During a game in 2018, Alex Smith suffered a compound fracture that broke both the tibia and fibula in his right leg. The gruesome injury aside, the former 49ers quarterback soon developed life-threatening necrotizing fasciitis — a rare bacterial infection — that resulted in sepsis and required him to undergo 17 surgeries.
In a battle to save his life and avoid amputating his leg, doctors had to remove a great deal of his muscle tissue leading to volumetric muscle loss (VML). When Smith returned to the field after nearly two years of recovery, many called his comeback a “miracle”.
Skeletal muscle is one of the most dynamic tissues of the human body. It defines how we move and can repair itself after injury using stem cells. However, when significant chunks of muscle are destroyed through severe injury (e.g. gunshot wound) or excessive surgery (like that of Smith’s), VML overwhelms the regenerative capacity of the muscle stem cells.
Despite the prevalence of these injuries, no standardized evaluation protocol exists for the characterization and quantification of VML and little is understood about why it consistently overwhelms the body’s natural regenerative processes. Current treatment options include functional free muscle transfer and the use of advanced bracing designs.
However, new research from the University of Michigan (U-M) may have just discovered why tissues often fail to regenerate from traumatic muscle loss injuries.
When researchers from U-M collaborated with partners at Georgia Tech, Emory University and the University of Oregon to study VML injuries in mice, they found that that sometimes post-injury immune cells become dysregulated and prevent stem cell repair. In VML injuries that don’t heal, neutrophils — a type of white blood cell — remain at the injured site longer than normal meaning that they’re not doing their job properly.
In addition, researchers found that intercellular communication between neutrophils and natural killers cells impacted muscle stem cell-mediated repair. When neutrophils communicated with natural killer cells, they were essentially prompted to self-destruct.
The findings suggest that by altering how the two cell types communicate, different healing outcomes may be possible and could offer new treatment strategies that eventually restore function and prevent limb loss. The team of researchers hope that better treatments could mean that recovery from VML injuries is no longer considered a “miracle”.
One of the wonders of regenerative medicine is its broad applicability, which provides us with the opportunity to build upon existing knowledge and concepts. In the midst of a global pandemic, researchers have responded to the needs of patients severely afflicted with COVID-19 by repurposing existing therapies being developed to treat patients. The California Institute for Regenerative Medicine (CIRM) responded immediately to the pandemic and to researchers wanting to help by providing $5 million in emergency funding for COVID-19 related projects. In a short time span, this funding has driven innovation in the form of 17 new projects targeting COVID-19, many of which are based on previously developed concepts being repurposed to deal with the novel coronavirus.
One such example is a clinical trial funded by CIRM that uses natural killer (NK) cells, a type of white blood cell that is a vital part of the immune system, which are administered to patients with COVID-19. NK cells play an important role in defense against cancer and in fighting off viral infections. In fact, this exact same therapy was previously used in a clinical trial for patients with Acute Myeloid Leukemia, a type of blood cancer.
Another clinical trial funded by CIRM uses mesenchymal stromal cells (MSCs), a type of stem cell, to treat acute respiratory distress syndrome (ARDS), a life-threatening lung injury that occurs when fluid leaks into the lungs. As a result of ARDS, oxygen cannot get into the body and patients have difficulty breathing. ARDS is one of the most serious and lethal consequences of COVID-19, which is why this trial was expanded after the coronavirus pandemic to include COVID-19 positive patients.
Despite these great strides in driving innovation of therapies, one challenge that still needs to be tackled is providing patients access to these therapies, particularly people from underrepresented and underserved communities. In California alone, there have been over 621,000 positive cases as of August 2020, with more cases every day. However, the impact of the pandemic is disproportionately affecting the Latinx and African American communities more than others. An analysis by the Los Angeles Times found that the Latinx and African American communities have double the mortality rate from the coronavirus in Los Angeles County. Additionally, a surge in cases is being seen in poorer communities in comparison to wealthier ones.
Until a vaccine can be successfully developed and implemented to obtain herd immunity, the number of cases will continue to climb. There is also the challenge of the long term health effects of COVID-19, which can consist of neurological, breathing, and heart problems according to an article in Science. Unfortunately, a study published in the New England Journal of Medicine found that despite disproportionately higher rates of COVID-19 infection, hospitalization and death among people of color, they are significantly underrepresented in COVID-19 clinical trials.
The challenge of underrepresentation in clinical trials and research needs to be addressed by creating a more diverse population of study participants, so as to better generalize results to the U.S. population as a whole. CIRM Board Member Ysabel Duron, a leading figure in cancer education in the Latinx community, has advocated for more inclusion and outreach efforts directed towards underserved and underrepresented communities. By communicating with patients in underserved and underrepresented communities, building relationships established on a foundation of trust, and connecting patients with potential trial matches, underrepresentation can be alleviated.
To help in addressing these disparities, CIRM has taken action by changing the requirements for its discovery stage research projects, which promote promising new technologies that could be translated to enable broad use and improve patient care, and clinical trial stage projects.
For clinical trials, all proposals must include a written plan in the application for outreach and study participation by underserved and disproportionately affected populations. Priority will be given to projects with the highest quality plans in this regard. For discovery projects, all proposals must provide a statement describing how their overall study plan and design has considered the influence of race, ethnicity, sex and gender diversity. Additionally, all proposals should discuss the limitations, advantages, and/or challenges in developing a product or tools that addresses the unmet medical needs of California’s diverse population, including underserved communities. There is still much more work that needs to be done to address health disparities, but steps such as these can help steer progress in the right direction.
Driving innovation while addressing health disparities among people of color is just one of many opportunities and challenges of regenerative medicine in a post pandemic world. This blog post is part of Signal’s fifth annual blog carnival. Please click here to read what other bloggers think about this topic.
Dr. Joshua Rhein, Assistant Professor of Medicine in the University of Minnesota Medical School’s Division of Infectious Diseases and International Medicine Image Credit: University of Minnesota
While doctors are still trying to better understand how to treat some of the most severe cases of COVID-19, researchers are looking at their current scientific “toolkit” to see if any potential therapies for other diseases could also help treat patients with COVID-19. One example of this is a treatment developed by Fate Therapeutics called FT516, which received support in its early stages from a Late Stage Preclinical grant awarded by CIRM.
FT516 uses induced pluripotent stem cells (iPSCs), which are a kind of stem cell made from reprogrammed skin or blood cells. These newly made stem cells have the potential to become any kind of cell in the body. For FT516, iPSCs are transformed into natural killer (NK) cells, which are a type of white blood cell that are a vital part of the immune system and play a role in fighting off viral infections.
Prior to the coronavirus pandemic, FT516 was used in a clinical trial to treat patients with acute myeloid leukemia (AML) and B-cell lymphoma, which are two different kinds of blood cancer.
Due to the natural ability of NK cells to fight off viruses, it is believed that FT516 may also help play a role in diminishing viral replication of the novel coronavirus in COVID-19 patients. In fact, Fate Therapeutics, in partnership with the University of Minnesota, has treated their first COVID-19 patient with FT516 in a new clinical trial.
In a news release, Dr. Joshua Rhein, Physician at the University of Minnesota running the trial site, elaborates on how FT516 could help COVID-19 patients.
“The medical research community has been mobilized to meet the unique challenges that COVID-19 presents. There are limited treatment options for COVID-19, and we have been inundated daily with reports of varying quality describing the potential of numerous therapies. We know that NK cells play an important role in responding to SARS-CoV-2, the virus responsible for COVID-19, and that these cells often become depleted in infected patients. Our intent is to replenish NK cells in order to restore a functional immune system and directly target the virus.”
In its own response to the coronavirus pandemic, CIRM has funded three clinical trials as part of $5 million in emergency funding for COVID-19 related projects. They include the following: a convalescent plasma study conducted by Dr. John Zaia at City of Hope, a treatment for acute respiratory distress syndrome (a serious and lethal consequence of COVID-19) conducted by Dr. Michael Matthay at UCSF, and a study that also uses NK cells to treat COVID-19 patients conducted by Dr. Xiaokui Zhang at Celularity Inc. Visit our dashboard page to learn more about these clinical projects.
Dr. Xiaokui Zhang (left), Dr. Albert Wong (center), and Dr. Preet Chaudhary (right)
Today the governing Board of the California Institute for Regenerative Medicine (CIRM) awarded $750,000 to Dr. Xiaokui Zhang at Celularity to conduct a clinical trial for the treatment of COVID-19. This brings the total number of CIRM clinical trials to 64, including three targeting the coronavirus.
This trial will use blood stem cells obtained from the placenta to generate natural killer (NK) cells, a type of white blood cell that is a vital part of the immune system, and administer them to patients with COVID-19. NK cells play an important role in defense against cancer and in fighting off viral infections. The goal is to administer these cells to locate the active sites of COVID-19 infection and destroy the virus-infected cells. These NK cells have been used in two other clinical trials for acute myeloid leukemia and multiple myeloma.
The Board also approved two additional awards for Discovery Stage Research (DISC2), which promote promising new technologies that could be translated to enable broad use and improve patient care.
One award for $100,000 was given to Dr. Albert Wong at Stanford. Dr. Wong has recently received an award from CIRM to develop a vaccine that produces a CD8+ T cell response to boost the body’s immune response to remove COVID-19 infected cells. The current award will enable him to expand on the initial approach to increase its potential to impact the Latinx and African American populations, two ethnicities that are disproportionately impacted by the virus in California.
The other award was for $249,996 and was given to Dr. Preet Chaudhary at the University of Southern California. Dr. Chaudary will use induced pluripotent stem cells (iPSCs) to generate natural killer cells (NK). These NK cells will express a chimeric antigen receptor (CAR), a synthetic receptor that will directly target the immune cells to kill cells infected with the virus. The ultimate goal is for these iPSC-NK-CAR cells to be used as a treatment for COVID-19.
“These programs address the role of the body’s immune T and NK cells in combatting viral infection and CIRM is fortunate enough to be able to assist these investigators in applying experience and knowledge gained elsewhere to find targeted treatments for COVID-19” says Dr. Maria T. Millan, the President & CEO of CIRM. “This type of critical thinking reflects the resourcefulness of researchers when evaluating their scientific tool kits. Projects like these align with CIRM’s track record of supporting research at different stages and for different diseases than the original target.”
The CIRM Board voted to endorse a new initiative to refund the agency and provide it with $5.5 billion to continue its work. The ‘California Stem Cell Research, Treatments and Cures Initiative of 2020 will appear on the November ballot.
The Board also approved a resolution honoring Ken Burtis, PhD., for his long service on the Board. Dr. Burtis was honored for his almost four decades of service at UC Davis as a student, professor and administrator and for his 11 years on the CIRM Board as both a member and alternate member. In the resolution marking his retirement the Board praised him, saying “his experience, commitment, knowledge, and leadership, contributed greatly to the momentum of discovery and the future therapies which will be the ultimate outcome of the dedicated work of the researchers receiving CIRM funding.”
Jonathan Thomas, the Chair of the Board, said “Ken has been invaluable and I’ve always found him to have tremendous insight. He has served as a great source of advice and inspiration to me and to the ICOC in dealing with all the topics we have had to face.”
Lauren Miller Rogen thanked Dr. Burtis, saying “I sat next to you at my first meeting and was feeling so extraordinarily overwhelmed and you went out of your way to explain all these big science words to me. You were always a source of help and support, and you explained things to me in a way that I always appreciated with my normal brain.”
Dr. Burtis said it has been a real honor and privilege to be on the Board. “I’ve been amazed and astounded at the passion and dedication that the Board and CIRM staff have brought to this work. Every meeting over the years there has been a moment of drama and then resolution and this Board always manages to reach agreement and serve the people of California.”
Colorized scanning electron micrograph of a natural killer cell. Photo credit: National Institute of Allergy and Infectious Diseases
Racing car drivers are forever tinkering with their cars, trying to streamline them and soup up their engines because while fast is good, faster is better. Researchers do the same things with potential anti-cancer therapies, tinkering with them to make them safer and more readily available to patients while also boosting their ability to fight cancer.
That’s what researchers at the University of California San Diego (UCSD), in a CIRM-funded study, have done. They’ve taken immune system cells – with the already impressive name of ‘natural killer’ (NK) cells – and made them even deadlier to cancers.
These natural killer (NK) cells are considered one of our immune system’s frontline weapons against outside threats to our health, things like viruses and cancer. But sometimes the cancers manage to evade the NKs and spread throughout the body or, in the case of leukemia, throughout the blood.
Lots of researchers are looking at ways of taking a patient’s own NK cells and, in the lab boosting their ability to fight these cancers. However, using a patient’s own cells is both time consuming and very, very expensive.
Dan Kaufman MD
Dr. Dan Kaufman and his team at UCSD decided it would be better to try and develop an off-the-shelf approach, a therapy that could be mass produced from a single batch of NK cells and made available to anyone in need.
Using the iPSC method (which turns tissues like skin or blood into embryonic stem cell-like cells, capable of becoming any other cell in the body) they created a line of NK cells. Then they removed a gene called CISH which slows down the activities of cytokines, acting as a kind of brake or restraint on the immune system.
In a news release, Dr. Kaufman says removing CISH had a dramatic effect, boosting the power of the NK cells.
“We found that CISH-deleted iPSC-derived NK cells were able to effectively cure mice that harbor human leukemia cells, whereas mice treated with the unmodified NK cells died from the leukemia.”
Dr. Kaufman says the next step is to try and develop this approach for testing in people, to see if it can help people whose disease is not responding to conventional therapies.
“Importantly, iPSCs provide a stable platform for gene modification and since NK cells can be used as allogeneic cells (cells that come from donors) that do not need to be matched to individual patients, we can create a line of appropriately modified iPSC-derived NK cells suitable for treating hundreds or thousands of patients as a standardized, ‘off-the-shelf’ therapy.”
Dr. Jianhua Yu (left), Dr. Helen Blau (center), and Dr. Albert Wong (right)
The COVID-19 virus targets many different parts of the body, often with deadly or life-threatening consequences. This past Friday the governing Board of the California Institute for Regenerative Medicine (CIRM) approved investments in three early-stage research programs taking different approaches to battling the virus.
Dr. Jianhua Yu at the Beckman Research Institute of City of Hope was awarded $150,000 to use stem cells from umbilical cord blood to attack the virus. Dr. Yu and his team have many years of experience in taking cord blood cells and turning them into what are called chimeric antigen receptor (CAR) natural killer (NK) cells. The goal is to deploy these CAR NK cells to specifically target cells infected with COVID-19. This leverages the body of work at the City of Hope to develop this technology for cancer.
Dr. Helen Blau of Stanford University was awarded $149,996 to target recovery of muscle stem cells of the diaphragm in COVID-19 patients who have an extended period on a ventilator.
Patients with severe coronavirus often suffer respiratory failure and end up on mechanical ventilation that takes over the work of breathing. Over time, the diaphragm, the main muscle responsible for inhaling and exhaling, weakens and atrophies. There is no treatment for this kind of localized muscle wasting and it is anticipated that some of these patients will take months, if not years, to fully recover. Dr. Blau’s team proposes to develop a therapy with Prostaglandin E2 and Bupivacaine based on data generated by Dr. Blau’s group that these drugs, already approved by the FDA for other indications, have the potential to stimulate muscle stem cell recovery.
Dr. Albert Wong, also from Stanford University, was awarded $149,999 to develop vaccine candidates against COVID-19.
Most vaccine candidates are focused on getting the body to produce an antibody response to block the virus. However, Dr. Wong thinks that to be truly effective, a vaccine also needs to produce a CD8+ T cell response to augment an effective immune response to remove the COVID-19 infected cells that are hijacked by the virus to spread and cause illness. This team will use the experience it gained using CIRM funds to vaccine against glioblastoma, a deadly brain cancer, to advance a similar approach to produce an effective cellular immune response to combat COVID-19.
“CIRM is committed to supporting novel, multi-pronged approaches to battle this COVID-19 crisis that leverage solid science and knowledge gained in other areas.” says Dr. Maria T. Millan, the President & CEO of CIRM. “These three projects highlight three very different approaches to combatting the acute devastating health manifestations of COVID-19 as well as the debilitating sequelae that impact the ability to recover from the acute illness. Through this COVID funding opportunity, CIRM is enabling researchers to re-direct work they have already done, often with CIRM support, to quickly develop new approaches to COVID-19.”
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 Diseases–Rocky 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.”
iPS Cell: Photo from the lab of Kathrin Plath at UCLA
One of the hottest areas in cancer research right now is the use of CAR-T treatments. These use the patient’s own re-engineered immune system cells to target and kill the tumor. But the thing that makes it so appealing – using the patient’s own cells – also makes it really complicated and expensive. Creating a custom-made therapy from each patient’s own cells takes time and costs a lot of money. But now a new approach could change that.
Fate Therapeutics has developed an off-the-shelf therapy (thanks to CIRM funding) that could, theoretically, be stored at hospitals and clinics around the country and used whenever it’s needed for anyone who needs it.
At this year’s meeting of the American Society of Hematology (ASH) Fate announced that the first patient treated with this new approach seems to be doing very well. The patient had acute myeloid leukemia and wasn’t responding to conventional treatments. However, following treatment with Fate’s FT516 the patient responded quickly and – according to STAT News’ Adam Feuerstein – was able to leave the hospital and spend Thanksgiving with his family.
Equally impressive is that 42 days after being treated with FT516, the man showed no signs of leukemia in either his bone marrow or blood.
FT516 is designed to provide a one-two combination attack on cancer. It’s made up of the wonderfully named natural killer (NK) cells, which are a critical part of our immune system defenses against cancer. These NK cells are created by using the iPSC process and have been genetically modified to express a protein that boosts their cancer-killing abilities.
Because these cells are manufactured they can, if effective, be produced in large numbers and stored for whenever needed. That would not only dramatically reduce costs but also make them more widely available when they are needed.
This is only one patient and the follow-up is still relatively short. Even so, the results are encouraging and certainly give hope that Fate is on to something big. We’ll be keeping track and let you know how things progress.
The Stem Cellar 