Blood stem cell transplant

A look back: CIRM funded trial aims to help patients suffering from chronic viral infections

/ Yimy Villa / 1 Comment
Dr. Michael Pulsipher

All this month we are using our blog and social media to highlight a new chapter in CIRM’s life, thanks to the voters approving Proposition 14. We are looking back at what we have done since we were created in 2004, and also looking forward to the future. Today we look at a way of making blood stem cell transplants safer and more readily available

Blood stem cell transplants have provided lifechanging treatments to individuals.  This statement is observed firsthand in several patients in CIRM funded trials for X-linked Chronic Granulomatous Disease (X-CGD), Sickle Cell Disease (SCD), and Severe Combined Immunodeficiency (SCID).  The personal journeys of Evangelina Padilla-Vaccaro, Evie Junior, and Brenden Whittaker speak volumes for the potential this treatment holds.  In these trials, defective blood stem cells from the patient are corrected outside the body and then returned to the patient in a transplant procedure.

Unfortunately, there is still a certain degree of risk that accompanies this procedure.  Before a blood stem cell transplant can be performed,  diseased or defective blood stem cells in the patient’s bone marrow need to be removed using chemotherapy or radiation to make room for the transplant.  This leaves the patient temporarily without an immune system and at risk for a life-threatening viral infection.  Additionally, viral infections pose a serious risk to patients with immune deficiency disorders, with viruses accounting upwards of 40% of deaths in these patients.

That’s why in October 2017, the CIRM ICOC Board awarded $4.8M to fund a clinical trial conducted by Dr. Michael Pulsipher at the Children’s Hospital of Los Angeles.  Dr. Pulsipher and his team are using virus-specific T cells (VSTs), a special type of cell that plays an important role in the immune response, to treat immunosuppressed or immune deficient patients battling life-threatening viral infections.  This trial includes patients with persistent viral infections after having received a blood stem cell transplant as well as those with immune deficiency disorders that have not yet received a blood stem cell transplant.  The VSTs used in this trial specifically treat cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus infections.  They are manufactured using cells from healthy donors and are banked so as to be readily available when needed. 

One challenge of receiving a stem cell transplant can be finding a patient and donor that are a close or identical match.  This is done by looking at specific human leukocyte antigens (HLA), which are protein molecules we inherit from our parents.  To give you an idea of how challenging this can be, you only have a 25% chance of being an HLA identical match with your sibling. 

Because VSTs are temporary soldiers that are administered to fight the viral infection and then disappear, Dr. Pulsipher and his team are using partially HLA-matched VSTs to treat patients in their trial.  Previous studies have indicated that partially HLA-matched T-cells can be effective in treating patients.  The availability of partially HLA-matched VST banks that can be used “off the shelf” improves accessibility and shortens the time for patients to receive VST therapy, which will save lives.

To learn more about Dr. Pulsipher’s work, please view the video below:

Stanford study successful in transplant of mismatched stem cells, tissue in mice

/ Yimy Villa / 1 Comment
Dr. Irv Weissman at Stanford University

A transplant can be a lifesaving procedure for many people across the United States. In fact, according to the Health Resources & Services Administration, 36,528 transplants were performed in 2018. However, as of January 2019, the number of men, women, and children on the national transplant waiting list is over 113,000, with 20 people dying each day waiting for a transplant and a new person being added to the list every 10 minutes.

Before considering a transplant, there needs to be an immunological match between the donated tissue and/or blood stem cells and the recipient. To put it simply, a “match” indicates that the donor’s cells will not be marked by the recipient’s immune cells as foreign and begin to attack it, a process known as graft-versus-host disease. Unfortunately, these matches can be challenging to find, particularly for some ethnic minorities. Often times, immunosuppression drugs are also needed in order to prevent the foreign cells from being attacked by the body’s immune system. Additionally, chemotherapy and radiation are often needed as well.

Fortunately, a CIRM-funded study at Stanford has shown some promising results towards addressing the issue of matching donor cells and recipient. Dr. Irv Weissman and his colleagues at Stanford have found a way to prepare mice for a transplant of blood stem cells, even when donor and recipient are an immunological mismatch. Their method involved using a combination of six specific antibodies and does not require ongoing immunosuppression.

The combination of antibodies did this by eliminating several types of immune cells in the animals’ bone marrow, which allowed blood stem cells to engraft and begin producing blood and immune cells without the need for continued immunosuppression. The blood stem cells used were haploidentical, which, to put it simply, is what naturally occurs between parent and child, or between about half of all siblings. 

Additional experiments also showed that the mice treated with the six antibodies could also accept completely mismatched purified blood stem cells, such as those that might be obtained from an embryonic stem cell line. 

The results established in this mouse model could one day lay the foundation necessary to utilize this approach in humans after conducting clinical trials. The idea would be that a patient that needs a transplanted organ could first undergo a safe, gentle transplant with blood stem cells derived in the laboratory from embryonic stem cells. The same embryonic stem cells could also then be used to generate an organ that would be fully accepted by the recipient without requiring the need for long-term treatment with drugs to suppress the immune system. 

In a news release, Dr. Weissman is quoted as saying,

“With support by the California Institute for Regenerative Medicine, we’ve been able to make important advances in human embryonic stem cell research. In the past, these stem cell transplants have required a complete match to avoid rejection and reduce the chance of graft-versus-host disease. But in a family with four siblings the odds of having a sibling who matches the patient this closely are only one in four. Now we’ve shown in mice that a ‘half match,’ which occurs between parents and children or in two of every four siblings, works without the need for radiation, chemotherapy or ongoing immunosuppression. This may open up the possibility of transplant for nearly everyone who needs it. Additionally, the immune tolerance we’re able to induce should in the future allow the co-transplantation of [blood] stem cells and tissues, such as insulin-producing cells or even organs generated from the same embryonic stem cell line.”

The full results to this study were published in Cell Stem Cell.

Stanford and University of Tokyo researchers crack the code for blood stem cells

/ Yimy Villa / 1 Comment
Blood stem cells grown in lab

Blood stem cells offer promise for a variety of immune and blood related disorders such as sickle cell disease and leukemia. Like other stem cells, blood stem cells have the ability to generate additional blood stem cells in a process called self-renewal. Additionally, they are able to generate blood cells in a process called differentiation. These newly generated blood cells have the potential to be utilized for transplantations and gene therapies.

However, two limitations have hindered the progress made in this field. One problem relates to the amount of blood stem cells needed to make a potential transplantation or gene therapy viable. Unfortunately, it has been challenging to isolate and grow blood stem cells in large quantity needed for these approaches. A part of this reason relates to getting the blood stem cells to self-renew rather than differentiate.

The second problem involves the existing blood stem cells in the patient’s body prior to transplantation. In order for the procedure to work, the patient’s own blood stem cells must be eliminated to make space for the transplanted blood stem cells. This is done through a process known as conditioning, which typically involves chemotherapy and/or radiation. Unfortunately, chemotherapy and radiation can cause life-threatening side effects due to its toxicity, particularly in pediatric patients, such as growth retardation, infertility and secondary cancer in later life. Very sick or elderly patients are unable to tolerate this conditioning process, making them ineligible for transplants.

A CIRM funded study by a team at Stanford and the University of Tokyo has unlocked the code related to the generation of blood stem cells.

The collaborative team was able to modify the components used to grow blood stem cells. By making these modifications, which effects the growth and physical conditions of blood stem cells, the researchers have shown for the first time that it’s possible to get blood stem cells from mice to renew themselves hundreds or even thousands of times within a period of just 28 days. 

Furthermore, the team showed that when they transplanted the newly grown cells into mice that had not undergone conditioning, the donor cells had engrafted and remained functional.

The team also found that gene editing technology such as CRISPR could be used while growing an adequate supply of blood stem cells for transplantation. This opens the possibility of obtaining a patient’s own blood stem cells, correcting the problematic gene, and reintroducing these back to the patient.

The complete study was published in Nature.

In a news release, Dr. Hiromitsu Nakauchi, a senior author of the study, is quoted as saying,

“For 50 years, researchers from laboratories around the world have been seeking ways to grow these cells to large numbers. Now we’ve identified a set of conditions that allows these cells to expand in number as much as 900-fold in just one month. We believe this approach could transform how [blood] stem cell transplants and gene therapy are performed in humans.” 

Friday Roundup: A better kind of blood stem cell transplant; Encouraging news from spinal cord injury trial; Finding an “elusive” cell that could help diabetics

/ Kevin McCormack / 2 Comments

Cool Instagram image of the week:

Pancreatic Progenitors

Diabetes Research Institute scientists have confirmed that the unique stem cells reside within large ducts of the human pancreas. Two such ducts (green) surrounded by three islets (white) are shown. [Diabetes Research Institute Foundation]

Chemo- and radiation-free blood stem cell transplant showing promise

Bubble baby disease, also known as severe combined immunodeficiency (SCID), is an inherited disorder that leaves newborns without an effective immune system. Currently, the only approved treatment for SCID is a blood stem cell transplant, in which the patient’s defective immune system cells are eliminated by chemotherapy or radiation to clear out space for cells from a healthy, matched donor. Even though the disease can be fatal, physicians loathe to perform a stem cell transplant on bubble baby patients:

Shizuru“Physicians often choose not to give chemotherapy or radiation to young children with SCID because there are lifelong effects: neurological impairment, growth delays, infertility, risk of cancer, etc.,” says Judith Shizuru, MD, PhD, professor of medicine at Stanford University.

To avoid these complications, Dr. Shizuru is currently running a CIRM-funded clinical trial testing a gentler approach to prepare patients for blood stem cell transplants. She presented promising, preliminary results of the trial on Tuesday at the annual meeting of Stanford’s Center for Definitive and Curative Medicine.

Trial participants are receiving a protein antibody called CD117 before their stem cell transplant. Previous studies in animals showed that this antibody binds to the surface of blood stem cells and blocks the action of a factor which is required for stem cell survival. This property of CD117 provides a means to get rid of blood stem cells without radiation or chemotherapy.

Early results in two participants indicate that, 6 and 9 months after receiving the CD117 blood stem cell transplants, the donor cells have successfully established themselves in the patients and begun making immune cells.

Spinal cord injury trial reports more promising results:

AsteriasRegular readers of our blog will already know about our funding for the clinical trial being run by Asterias Biotherapeutics to treat spinal cord injuries. The latest news from the company is very encouraging, in terms of both the safety and effectiveness of the treatment.

Asterias is transplanting stem cells into patients who have suffered recent injuries that have left them paralyzed from the neck down. It’s hoped the treatment will restore connections at the injury site, allowing patients to regain some movement and feeling in their hands and arms.

This week the company announced that of the 25 patients they have treated there have been no serious side effects. In addition:

  • Magnetic Resonance Imaging (MRI) scans show that in more than 90 percent of the patients the cells appear to show signs of engraftment
  • At least 75 percent of those treated have recovered at least one motor level, and almost 20 percent have recovered two levels

In a news release, Michael Mulroy, Asterias’ President and CEO, said:

“The positive safety profile to date, the evidence supporting engraftment of the cells post-implantation, and the improvements we are seeing in upper extremity motor function highlight the promising findings coming from this Phase 1/2a clinical trial, which will guide us as we work to design future studies.”

There you are! Finding the “elusive” human pancreatic progenitor cells – the story behind our cool Instagram image of the week.

Don’t you hate it when you lose something and can’t find it? Well imagine the frustration of scientists who were looking for a group of cells they were sure existed but for decades they couldn’t locate them. Particularly as those cells might help in developing new treatments for diabetes.

Diabetes-Research-Institute_University-of-Miami-Miller-School-of-MedicineWell, rest easy, because scientists at the Diabetes Research Institute at the University of Miami finally found them.

In a study, published in Genetic Engineering and Biotechnology News, the researchers show how they found these progenitor cells in the human pancreas, tucked away in the glands and ducts of the organ.

In type 1 diabetes, the insulin-producing cells in the pancreas are destroyed. Finding these progenitor cells, which have the ability to turn into the kinds of cells that produce insulin, means researchers could develop new ways to regenerate the pancreas’ ability to function normally.

That’s a long way away but this discovery could be an important first step along that path.