Category Archives: Stem Cell Treatment

Novel immune cell therapy may be a promising strategy for combating HBV infection – News-Medical.Net

By Stem Cell Treatment

Chronic infection with the hepatitis B virus (HBV) causes progressive liver problems, and eradication of the virus remains a formidable challenge. New research in FEBS Letters indicates that treatment that boosts the effects of immune cells called stem cell memory T cells (TSCMs) may be a promising strategy for combating HBV.

In the study, investigators identified TSCMs in patients with chronic HBV infection and analyzed their effects in a mouse model of HBV. After introducing TSCMs from patients into the mice, the immune cells differentiated into cytotoxic T cells and activated a strong response that resulted in the elimination of HBV-infected liver cells. Therefore, augmenting patients' TSCMs may help the immune system overcome the virus.

Our hepatitis model may reveal how TSCMs differentiate into cytotoxic T cells and uncover the fate of differentiated T cells. Such information could greatly advance future research on T cell-based therapies."

Hiromi Abe-Chayama, PhD, corresponding authorof Hiroshima University, Japan

Source:

Journal reference:

Abe-Chayama, H.,et al.(2024) Hepatitis B virus-specific human stem cell memory T cells differentiate into cytotoxic T cells and eradicate HBV-infected hepatocytes in mice. FEBS Letters. doi.org/10.1002/1873-3468.14842.

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Novel immune cell therapy may be a promising strategy for combating HBV infection - News-Medical.Net

Pluripotent positives in allogeneic stem cell therapies – BioProcess Insider

By Stem Cell Treatment

Ricardo Baptista, former chief technology officer at cell therapy developer Alder Therapeutics, told delegates The use of pluripotent stem cells is gaining traction when it comes to allogeneic stem cell therapies.

Baptista said there are several reasons for this and listed the benefits of using pluripotent stem cells. He discussed how pluripotent cells can be cultured in all systems, including 2D, 3D, static and dynamic. Additionally, Baptista said the lines can be edited [which equates] to the concept of a universal cell line and theoretically an unlimited choice of cells.

In turn, this means the therapies can be used off-the-shelf and target diseases with point-of-care therapy. Moreover, it is cell banks-based and there is the possibility to generate universal cells and the potential to leverage processing technologies from biopharma.

Baptista added there is an increased number of doses per lot and the costs of goods [is] spread across multiple doses, meaning the therapies are more easily accessible to a wider patient population.

Currently all approved chimeric antigen receptor (CAR) T-cell therapies are autologous. Autologous products are made by taking, reengineering, and reintroducing a patients own cells. Autologous methods of treatment usually have a low risk of rejection but are not always suitable for all patients because of the limitations in the quality and availability of the individuals cells.

Allogeneic therapies, however, can use cells or tissues from different individuals. As these are not personalized therapies, one advantage over autologous is the relative ease to mass-produce such products and thus, increase patient access. While allogeneic treatments could potentially treat more people, it has not yet fully reached commercialization due to the risk of rejection and immunosuppressive and matching measures required.

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Pluripotent positives in allogeneic stem cell therapies - BioProcess Insider

Tr1X Announces FDA Clearance of First Investigational New Drug Application for TRX103, an Allogeneic Regulatory T … – BioSpace

By Stem Cell Treatment

SAN DIEGO, April 10, 2024 /PRNewswire/ --Tr1X, Inc., anautoimmune and inflammatory disease cell therapy company focused on the development of novel allogeneic regulatory T cell therapies (Allo-Tregs) and allogeneic regulatory T cells expressing Chimeric Antigen Receptors (Allo-CAR Tregs), today announced the U.S. Food and Drug Administration (FDA) accepted the company's Investigational New Drug (IND) application for TRX103 for the prevention of Graft versus Host Disease (GvHD) in patients undergoing HLA-mismatched hematopoietic stem cell transplantation (HSCT). The company plans to initiate a Phase 1 study of TRX103, an investigational allogeneic off-the-shelf Tr1 Treg therapy, for this indication in the second quarter of 2024. Additionally, the company is on track to submit an IND for TRX103 for patients with refractory Crohn's disease in the third quarter of 2024.

"The FDA's clearance of our IND for TRX103, the first ever allogeneic engineered Tr1 regulatory T cell product, is an important milestone that could quickly provide us with proof-of-concept data while we continue to develop TRX103 for multiple autoimmune and inflammatory diseases, including Crohn's disease," said Maria Grazia Roncarolo M.D., Co-Founder, President and Head of R&D at Tr1X. "Donor-derived autologous Tr1 cells have shown clinical promise in improving immune reconstitution and reducing GvHD but have limited potential due to lack of feasibility and high cost. TRX103, an off-the-shelf product with unique biological properties compared to other Treg and CAR-T cell therapies, has the potential to reduce inflammation, suppress pathogenic cells, and reset the immune system. TRX103 is currently produced cost effectively at scale in a fully closed end-to-end system using a process that yields billions of cells in a single campaign. This should enable Tr1X to develop further pipeline candidates that address even larger patient populations with equally unmet medical needs."

"Allogeneic stem cell transplantation is the only curative treatment formany advanced blood cancers and genetic and acquired diseases.However, there remains a burden of morbidity and mortalityrelated to GvHD and its complications, including severe infections," said Monzr M. Al Malki, M.D., lead investigator of the Phase 1 study, Associate Professor in the Department of Hematology & Hematopoietic Cell Transplantation, and Director of the Unrelated Donor, Haploidentical and Cord Blood Transplant Programs at City of Hope National Medical Center. "As a result, innovative treatments are urgently needed. We look forward to starting this first-in-human trial to evaluate the safety, tolerability and clinical activity of these allogeneic Tr1 Treg cells and their potential to benefit patients in this setting."

About TRX103 TRX103 is an investigational allogeneic off-the-shelf engineered T cell product generated from CD4+ cells sourced from healthy donors. These donor-derived CD4+ cells are engineered to produce cells that mimic the function of Tr1 regulatory T cells. Tr1X is developing TRX103 for the treatment of several immune and inflammatory disorders. Multiple preclinical models of disease have shown TRX103 to be tolerable and effective and to have the potential to reset immune systems to a healthy state. TRX103 has the potential to overcome major limitations of current cell therapies for autoimmune diseases, which include limited persistence and side effects including cytokine release syndrome (CRS) and neurotoxicity.

About Tr1X Tr1X is a privately held biotechnology company focused on engineering cures for immune and inflammatory diseases. Founded by industry veterans, including the scientists behind the discovery of Tr1 cells, the company's pipeline of off-the-shelf allogeneic cell therapies is being developed for the treatment of and potential cure of autoimmune diseases with high unmet medical need. The company is backed by leading investors, including The Column Group, NEVA SGR and Alexandria Venture Investments, and has received additional grant support from the California Institute for Regenerative Medicine (CIRM). For more information visit http://www.tr1x.bio.

Investor Contact: Tr1X Investor Relations investors@tr1x.bio

Media Contact: Julie Normart jnormart@realchemistry.com

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SOURCE Tr1X, Inc.

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Tr1X Announces FDA Clearance of First Investigational New Drug Application for TRX103, an Allogeneic Regulatory T ... - BioSpace

Stem cell treatment for spinal injury, and BRCA breakthrough | Podcasts – The Naked Scientists

By Stem Cell Treatment

Could an injection of stem cells grown from your own abdominal fat be the key to improving outcomes for people with spinal cord injuries? In an early stage trial in America, scientists have found that over two thirds of the small group of patients they treated showed improvements. They think that the stem cells are boosting the blood supply to the injured region of the spinal cord, and helping to control inflammation, which may lead to reduced scarring and better prospects for recovering some of the lost nerve connections. Mohamad Bydon is a neurosurgeon at the Mayo Clinic and led the new study

Mohamad - The historical teaching around spinal cord injury is you deliver surgery, you do physiotherapy, and that's basically it. And things haven't really advanced in a long, long time. So what we wanted to do was really impact the space and say, are there other treatments that we could add to augment the recovery, to aid the recovery, to improve the recovery?

Chris - And your intervention? What's the rationale behind what you're doing and how are you doing it?

Mohamad - So at a very high level, at a 30,000 foot view, the question becomes, what are the other things that we can add? And that's where we believe regenerative medicine will be a part of this paradigm. It's not going to be the only answer: you still need your surgery, you still need your physical therapy, there's other things like stimulation that are being discussed, but we believe regenerative therapy, specifically with stem cells, will be beneficial in helping to improve outcomes for patients.

Chris - So what stem cells? Where from and what do you do with them?

Mohamad - So stem cells are cells that can become a number of different things once they enter the body and they come from a number of different areas. Specifically in this study we used what are known as mesenchymal stem cells, adipose derived. Those words mean stem cells from your own fat, belly fat. I had a colleague who said to me recently, 'Who knew that belly fat could be so useful?' So, from your own belly fat, we remove that and expand the cells until we get to the right number of cells and then we proceed to reinject those cells once they're expanded and cultured into the spinal cord.

Chris - How many cells were you putting in once you'd grown them or expanded them and where exactly were they going? Were they going into the substance of the spinal cord or around it?

Mohamad - There were 100 million cells. Frankly, we need to work on dosing still, but a hundred million is the dose that we expand the cells to. Once we do that expansion, we proceed to inject it into the faecal sac. There's the substance of the spinal cord itself, and then there's a sac that surrounds the spinal cord - it's called the faecal sac or the dura mater - and that is a lining that surrounds the spinal cord. It also surrounds the brain. Inside that layer there's something called cerebrospinal fluid. So what we do is we put these cells inside the dura, into the fluid, and then the cells go to the area of highest injury and area of highest inflammation, which is the area of injury.

Chris - What do the cells look like? Are they still very much stem cells at this time when you're doing this? And then when they go to the areas of injury, is this only in people who've just had an injury or will they go to areas of injury that happened years ago?

Mohamad - Good question. The cells definitively are stem cells and there are certain markers and hallmark features that stem cells have. To your question on longevity, our current trial is in patients who've had their injury within a year. Many trials deliver therapy to patients who've had the injury right away; you had your injury yesterday, we're going to give you therapy today. This trial was not designed like that because some patients have natural improvement and so the earliest we injected any patient was at seven months. The latest that we injected any patient was at 22 months. Some of the patients that we injected out to 22 months had a very significant response. Now, we haven't done studies looking at longer, although now we're starting studies to look longer out. So what would it look like if we did patients after five years, ten years? What would that look like? Those are also things that we're evaluating and looking to treat.

Chris - Do you know for sure that the stem cells when you put them in actually go to the injury side or do they just go everywhere and some randomly crop up at the site of the injury? Have you actually followed them to see what happens to them and how long they persist for after you put them in?

Mohamad - We've done testing on this and we know that the cells go to the site of injury at the same time. The cells have an impact across the spinal cord and the brain and that's okay. The impact that we've seen has been positive or had no impact. So, we haven't seen it be negative. The cells themselves then work through a couple of different potential mechanisms once they get there. There's potentially a regenerative mechanism through the stem cells themselves regenerating that area, but the other potential mechanism is a vascular mechanism where the stem cells induce a more vascular area where scar tissue would normally be a very nonvascular area without blood vessels. Blood vessels are important because they deliver good nutrients, they take out bad nutrients, and so areas of injury tend to wall themselves off and lose their vasculature. These cells can be very helpful because they can reset the vasculature in those areas, allowing the areas to heal more properly.

Chris - For the patients, what were the outcomes like and in what ways did people improve in ways that you wouldn't have anticipated had they just been managed the way we normally, historically, have been managing spinal cord injuries?

Mohamad - What we looked at, in terms of safety, we found adverse events. Mostly, they were headaches or back pain that would improve over a few days. We never saw any significant or long-term side effects. On the effectiveness side, in terms of our secondary endpoint on effectiveness, what we found was that seven of the ten patients showed some improvement, three of them being very significant improvement, four of them being mild to moderate improvement, and the other three patients showed no improvement but did not get worse. Some patients who required a harness and multiple assistance to be able to bear weight and get up could now walk without that: they could walk on their own. Other patients had improvement in bowel and bladder function.

Chris - How do you know, though, that you didn't, just by chance, select people for this study who are that bit fitter? They're more likely to have a good outcome and, had they been just left to their own devices with the gold standard care they would otherwise have had, they would've ended up at the same endpoint?

Mohamad - This is a good question, and this is a question that we debated at length with the regulatory bodies. Most studies in this space treat patients right after the injury, in which case your question becomes very relevant. In our case, we waited. Most of the improvement after a spinal cord injury occurs within the first six months. Much less improvement occurs as you keep going over time, much, much less. The earliest we ever treated a patient was seven months and we had patients that we treated as late as 22 months and everybody had plateaued. Nobody was continuing their improvement. Remember, this is a phase 1 trial of ten patients. The definitive trial would be randomised controlled, which we're doing now, which is a phase 2 randomised controlled trial of best medical management versus our interventional therapy. But this is a signal and this is an important signal that will inform our future trials.

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Stem cell treatment for spinal injury, and BRCA breakthrough | Podcasts - The Naked Scientists

Paralysed patients could regain movement and sensation, stem cell treatment trial finds – The Telegraph

By Stem Cell Treatment

Dr Mohamad Bydon, a Mayo Clinic neurosurgeon and first author of the study, said the results indicate that severe spinal cord injuries that were once thought hopeless, could be treatable in the future.

For years, treatment of spinal cord injury has been limited to supportive care, more specifically stabilisation surgery and physical therapy, said Dr Bydon.

Many historical textbooks state that this condition does not improve. In recent years, we have seen findings from the medical and scientific community that challenge prior assumptions.

This research is a step forward toward the ultimate goal of improving treatments for patients.

In Britain, an estimated 50,000 people are living with a spinal cord injury with about 2,500 new injuries each year.

Although operations to realign the spine and remove bone fragments or fuse bones can be effective, many people are left without movement below the site of the injury and show little improvement over time.

In the study, six people with neck injuries and four with back injuries, aged between 18 and 65 were assessed using the American Spinal Injury Association (ASIA) Impairment Scale, which has five levels, ranging from complete loss of function to normal function.

After treatment, seven participants who improved each moved up at least one level on the ASIA scale, with two patients moving up two levels. Three patients showed no improvement.

The spinal cord has limited ability to repair its cells or make new ones. Patients typically experience most of their recovery in the first six to 12 months after injuries occur. Improvement generally stops 12 to 24 months after injury.

However, during the trial two patients with cervical spine injuries of the neck received stem cells 22 months after their injuries and improved one level on the ASIA scale after treatment.

Some also regained movement and improved bowel function.

In spinal cord injury, even a mild improvement can make a significant difference in that patients quality of life, added Dr Bydon.

Spinal cord injury is a complex condition. Future research may show whether stem cells in combination with other therapies could be part of a new paradigm of treatment to improve outcomes for patients.

This study documents the safety and potential benefit of stem cells and regenerative medicine.

Fat tissue was used because it is abundant and easy to get hold of in the body and has the most mesenchymal stem cells.

Despite the success of the treatment, scientists are still unsure how the stem cells are boosting regeneration. In animal trials, it has been shown that they flock towards areas of inflammation, helping to regulate the immune response.

As part of the study, researchers took lumbar punctures from the patients to gather their cerebrospinal fluid before and after treatment to see if they could pick up any changes

After treatment, they found an increased level of a protein called Vascular endothelial growth factor, in seven patients. The protein promotes the growth of new blood vessels and forms part of the mechanism that restores the blood supply to cells and tissues.

The phase one trial, which was primarily looking at the safety of the treatment, reported no serious adverse events with only mild side effects such as headache and musculoskeletal pain that resolved with over-the-counter treatment. Further trials are expected to follow.

The study was published in the journal Nature Communications.

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Paralysed patients could regain movement and sensation, stem cell treatment trial finds - The Telegraph

Study documents safety, improvements from stem cell therapy after spinal cord injury – Mayo Clinic

By Stem Cell Treatment

Neurosciences

April 1, 2024

ROCHESTER, Minn. A Mayo Clinic study shows stem cells derived from patients' own fat are safe and may improve sensation and movement after traumatic spinal cord injuries. The findings from the phase 1 clinical trial appear in Nature Communications. The results of this early research offer insights on the potential of cell therapy for people living with spinal cord injuries and paralysis for whom options to improve function are extremely limited.

In the study of 10 adults, the research team noted seven participants demonstrated improvements based on the American Spinal Injury Association (ASIA) Impairment Scale. Improvements included increased sensation when tested with pinprick and light touch, increased strength in muscle motor groups, and recovery of voluntary anal contraction, which aids in bowel function. The scale has five levels, ranging from complete loss of function to normal function. The seven participants who improved each moved up at least one level on the ASIA scale. Three patients in the study had no response, meaning they did not improve but did not get worse.

"This study documents the safety and potential benefit of stem cells and regenerative medicine," says Mohamad Bydon, M.D., a Mayo Clinic neurosurgeon and first author of the study. "Spinal cord injury is a complex condition. Future research may show whether stem cells in combination with other therapies could be part of a new paradigm of treatment to improve outcomes for patients."

No serious adverse events were reported after stem cell treatment. The most commonly reported side effects were headache and musculoskeletal pain that resolved with over-the-counter treatment.

In addition to evaluating safety, this phase 1 clinical trial had a secondary outcome of assessing changes in motor and sensory function. The authors note that motor and sensory results are to be interpreted with caution given limits of phase 1 trials. Additional research is underway among a larger group of participants to further assess risks and benefits.

The full data on the 10 patients follows a 2019 case report that highlighted the experience of the first study participant who demonstrated significant improvement in motor and sensory function.

Watch: Dr. Mohamad Bydon discusses improvements in research study

Journalists: Broadcast-quality sound bites are available in the downloads at the end of the post. Please courtesy: "Mayo Clinic News Network." Name super/CG: Mohamad Bydon, M.D./Neurosurgery/Mayo Clinic.

In the multidisciplinary clinical trial, participants had spinal cord injuries from motor vehicle accidents, falls and other causes. Six had neck injuries; four had back injuries. Participants ranged in age from 18 to 65.

Participants' stem cells were collected by taking a small amount of fat from a 1- to 2-inch incision in the abdomen or thigh. Over four weeks, the cells were expanded in the laboratory to 100 million cells and then injected into the patients' lumbar spine in the lower back. Over two years, each study participant was evaluated at Mayo Clinic 10 times.

Although it is understood that stem cells move toward areas of inflammation in this case the location of the spinal cord injury the cells' mechanism of interacting with the spinal cord is not fully understood, Dr. Bydon says. As part of the study, researchers analyzed changes in participants' MRIs and cerebrospinal fluid as well as in responses to pain, pressure and other sensation. The investigators are looking for clues to identify injury processes at a cellular level and avenues for potential regeneration and healing.

The spinal cord has limited ability to repair its cells or make new ones. Patients typically experience most of their recovery in the first six to 12 months after injuries occur. Improvement generally stops 12 to 24 months after injury. In the study, one patient with a cervical spine injury of the neck received stem cells 22 months after injury and improved one level on the ASIA scale after treatment.

Two of three patients with complete injuries of the thoracic spine meaning they had no feeling or movement below their injury between the base of the neck and mid-back moved up two ASIA levels after treatment. Each regained some sensation and some control of movement below the level of injury. Based on researchers' understanding of traumatic thoracic spinal cord injury, only 5% of people with a complete injury would be expected to regain any feeling or movement.

"In spinal cord injury, even a mild improvement can make a significant difference in that patient's quality of life," Dr. Bydon says.

Stem cells are used mainly in research in the U.S., and fat-derived stem cell treatment for spinal cord injury is considered experimental by the Food and Drug Administration.

Between 250,000 and 500,000 people worldwide suffer a spinal cord injury each year, according to theWorld Health Organization.

An important next step is assessing the effectiveness of stem cell therapies and subsets of patients who would most benefit, Dr. Bydon says. Research is continuing with a larger, controlled trial that randomly assigns patients to receive either the stem cell treatment or a placebo without stem cells.

"For years, treatment of spinal cord injury has been limited to supportive care, more specifically stabilization surgery and physical therapy," Dr. Bydon says. "Many historical textbooks state that this condition does not improve. In recent years, we have seen findings from the medical and scientific community that challenge prior assumptions. This research is a step forward toward the ultimate goal of improving treatments for patients."

Dr. Bydon is the Charles B. and Ann L. Johnson Professor of Neurosurgery. This research was made possible with support from Leonard A. Lauder, C and A Johnson Family Foundation, The Park Foundation, Sanger Family Foundation, Eileen R.B. and Steve D. Scheel, Schultz Family Foundation, and other generous Mayo Clinic benefactors. The research is funded in part by a Mayo Clinic Transform the Practice grant.

Review thestudyfor a complete list of authors and funding.

###

About Mayo Clinic

Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit theMayo Clinic News Networkfor additional Mayo Clinic news.

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Study documents safety, improvements from stem cell therapy after spinal cord injury - Mayo Clinic

Paralysed surfer attributes recovery to stem cell treatment – The Times

By Stem Cell Treatment

On February 12, 2017, Chris Barr said goodbye to his wife and headed off to the beach for some surfing. The next time his wife saw him he was in a hospital bed, sand still in his hair, his neck broken after falling from a wave. There, she was told that he would likely be paralysed permanently, and need mechanical assistance breathing.

Today Barr, 57, from the US, can not only breathe on his own, but walk and feed himself too. He attributes some of his recovery to an experimental treatment in which stem cells taken from fat in his stomach were injected into his spine.

The technique, described in a paper in the journal Nature Communications, has undergone its first stage of human trials

Originally posted here:
Paralysed surfer attributes recovery to stem cell treatment - The Times

Stem Cells Spark Hope in Spinal Cord Recovery – Neuroscience News

By Stem Cell Treatment

Summary: A phase 1 clinical trial has revealed that stem cells derived from patients own fat may safely enhance sensation and movement in individuals with traumatic spinal cord injuries. In the study, seven out of ten adults showed measurable improvements on the ASIA Impairment Scale, experiencing increased sensation, muscle strength, and improved bowel function without serious side effects.

The findings challenge the longstanding belief that spinal cord injuries are irreparable, offering new hope for treatments. With the spinal cords limited repair capability, this research signifies a crucial step towards innovative therapies, emphasizing the need for further studies to unlock the full potential of stem cell treatments.

Key Facts:

Source: Mayo Clinic

AMayo Clinicstudy shows stem cells derived from patients own fat are safe and may improve sensation and movement after traumaticspinal cord injuries.

The findings from the phase 1 clinical trial appear inNature Communications.

The results of this early research offer insights on the potential of cell therapy for people living with spinal cord injuries and paralysis for whom options to improve function are extremely limited.

In the study of 10 adults, the research team noted seven participants demonstrated improvements based on the American Spinal Injury Association (ASIA) Impairment Scale. Improvements included increased sensation when tested with pinprick and light touch, increased strength in muscle motor groups, and recovery of voluntary anal contraction, which aids in bowel function.

The scale has five levels, ranging from complete loss of function to normal function. The seven participants who improved each moved up at least one level on the ASIA scale. Three patients in the study had no response, meaning they did not improve but did not get worse.

This study documents the safety and potential benefit of stem cells and regenerative medicine, saysMohamad Bydon, M.D., a Mayo Clinic neurosurgeon and first author of the study.

Spinal cord injury is a complex condition. Future research may show whether stem cells in combination with other therapies could be part of a new paradigm of treatment to improve outcomes for patients.

No serious adverse events were reported after stem cell treatment. The most commonly reported side effects were headache and musculoskeletal pain that resolved with over-the-counter treatment.

In addition to evaluating safety, this phase 1 clinical trial had a secondary outcome of assessing changes in motor and sensory function. The authors note that motor and sensory results are to be interpreted with caution given limits of phase 1 trials. Additional research is underway among a larger group of participants to further assess risks and benefits.

The full data on the 10 patients follows a 2019case reportthat highlighted the experience of the first study participant who demonstrated significant improvement in motor and sensory function.

Stem cells mechanism of action not fully understood

In the multidisciplinary clinical trial, participants had spinal cord injuries from motor vehicle accidents, falls and other causes. Six had neck injuries; four had back injuries. Participants ranged in age from 18 to 65.

Participants stem cells were collected by taking a small amount of fat from a 1- to 2-inch incision in the abdomen or thigh. Over four weeks, the cells were expanded in the laboratory to 100 million cells and then injected into the patients lumbar spine in the lower back. Over two years, each study participant was evaluated at Mayo Clinic 10 times.

Although it is understood that stem cells move toward areas of inflammation in this case the location of the spinal cord injury the cells mechanism of interacting with the spinal cord is not fully understood, Dr. Bydon says.

As part of the study, researchers analyzed changes in participants MRIs and cerebrospinal fluid as well as in responses to pain, pressure and other sensation. The investigators are looking for clues to identify injury processes at a cellular level and avenues for potential regeneration and healing.

The spinal cord has limited ability to repair its cells or make new ones. Patients typically experience most of their recovery in the first six to 12 months after injuries occur. Improvement generally stops 12 to 24 months after injury.

One unexpected outcome of the trial was that two patients with cervical spine injuries of the neck received stem cells 22 months after their injuries and improved one level on the ASIA scale after treatment.

Two of three patients with complete injuries of the thoracic spine meaning they had no feeling or movement below their injury between the base of the neck and mid-back moved up two ASIA levels after treatment.

Each regained some sensation and some control of movement below the level of injury. Based on researchers understanding of traumatic thoracic spinal cord injury, only 5% of people with a complete injury would be expected to regain any feeling or movement.

In spinal cord injury, even a mild improvement can make a significant difference in that patients quality of life, Dr. Bydon says.

Stem cells are used mainly in research in the U.S., and fat-derived stem cell treatment for spinal cord injury is considered experimental by the Food and Drug Administration.

Between 250,000 and 500,000 people worldwide suffer a spinal cord injury each year, according to theWorld Health Organization.

An important next step is assessing the effectiveness of stem cell therapies and subsets of patients who would most benefit, Dr. Bydon says. Research is continuing with a larger, controlled trial that randomly assigns patients to receive either the stem cell treatment or a placebo without stem cells.

For years, treatment of spinal cord injury has been limited to supportive care, more specifically stabilization surgery and physical therapy, Dr. Bydon says.

Many historical textbooks state that this condition does not improve. In recent years, we have seen findings from the medical and scientific community that challenge prior assumptions. This research is a step forward toward the ultimate goal of improving treatments for patients.

Dr. Bydon is the Charles B. and Ann L. Johnson Professor of Neurosurgery. This research was made possible with support from Leonard A. Lauder, C and A Johnson Family Foundation, The Park Foundation, Sanger Family Foundation, Eileen R.B. and Steve D. Scheel, Schultz Family Foundation, and other generous Mayo Clinic benefactors. The research is funded in part by a Mayo Clinic Transform the Practice grant.

Review thestudyfor a complete list of authors and funding.

Author: Megan Luihn Source: Mayo Clinic Contact: Megan Luihn Mayo Clinic Image: The image is credited to Neuroscience News

Original Research: Open access. Intrathecal delivery of adipose-derived mesenchymal stem cells in traumatic spinal cord injury: Phase I trial byMohamad Bydon et al. Nature Communications

Abstract

Intrathecal delivery of adipose-derived mesenchymal stem cells in traumatic spinal cord injury: Phase I trial

Intrathecal delivery of autologous culture-expanded adipose tissue-derived mesenchymal stem cells (AD-MSC) could be utilized to treat traumatic spinal cord injury (SCI).

This Phase I trial (ClinicalTrials.gov: NCT03308565) included 10 patients with American Spinal Injury Association Impairment Scale (AIS) grade A or B at the time of injury.

The studys primary outcome was the safety profile, as captured by the nature and frequency of adverse events.

Secondary outcomes included changes in sensory and motor scores, imaging, cerebrospinal fluid markers, and somatosensory evoked potentials. The manufacturing and delivery of the regimen were successful for all patients.

The most commonly reported adverse events were headache and musculoskeletal pain, observed in 8 patients. No serious AEs were observed. At final follow-up, seven patients demonstrated improvement in AIS grade from the time of injection.

In conclusion, the study met the primary endpoint, demonstrating that AD-MSC harvesting and administration were well-tolerated in patients with traumatic SCI.

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Stem Cells Spark Hope in Spinal Cord Recovery - Neuroscience News

Emerging Frontiers in Immunotherapy: The Promise of NK-Cell Therapies – Targeted Oncology

By Stem Cell Treatment

Katy Rezvani, MD, PhD

Professor

Department of Stem Cell Transplantation

Division of Cancer Medicine

Section Chief

Cellular Therapy

Director

Translational Research

Department of Stem Cell Transplantation-Research

Division of Internal Medicine

Sally Cooper Murray Endowed Chair in Cancer Research

The University of Texas MD Anderson Cancer Center

Houston, TX

The landscape of cancer therapy has been witnessing a paradigm shift with the advent of immunotherapy treatments, especially for patients with hematologic malignancies. Immunotherapies such as immune checkpoint inhibitors and autologous chimeric antigen receptor (CAR) T-cell therapies have led to considerable improvements in survival yet still come with efficacy limitations, manufacturing challenges, financial toxicity, and significant safety risks. Switching to an allogeneic approach could help overcome such limitations and allow for treatment of more patients with fewer donors.

Natural killer (NK)cell therapies are increasingly being explored as an alternative and promising approach to immunotherapy. Katy Rezvani, MD, PhD, said NK-cell therapies are of interest as a possible faster, cheaper, safer alternative to CAR T-cell therapy.

These cells have a lot of promise[and they give] me a lot of hope that CAR NK cells could add to the armamentarium of what we have available for cancer immunotherapy, said Rezvani, a professor of medicine in the Department of Stem Cell Transplantation at The University of Texas MD Anderson Cancer Center in Houston, in an interview with Targeted Therapies in Oncology.

NK cells are part of the innate immune system and can target cancer cells that downregulate HLA class I molecules.1 These cytotoxic lymphocytes are tasked with the surveillance of stressed cells,2-4 making them our first line of defense to virally infected cells and abnormal cells, Rezvani explained.

NK cells are of interest for adoptive cell therapies because they do not require full HLA matching, reducing the risk of graft-vs-host disease (GVHD) as well as lengthy manufacturing times for unique products.1-5 This allows NK-cell therapies to be a more off-the-shelf, readily accessible treatment for more patients compared with first-generation CAR T-cell therapy.

CAR T-cell treatments are also associated with other significant safety concerns, such as cytokine release syndrome (CRS) and immune effector cellassociated neurotoxicity syndrome (ICANS) toxicity, which are reduced with NK-cell therapies.4,5

NK-cell therapies are viewed as a possibility for overcoming the manufacturing times of CAR T-cell therapies and the large price tag associated with the treatment as well as the safety risks.5 On the other hand, NK cells have a limited life span after transfusion.1,4 They can be modified with genetic engineering to allow for greater efficacy.4,5

Sources for NK-cell production include cell lines, peripheral blood cells, umbilical cord blood, and induced pluripotent stem cells (iPSCs)an emerging origin source.4,6 Current research focuses most on cord bloodderived NK cells, which require donation and expansion. iPSC-derived NK cells do not require collection of cells from a donor.6 Clinical trials are beginning to show promise for CAR-NK-cell therapies, based on the benefits seen with CAR T-cell therapies.

Although still in the early stages of discovery and study, NK-cell therapies are beginning to show promise in clinical trials for their safety and convenience, as well as for efficacy on par with current CAR T-cell therapies.1 At the recent 65th American Society of Hematology (ASH) Annual Meeting and Exposition, findings were presented from early-stage studies of CAR NK-cell therapies showing their potential.

Rezvani, the recipient of the E. Donnall Thomas Lecture and Prize, presented the latest research on this cellular therapy. Rezvani highlighted studies of an anti-CD19 CAR NK agent.2 Following the success and approval of autologous anti-CD19 CAR T-cell products, a CAR NK-cell therapy derived from cord blood was created that was directed against CD19 for patients with CD19-positive malignancies; CAR NK cells did not require HLA matching with the recipient.1,2

In the phase 1/2 trial (NCT03056339), 11 patients with relapsed or refractory CD19-positive hematologic malignancies5 with chronic lymphocytic lymphoma, 2 with diffuse large B-cell lymphoma, and 4 with follicular lymphoma, 3 of which were transformedreceived the therapy in a single treatment. Objective responses were seen in 8 of 11 patients (73%) within a month of treatment, and all but 1 were complete responses (CRs). CAR NK cells were also detectable for up to a year after infusion.

No cases of CRS, neurotoxicity, tumor lysis syndrome, hemophagocytic lymphohistiocytosis, or GVHD were observed in any of the patients. Observed grade 3/4 adverse events (AEs) were predominantly hematologic.

Further results of the study in 37 patients with relapsed/refractory CD19-positive B-cell malignancies showed an objective response rate (ORR) of 48.6% at day 30 and day 100. CRs were seen in 29.7% of patients by day 100 and 37.8% by 1 year. Responses were seen at a median of 30 days and were durable for 9 of the 10 patients who had a CR.2,7

The responses that we observed were pretty similar to what you would get with [autologous CD19 CAR] T cells, Rezvani noted. Neither neurotoxicity nor GVHD was reported in any of the patients, but 1 case of CRS was observed.7

Rezvani stressed that donor selection was vital in this study and for future studies of cord bloodderived NK cells. Optimal cord blood was determined to be units that were frozen within 24 hours of collection and had a nucleated red blood cell count of less than 80 million.6 [We found that] the most important determinants of whos going to respond or not was the quality of the cord blood that was used for the manufacturing of CAR NK cells, Rezvani said. The impact that we ended up seeing was huge.

The rate of overall survival (OS) at 1 year was 94% in patients who received cord blood from optimal donors and 48% from those who received cells from suboptimal donors. The progression-free survival rates at 1 year were 69% and 5% for patients who received cord blood from optimal and suboptimal donors, respectively.2

Rezvani added that optimal cord blood could maintain long-term cytotoxicity and had greater in vitro proliferation compared with suboptimal cord blood. Further, optimal cords had greater polyfunctionality vs suboptimal cords, which were characterized by a signature associated with hypoxia and exhaustion.7

A phase 1 study (NCT04623944) presented at ASH showed promise for another CAR NK-cell therapy, NKX101, in patients with acute myeloid leukemia (AML). The agent is composed of NK cells derived from healthy donors that were engineered to express a natural killer group 2D (NKG2D)directed CAR and IL-15.8

The first cohort included 6 patients with relapsed/refractory AML who received 3 doses of NKX101 per treatment cycle; 83% had poor-risk factors. Early responses were seen, with 67% of patients achieving a CR or CR with incomplete hematologic recovery (CRi). Two patients achieved minimal residual disease negativity after only 1 treatment cycle. Three patients were continuing treatment.

All 6 patients reported treatment-emergent AEs of grade 3 or higher, with myelosuppression and infection being most common. No cases of CRS, ICANS, or GVHD of any grade were reported in the cohort. One case of a grade 5 AE was observed but was considered not related to treatment.

A phase 1/2 study presented at ASH showed first-in-human data for the CD123 NK-cell engager SAR443579 in patients with relapsed/refractory AML, B-cell acute lymphoblastic leukemia, or high-risk myelodysplasia (NCT05086315). SAR443579 is a trifunctional anti-CD123 NK-cell engager that targets the CD123 antigen as well as engaging NKp46 and CD16a.9

In the dose-escalation portion of the study, CRs/CRis were reported in 33% of patients with AML treated with up to a maximum dose of 1000 g/kg/infusion. Treatment was ongoing in 3 patients who achieved a CR.

Grade 3 or higher treatment-emergent AEs were reported in 60.5% of patients across dose levels and grade 5 events were seen in 11.6%, although all were considered not related to treatment with SAR443579. The most common events observed were infusion-related reactions (67.4%) and constipation (25.6%). CRS was reported in 2 patients but no cases of ICANS were observed. In June 2023, the agent received an FDA fast track designation for the treatment of patients with hematologic malignancies.10

During the ASH meeting, Yago L. Nieto, MD, PhD, presented findings from a phase 1/2 study of AFM13 (Acimtamig), a tetravalent bispecific antibody construct with CD30 and CD16a, in combination with cord bloodderived, cytokine-induced, memory-like expanded NK cells in patients with relapsed/refractory CD30-positive lymphomas (NCT04074746).11

A total of 42 heavily pretreated patients who were double refractory to brentuximab vedotin (Adcetris) and checkpoint inhibitors, most with Hodgkin lymphoma (88%), received NK cells 15 days before treatment with AFM13. The ORR was 93% and the CR rate was 67%. At the recommended phase 2 dose level (108 NK/kg), the ORR was 94% and the CR rate was 72%. Responses were reported in 97% of patients with classical Hodgkin lymphoma (n =32) and CRs in 78%.

The median OS in patients who received 2 cycles of treatment was 85% at 6 and 12 months. In patients who received 4 cycles, the median OS was 87% at 6 months and 85% at 12 months. In patients with Hodgkin lymphoma, the median OS was 92% at 6 and 12 months for those who received 2 cycles of treatment and 85% and 82%, respectively, for those who received 4 cycles.

No cases of CRS, neurotoxicity, or GVHD were reported in the study; even infusion-related reactions were considered infrequent. Moderate neutropenia and thrombocytopenia were seen with the lymphodepleting chemotherapy.

The safety didnt come as a surprise; we expected that. What really came as a surprise was the high level of activity in the heavily pretreated patients with refractory tumors we treated, said Nieto, a professor in the Department of Stem Cell Transplantation at The University of Texas MD Anderson Cancer Center in Houston during an interview with Targeted Therapies in Oncology. He added that 6 of 7 patients who had a response subsequently consolidated with a stem cell transplant remained in CR at more than 18 months, making it an effective bridging therapy.

In September 2023, AFM13 in combination with allogeneic NK cells (AB-101) received an FDA fast track designation for the treatment of patients with relapsed/refractory Hodgkin lymphoma.12 Going forward, AFM13 is being explored in combination with AB-101 in patients with relapsed/refractory Hodgkin lymphoma and CD30-positive peripheral T-cell lymphoma in a phase 2 trial (LuminICE-203; NCT05883449). The combination is expected to augment the innate immunity of AFM13 alone to boost the antitumor cytotoxicity in patients with CD30-positive tumors.12,13 Nieto also explained that the AFM13 and NK-cell therapy model can be extrapolated to treat other malignancies by choosing an alternate bispecific antibody for the tumor type.

An ongoing phase 1 trial (NCT05182073) of FT576, a multiplex-engineered, BCMA-targeted CAR NK-cell therapy, in patients with relapsed/refractory multiple myeloma has shown early promise and safety for the iPSC-derived agent as a monotherapy and in combination with daratumumab (Darzalex).14 No cases of CRS, ICANS, or GVHD were reported in the trial at any dose level with or without added daratumumab. Additionally, no dose-limiting toxicities or serious treatment-related AEs were observed.

Among 9 patients treated as of the interim report, responses were seen in 33% of patients and stable disease in 55%. One patient treated with FT576 monotherapy, who had received 5 prior lines of therapy and was triple refractory, achieved a very good partial response.

As of now, efficacy with NK-cell therapies is considered similar to that of CAR T-cell therapies, although the studies of these agents is in the early stages. However, current constructs of first-generation CAR NK-cell therapies have limited long-term efficacy due to shorter in vivo persistence and cell exhaustion. To potentially improve the efficacy beyond that of autologous approaches and even to generate efficacy in solid tumors, newer approaches are being considered, including engaging different targets, transducing T-cell receptor (TCR)expressing NK cells, multiplexed engineering, and combination regimens.2,15

The potential is huge [for] what we can achieve with these cells. With our increasing understanding of NK biology, of access to big data, and also the engineering tools that we have available to usenot just CAR transduction, but for instance with TCR into NK cells, with CRISPR [clustered regularly interspaced short palindromic repeats] gene editing of your NK cells to make them more resistant to the impact of the tumor microenvironment, and combination with various drugsI think the field could see major advances in a relatively short period of time, Rezvani said.

Targeting CD70 is showing promise as it is expressed in primary AML samples. Investigators created a number of second-generation CAR constructs to determine the most optimal one and found that anti- CD70 CAR NK cells with IL-15 allowed for the most superior antitumor activity of the various constructs in aggressive CD70-positive AML models.16 The construct is now being used in an ongoing phase 1/2 basket trial in patients with CD70-expressing hematologic malignancies (NCT05092451) and being explored across 3 dose levels.2

To date, NK-cell therapies have not seen the same success in solid tumors as in hematologic malignancies. This is believed to be because of the immunosuppressive tumor microenvironment that hampers NK cell activation and function. Advances in understanding these barriers and developing strategies to overcome them are critical for enhancing the therapeutic potential of NK-cell therapies in solid tumors.1,2,15

TROP2 is a target of interest with NK cells to treat patients with solid tumors as it is overexpressed in many epithelial cancers but not in healthy tissues.2 The FDA has approved investigational new drug applications for the study of CAR TROP2/IL-15 NK cells delivered intravenously to patients with advanced solid tumors (NCT06066424) and delivered intraperitoneally to patients with ovarian cancer and pancreatic cancer (NCT05922930).

Genetically engineered New York esophageal squamous cell carcinoma 1 (NY-ESO-1)targeted, TCR/IL-15expressing cord bloodderived NK cells are being investigated in a phase 1/1b trial of patients with advanced synovial sarcoma and myxoid/round cell liposarcoma (NCT06083883) as well as in a phase 1 trial for patients with NY-ESO-1positive relapsed/refractory multiple myeloma or plasma cell leukemia (NCT06066359). NY-ESO-1 is considered highly immunogenic and is expressed in many cancer cells but not in healthy tissue, making it an attractive target.

The phase 1b ADVENT-AML trial is exploring the use of allogeneic NK cells in combination with azacitidine and venetoclax (Venclexta) in patients with newly diagnosed AML (NCT05834244). The synergy of the regimen allows for upregulation of silenced NKG2D ligands, priming of leukemia cells, and reduction of disease burden.17

Multiplexed CRISPR gene-edited therapies are being created to design the safest and most effective products for patients. By employing CRISPR/Cas9 technology, multiple genes within NK cells can be simultaneously edited to enhance their persistence, cytotoxicity, and ability to navigate immunosuppressive barriers.2,15

A phase 1 trial is exploring the treatment of patients with recurrent glioblastoma with multiplex CRISPR gene-edited NK cells with deleted TGFBR2 and NR3C1 (NCT04991870). With new, innovative approaches and clinical trials quickly emerging, the field of NK-cell therapies is surely one to watch.

Excerpt from:
Emerging Frontiers in Immunotherapy: The Promise of NK-Cell Therapies - Targeted Oncology