Novel clinical trial for COVID-19 using immune cells

This scanning electron microscope image shows SARS-CoV-2 (yellow)—also known as 2019-nCoV, the virus that causes COVID-19—isolated from a patient in the U.S., emerging from the surface of cells (blue/pink) cultured in the lab.
Image Credit: National Institute of Allergy and Infectious DiseasesRocky Mountain Laboratories

During this global pandemic, many scientists are pursuing various avenues for potential treatments of COVID-19.  The Infectious Disease Research Institute (IDRI), in collaboration with Celularity Inc., will conduct a clinical trial with 100 patients using an immunotherapy for treatment of COVID-19.

The treatment will involve administering specialized immune cells called Natural Killer (NK) cells, which are a type of white blood cell that are a vital part of the immune system. Previously, these cells have been administered in early safety studies to treat patients with blood cancers. NK cells play an important role in fighting off viral infections. In initial patients with severe cases of COVID-19, low NK cell counts were observed.

The NK cells used in this study are derived from blood stem cells obtained from the placenta. They will be administered to patients diagnosed with a COVID-19 infection causing pneumonia.

In a press release, IDRI’s CEO Corey Casper talks in more detail about how the NK cells could help treat patients with COVID-19.

“The hypothesis is that administering NK cells to patients with moderate to severe COVID-19 will allow the immune cells find the sites of active viral infection, kill the virus, and induce a robust immune response that will help heal the damage and control the infection.”

In the same press release, Corey Casper also mentions the other applications this treatment could have.

“Beyond its promise as a critically needed treatment for COVID-19, the biology of NK cells indicates a possibility that this immunotherapy could be used as an off-the-shelf treatment for future pandemic infections.”

New hope for stem cell therapy in patients with leukemia

LeukemiaWhiteBloodCell

Leukemia white blood cell

Of the many different kinds of cancer that affect humans, leukemia is the most common in young people. As with many types cancer, doctors mostly turn to chemotherapy to treat patients. Chemotherapy, however, comes with its own share of issues, primarily severe side effects and the constant threat of disease recurrence.

Stem cell therapy treatment has emerged as a potential cure for some types of cancer, with leukemia patients being among the first groups of patients to receive this type of treatment. While exciting because of the possibility of a complete cure, stem cell therapy comes with its own challenges. Let’s take a closer look.

Leukemia is characterized by abnormal white blood cells (also known as the many different types of cells that make up our immune system) that are produced at high levels. Stem cell therapy is such an appealing treatment option because it involves replacing the patient’s aberrant blood stem cells with healthy ones from a donor, which provides the possibility of complete and permanent remission for the patient.

Unfortunately, in approximately half of patients who receive this therapy, the donor cells (which turn into immune cells), can also destroy the patients healthy tissue (i.e. liver, skin etc…), because the transplanted blood stem cells recognize patient’s tissue as foreign. While doctors try to lessen this type of response (also known as graft versus host disease (GVHD)), by suppressing the patient’s immune system, this procedure lessens the effectiveness of the stem cell therapy itself.

Now scientists at the University of Zurich have made an important discovery – published in the journal Science Translational Medicine – that could mitigate this potentially fatal response in patients. They found that a molecule called GM-CSF, is a critical mediator of the severity of GVHD. Using a mouse model, they showed that if the donor cells were unable to produce GM-CSF, then mice fared significantly better both in terms of less damage to tissues normally affected by GVHD, such as the skin, and overall survival.

While exciting, the scientists were concerned about narrowing in on this molecule as a potential target to lessen GVHD, because GM-CSF, an important molecule in the immune system, might also be important for ensuring that the donor immune cells do their jobs properly. Reassuringly, the researchers found that blocking GM-CSF’s function had no effect on the ability of the donor cells to exert their anti-cancer effect. This was surprising because previously the ability of donor cells to cause GVHD, versus protect patients from the development of cancer was thought to occur via the same biological mechanisms.

Most excitingly, however, was that finding that high levels of GM-CSF are also observed in patient samples, and that the levels of GM-CSF correlate to the severity of GVHD. Dr. Burkhard Becher and his colleagues, the authors of this study, now want to run a clinical trial to determine whether blocking GM-CSF blocks GVHD in humans like it does in mice. In a press release, Dr. Becher states the importance of these findings:

“If we can stop the graft-versus-host response while preserving the anti-cancer effect, this procedure can be employed much more successfully and with fewer risks to the patient. This therapeutic strategy holds particular promise for patients with the poorest prognosis and highest risk of fatality.”

Avoiding drug trial tragedies: new stem cell-based test predicts dangerous drug toxicity

In 2006 Ryan Wilson, a healthy 20 year old Londoner, volunteered for a first-in-human clinical trial to help test the safety of a new drug, TGN1412, intended to treat rheumatoid arthritis and leukemia. The cash he’d get in exchange for his time would help fund his upcoming vacation.

Instead, he nearly died.

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The TGN1412 drug trial disaster got a lot of high profile news coverage in 2006. (image credit: BBC News)

Even though the drug amount injected in his body was 500 times lower than the dose found to be safe in animals, Wilson experienced a catastrophic immune reaction, called a cytokine storm, that led to heart, kidney and liver failure, pneumonia and the loss of his toes and three fingers to dry gangrene. The other five healthy volunteers were also severely injured.

TGN1412’s devastating effect was unfortunately missed in preclinical laboratory and animal studies prior to the human trial. Unlike the pills in your medicine cabinet which are made up of synthesized chemicals, TGN1424 belongs to a growing class of medicines called biologics which come from biological sources such as proteins, DNA, sugars and cells. There is a concern that once a biologic is injected in a patient, the immune system may mount a strong attack all over the body. If that happens, too many immune cells, or white blood cells, are activated and release proteins, called cytokines, which in turn activate more immune cells and the reaction spirals into a dangerous cytokine storm like in Ryan Wilson’s case.

Clearly this tragedy begs for tests that can better predict drug toxicity in humans well before the first trial participants step into the clinic. On Monday a research team from the Imperial College London reported in the journal FASEB that they have done just that using human blood stem cells.

The team’s novel test is not so different than previous ones. Both tests are carried out in a petri dish using two human cell types: white blood cells and endothelial cells, a component of blood vessels. Both tests are also designed to mimic the human immune system’s response to biologics by measuring the release of cytokines.

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Endothelial cells grown from blood stem cells. (credit: Imperial College London)

But the Imperial College London team’s test differs from others in one important way: both the white blood cell and endothelial cell types come from the same individual. First they collect a donor’s blood stem cells and specialize them into endothelial cells. Then white blood cells are also collected from the same donor.

The prior tests, on the other hand, rely on cells from two different donors. Because the two cell types aren’t necessarily tissue-matched, the white blood cells may already be primed for an immune response even before a biologic is added to the test. In fact, these prior tests weren’t able to distinguish between a biologic known to cause a limited immune response versus TGN1424, known to cause a cytokine storm. The newly developed test, however, accurately predicts both the toxic cytokine storm caused by TGN1424 and the absence of a response by several approved biologics, such as the breast cancer drug Herceptin.

In a college news release, Jane Mitchell, the senior author on the report, sees the big picture importance of her lab’s work:

“As biological therapies become more mainstream, it’s more likely that drugs being tested on humans for the first time will have unexpected and potentially catastrophic effects. We’ve used adult stem cell technology to develop a laboratory test that could prevent another disaster like the TGN1412 trial.”

Their results also highlight the often-overlooked power of stem cells to not just deliver therapies but to help develop safer ones.

Harder, Better, Faster, Stronger: Scientists Work to Create Improved Immune System One Cell at a Time

The human immune system is the body’s best defense against invaders. But even our hardy immune systems can sometimes be outpaced by particularly dangerous bacteria, viruses or other pathogens, or even by cancer.

Salk Institute scientists have developed a new cellular reprogramming technique that could one day boost a weakened immune system.

Salk Institute scientists have developed a new cellular reprogramming technique that could one day boost a weakened immune system.

But what if we could give our immune system a boost when it needs it most? Last week scientists at the Salk Institute for Biological Sciences devised a new method of doing just that.

Reporting in the latest issue of the journal Stem Cells, Dr. Juan Carlos Izpisua Belmonte and his team announce a new method of creating—and then transplanting—white blood cells into laboratory mice. This new and improved method could have significant ramifications for how doctors attack the most relentless disease.

The authors achieved this transformation through the reprogramming of skin cells into white blood cells. This process builds on induced pluripotent stem cell, or iPS cell, technology, in which the introduction of a set of genes can effectively turn one cell type into another.

This Nobel prize-winning approach, while revolutionary, is still a many months’ long process. In this study, the Salk team found a way to shorten the cellular ‘reprogramming’ process from several months to just a few weeks.

“The process is quick and safe in mice,” said Izpisua Belmonte in a news release. “It circumvents long-standing obstacles that have plagued the reprogramming of human cells for therapeutic and regenerative purposes.”

Traditional reprogramming methods change one cell type, such as a skin cell, into a different cell type by first taking them back into a stem cell-like, or ‘pluripotent’ state. But here, the research team didn’t take the cells all the way back to pluripotency. Instead, they simply wiped the cell’s memory—and gave it a new one. As first author Dr. Ignacio Sancho-Martinez explained:

“We tell skin cells to forget what they are and become what we tell them to be—in this case, white blood cells. Only two biological molecules are needed to induce such cellular memory loss and to direct a new cell fate.”

This technique, which they dubbed ‘indirect lineage conversion,’ uses the molecule SOX2 to wipe the skin cell’s memory. They then use another molecule called miRNA 125b to reprogram the cell into a white blood cell.

These newly generated cells appear to engraft far better than cells derived from traditional iPS cell technology, opening the door to therapies that more effectively introduce these immune cells into the human body. As Sanchi-Martinez so eloquently stated:

“It is fair to say that the promise of stem cell transplantation is now closer to realization.”

Unique Cellular Signal Directs Cells to Gobble Up Toxic Waste; Could Serve as New Weapon to Fight Disease

White blood cells have a lot of work to do. They are our body’s main defense against foreign invaders—and are quite adept at it. Tasked with cleanup duty, they target and destroy cells that have been infected with bacteria, viruses or other harmful, disease-causing pathogens.

But as good as they are at their job—they aren’t perfect. Sometimes they need a little help. This is where modern medicine steps in to help the body fight disease.

A healthy cell (green) that has recognized and engulfed dying cells (purple) is shown. [Credit: Toru Komatsu/University of Tokyo]

A healthy cell (green) that has recognized and engulfed dying cells (purple) is shown. [Credit: Toru Komatsu/University of Tokyo]

But what if we could reprogram human cells, and supercharge them—so that they are then able to do the job that as of right now, only the most advanced drugs could accomplish. This is the hope of scientists from Johns Hopkins University, who today report that they are on the path towards doing just that.

Published online in the journal Science Signaling, Dr. Takanari Inoue and his team at Hopkins—along with his collaborators at the University of Tokyo—have together pioneered an innovative way to transform cells not normally involved in fighting disease into a new, cellular line of defense.

This discovery could potentially alter how our bodies combat some of humankind’s most relentless diseases—including pathogens that are skilled at evading white blood cells, or even cancer cells that can grow out of control and lead to dangerous tumors.

As Inoue explained in today’s news release:

“Our goal is to build artificial cells reprogramed to eat up dangerous junk in the body, which could be anything from bacteria to…the body’s own rogue cancer cells. By figuring out how to get normally inert cells to recognize and engulf dying cells, we’ve taken an important first step in that direction.”

A class of white blood cells called macrophages normally target and destroy dangerous cellular ‘junk’ via a process called phagocytosis. Phagocytosis is a fundamental but complex cellular process, so Inoue and his team broke it down step by step. In this way, they hoped to find out the bare minimum process needed, in order to give cells the power of phagocytosis.

The team started with a type of laboratory grown cell called HeLa. The first step was to tweak HeLa cells so that they could target and attach to dying cells. The second step was to destroy those dying cells.

The first step was accomplished simply by modifying a particular protein that sits on the surface of HeLa cells so that damaged or dying cells would be attracted to them. By making this modification, up to six dying cells locked onto each HeLa cell.

Next, the team switched on a gene in the HeLa called Rac. Previous research by other teams had found that turning on Rac causes a cell to engulf whatever is attached to it. In this case, activating Rac spurred the HeLa cells to swallow up the dying cells already attached to its surface. In effect, they had changed the cells’ job description—allowing them to mimic the phagocytosis process normally reserved for certain white blood cells.

As Inoue elaborated:

“We’ve shown it’s possible to endow ordinary cells with the power to do something unique: take on the role of a specialized macrophage.”

These results, while encouraging, are still preliminary. For example, even though the HeLa cells engulfed the dying cells, they likely weren’t destroyed. This next step in phagocytosis will be critical if the researchers are to further develop the idea of modifying the body’s own cells to combat disease.

Out with the Old and in with the New: Starvation Sparks Stem Cells to Replenish Immune System

New research from California scientists has revealed a startling side effect to prolonged starvation, or fasting.

In the latest issue of the journal Cell Stem Cell, scientists from the University of Southern California describe how fasting triggers the human immune system to flush out old, damaged cells and replace them with new ones. This marks the first time that this phenomenon has been directly observed, and has major implications for diseases associated with a declining immune system, including a variety of age-related conditions and cancer chemotherapy.

Scientists have discovered how cycles of prolonged fasting can help flush out damaged immune system cells.

Scientists have discovered how cycles of prolonged fasting can help flush out damaged immune system cells.

In lab experiments first in animal models, and then followed by a Phase 1 human clinical trial, the research team found that regular cycles of fasting, each lasting two to four days, triggered the immune system to flush out immune cells. Much to the team’s surprise, however, they also found that these fasting cycles also triggered stem cells—which had been dormant—to spring into action and produce a fresh supply.

While initially unexpected, these findings made sense to the team. As corresponding author Dr. Valter Longo explained in today’s news release:

“When you starve, the system tries to save energy, and one of the things it can do to save energy is to recycle a lot of the immune cells that are not needed, especially those that may be damaged. What we started noticing in both our human work and animal work is that the white blood cell count goes down with prolonged fasting. Then when you re-feed, the blood cells come back. So we started thinking, well, where does it come from?”

Scientists have long known that when fasting, your body turns to its reserves for nutrients, using up stores of glucose and fat. At the same time, your body also breaks down white blood cells—the major component of the immune system.

So, Longo and his team mapped precisely how this change takes place. They observed that prolonged fasting also reduced levels of an enzyme called PKA. In a previous study, the team had found a link between reduced PKA levels and increased longevity in simple organisms. Research by other groups also found a connection between PKA and the ability of stem cells to self-renew. In this study, the team further defined that relationship. As Longo continued:

“PKA is the key gene that needs to shut down in order for these stem cells to switch into regenerative mode. And the good news is that the body got rid of the parts of the system that might be damaged or old…during fasting. Now if you start with a system heavily damaged, fasting cycles can generate, literally, a new immune system.”

These findings are particularly encouraging with regards to chemotherapy, which has the unfortunate side effect of often damaging the body’s immune system. But if the patient also participates in cycles of fasting, Longo and his team hypothesize that this could help repair their immune system at a much faster pace, improving their quality of life during treatment.

In order to test this hypothesis, the team then turned to the Phase 1 human clinical trial. They instructed patients currently undergoing chemotherapy to fast for a period of 72 hours. The team found that this fasting did protect against at least some of the toxic effects of chemotherapy treatment.

The next steps, says Longo, are to conduct additional experiments in both animal models and clinical trials. But the team is optimistic that these results could apply beyond chemotherapy.

“We are investigating the possibility that these effects are applicable to many different systems and organs, not just the immune system.”