regenerate and repair the damaged tissue.

This research is based on an earlier project that CIRM funded. It highlights our commitment to helping good science progress, hopefully from the bench to the bedside where it can help patients.

Dr. Kevin Stone: Photo courtesy Stone Research Foundation

Dr. Kevin Stone and his team at The Stone Research Foundation for Sports Medicine and Arthritis were awarded $1,316,215 to develop an approach to treat and repair damaged cartilage using a patient’s own stem cells.

They are using a paste combining the patient’s own articular tissue as well as Mesenchymal Stem Cells (MSC) from their bone marrow. This mixture is combined with an adhesive hydrogel to form a graft that is designed to support cartilage growth and can also stick to surfaces without the need for glue. This paste will be used to augment the use of a microfracture technique, where micro-drilling of the bone underneath the cartilage tear brings MSCs and other cells to the fracture site. The hope is this two-pronged approach will produce an effective and functional stem cell-based cartilage repair procedure.

If effective this could produce a minimally invasive, low cost, one-step solution to help people with cartilage injuries and arthritis.

The full list of DISC2 grantees is:

ApplicationTitlePrincipal Investigator and InstitutionAmount
DISC2-13212Preclinical development of an exhaustion-resistant CAR-T stem cell for cancer immunotherapy  Ansuman Satpathy – Stanford University    $ 1,420,200  
DISC2-13051Generating deeper and more durable BCMA CAR T cell responses in Multiple Myeloma through non-viral knockin/knockout multiplexed genome engineering  Julia Carnevale – UC San Francisco  $ 1,463,368  
DISC2-13020Injectable, autologous iPSC-based therapy for spinal cord injury  Sarah Heilshorn – Stanford University    $789,000
DISC2-13009New noncoding RNA chemical entity for heart failure with preserved ejection fraction.  Eduardo Marban – Cedars-Sinai Medical Center  $1,397,412  
DISC2-13232Modulation of oral epithelium stem cells by RSpo1 for the prevention and treatment of oral mucositis  Jeffrey Linhardt – Intact Therapeutics Inc.  $942,050  
DISC2-13077Transplantation of genetically corrected iPSC-microglia for the treatment of Sanfilippo Syndrome (MPSIIIA)  Mathew Blurton-Jones – UC Irvine    $1,199,922  
DISC2-13201Matrix Assisted Cell Transplantation of Promyogenic Fibroadipogenic Progenitor (FAP) Stem Cells  Brian Feeley – UC San Francisco  $1,179,478  
DISC2-13063Improving the efficacy and tolerability of clinically validated remyelination-inducing molecules using developable combinations of approved drugs  Luke Lairson – Scripps Research Inst.  $1,554,126  
DISC2-13213Extending Immune-Evasive Human Islet-Like Organoids (HILOs) Survival and Function as a Cure for T1D  Ronald Evans – The Salk Institute for Biological Studies    $1,523,285  
DISC2-13136Meniscal Repair and Regeneration  Darryl D’Lima – Scripps Health      $1,620,645  
DISC2-13072Providing a cure for sphingosine phosphate lyase insufficiency syndrome (SPLIS) through adeno-associated viral mediated SGPL1 gene therapy  Julie Saba – UC San Francisco  $1,463,400  
DISC2-13205iPSC-derived smooth muscle cell progenitor conditioned medium for treatment of pelvic organ prolapse  Bertha Chen – Stanford University  $1,420,200  
DISC2-13102RNA-directed therapy for Huntington’s disease  Gene Wei-Ming Yeo  – UC San Diego  $1,408,923  
DISC2-13131A Novel Therapy for Articular Cartilage Autologous Cellular Repair by Paste Grafting  Kevin Stone – The Stone Research Foundation for Sports Medicine and Arthritis    $1,316,215  
DISC2-13013Optimization of a gene therapy for inherited erythromelalgia in iPSC-derived neurons  Ana Moreno – Navega Therapeutics    $1,157,313  
DISC2-13221Development of a novel stem-cell based carrier for intravenous delivery of oncolytic viruses  Edward Filardo – Cytonus Therapeutics, Inc.    $899,342  
DISC2-13163iPSC Extracellular Vesicles for Diabetes Therapy  Song Li – UC Los Angeles  $1,354,928  

Stem Cell Agency Board Invests in Therapy Targeting Deadly Blood Cancers

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Dr. Ezra Cohen, photo courtesy UCSD

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

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

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

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

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

National Academy of Medicine honors CIRM Grantees

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

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

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

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

The CIRM grantees elected last year are:

Dr. Antoni Ribas: Photo courtesy UCLA

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

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

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

Looks like he chose his career path wisely.

Dr. Jeffrey Goldberg: Photo courtesy Stanford

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

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

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

Dr. Mark Anderson; photo courtesy UCSF

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

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

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

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

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

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

Paving the Way

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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.

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

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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.

Cures, clinical trials and unmet medical needs

/ Kevin McCormack / Leave a comment

When you have a great story to tell there’s no shame in repeating it as often as you can. After all, not everyone gets to hear first time around. Or second or third time. So that’s why we wanted to give you another opportunity to tune into some of the great presentations and discussions at our recent CIRM Alpha Stem Cell Clinic Network Symposium.

It was a day of fascinating science, heart-warming, and heart-breaking, stories. A day to celebrate the progress being made and to discuss the challenges that still lie ahead.

There is a wide selection of topics from “Driving Towards a Cure” – which looks at some pioneering work being done in research targeting type 1 diabetes and HIV/AIDS – to Cancer Clinical Trials, that looks at therapies for multiple myeloma, brain cancer and leukemia.

The COVID-19 pandemic also proved the background for two detailed discussions on our funding for projects targeting the coronavirus, and for how the lessons learned from the pandemic can help us be more responsive to the needs of underserved communities.

Here’s the agenda for the day and with each topic there’s a link to the video of the presentation and conversation.

Thursday October 8, 2020

View Recording: CIRM Fellows Trainees

9:00am Welcome Mehrdad Abedi, MD, UC Davis Health, ASCC Program Director  

Catriona Jamieson, MD,  View Recording: ASCC Network Value Proposition

9:10am Session I:  Cures for Rare Diseases Innovation in Action 

Moderator: Mark Walters, MD, UCSF, ASCC Program Director 

Don Kohn, MD, UCLA – View Recording: Severe combined immunodeficiency (SCID) 

Mark Walters, MD, UCSF, ASCC Program Director – View Recording: Thalassemia 

Pawash Priyank, View Recording: Patient Experience – SCID

Olivia and Stacy Stahl, View Recording: Patient Experience – Thalassemia

10 minute panel discussion/Q&A 

BREAK

9:55am Session II: Addressing Unmet Medical Needs: Driving Towards a Cure 

Moderator: John Zaia, MD, City of Hope, ASCC Program Direction 

Mehrdad Abedi, MD, UC Davis Health, ASCC Program Director – View Recording: HIV

Manasi Jaiman, MD, MPH, ViaCyte, Vice President, Clinical Development – View Recording: Diabetes

Jeff Taylor, Patient Experience – HIV

10 minute panel discussion/Q&A 

BREAK

10:40am Session III: Cancer Clinical Trials: Networking for Impact 

Moderator: Catriona Jamieson, MD, UC San Diego, ASCC Program Director 

Daniela Bota, MD, PhD, UC Irvine, ASCC Program Director – View Recording:  Glioblastoma 

Michael Choi, MD, UC San Diego – View Recording: Cirmtuzimab

Matthew Spear, MD, Poseida Therapeutics, Chief Medical Officer – View Recording: Multiple Myeloma  

John Lapham, Patient Experience –  View Recording: Chronic lymphocytic leukemia (CLL) 

10 minute panel discussion/Q&A 

BREAK

11:30am Session IV: Responding to COVID-19 and Engaging Communities

Two live “roundtable conversation” sessions, 1 hour each.

Roundtable 1: Moderator Maria Millan, MD, CIRM 

CIRM’s / ASCC Network’s response to COVID-19 Convalescent Plasma, Cell Therapy and Novel Vaccine Approaches

Panelists

Michael Matthay, MD, UC San Francisco: ARDS Program

Rachael Callcut, MD, MSPH, FACS, UC Davis: ARDS Program 

John Zaia, MD, City of Hope: Convalescent Plasma Program 

Daniela Bota, MD, PhD, UC Irvine: Natural Killer Cells as a Treatment Strategy 

Key questions for panelists: 

  • Describe your trial or clinical program?
  • What steps did you take to provide access to disproportionately impacted communities?
  • How is it part of the overall scientific response to COVID-19? 
  • How has the ASCC Network infrastructure accelerated this response? 

Brief Break

Roundtable 2: Moderator Ysabel Duron, The Latino Cancer Institute and Latinas Contra Cancer

View Recording: Roundtable 2

Community Engagement and Lessons Learned from the COVID Programs.  

Panelists

Marsha Treadwell, PhD, UC San Francisco: Community Engagement  

Sheila Young, MD, Charles R. Drew University of Medicine and Science: Convalescent Plasma Program in the community

David Lo, MD, PhD,  UC Riverside: Bringing a public health perspective to clinical interventions

Key questions for panelists: 

  • What were important lessons learned from the COVID programs? 
  • How can CIRM and the ASCC Network achieve equipoise among communities and engender trust in clinical research? 
  • How can CIRM and the ASCC Network address structural barriers (e.g. job constrains, geographic access) that limit opportunities to participate in clinical trials?