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

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.

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

Stem Cells Spark Hope in Spinal Cord Recovery – Neuroscience News

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

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

Scientists Uncover Cause of Inherited Bone Marrow Failure – Mirage News

An international study led by researchers from Children's Hospital of Philadelphia (CHOP) has discovered an important biological cause of Fanconi anemia, a rare inherited disorder that almost universally leads to bone marrow failure. The researchers also confirmed that a readily available bile acid may help correct some of these biological issues and provide more options for potential treatment. The findings were recently published by the journal Nature Communications.

Fanconi anemia was discovered nearly a century ago. Over the course of decades of study, researchers had previously linked Fanconi anemia to DNA damage that impairs the function of hematopoietic stem cells (HSCs), which are responsible for lifelong function and renewal of blood cells. DNA damage leads to cell death and eventually gives way to frank bone marrow failure. Since stem cells are impacted, a stem cell transplant is the only treatment currently available for Fanconi anemia. However, not all patients have matching donors, and those who do can still experience side effects from the treatment.

Prior research by the group revealed that the loss of stem cells that leads to Fanconi anemia begin before birth, making the underlying biology behind this condition very difficult to study. Using mouse models and a combination of other techniques, researchers were able to determine the events before birth that eventually accelerate bone marrow failure by early school age in these patients.

Peter Kurre, MD "Fanconi anemia is thought to be a DNA disorder, and those who have been researching it have focused solely on this aspect," said senior author Peter Kurre, MD, Director of the Pediatric Comprehensive Bone Marrow Failure Center at CHOP. "What our research demonstrates for the first time is that Fanconi anemia is caused by an accumulation of misfolded proteins that preclude proper cell cycle progression and stem cell expansion, which in turn leads to rapid bone marrow failure after birth."

The study found that increased protein synthesis rates in fetal HSCs occur at the onset of Fanconi anemia. The proteins are misfolded in fetal liver HSCs, which leads to stress on the endoplasmic reticulum, a network of tubules in our cells responsible for producing healthy proteins needed for a variety of functions. This accumulation of misfolded proteins confers cellular stress signals that slow down cell cycle progression and emergence of a sufficient number of stem cells, causing rapid bone marrow failure early in life.

With this new knowledge of the mechanisms behind Fanconi anemia, the researchers then used tauroursodeoxycholic acid (TUDCA), a bile salt that has been studied for use in preventing and treating gallstones and helping to reduce the side effects associated with certain inflammatory disorders. In HSC of the Fanconi anemia animal model, TUDCA restored proper protein folding.

"When TDUCA was given, we were able to confirm the restoration of folding as well as improved function of the stem cells," said Narasaiah Kovuru, PhD, a postdoctoral researcher in the Kurre Laboratory and first author of the study.

With this combination of information, the researchers determined that the degradation of protein homeostasis - the proper regulation of proteins in these cells - is driven by excess inflammatory activity in HSCS within the fetal liver, and dampening this activity helps restore HSCs to their normal numbers.

"Regulating protein production, folding and degradation properly is like the story of Goldilocks and the Three Bears, in that too much or too little protein is a problem, and the levels need to be just right for proper function," Kurre said. "This study reveals the direction our research should go next to determine what mechanisms are at play that alter these protein levels and what alternate treatment options we might be able to develop for patients for whom stem cell transplantation is not an option."

This study was supported by National Institutes of Health grant R01-HL150882.

Kovuru et al, "Deregulated protein homeostasis constrains fetal hematopoietic stem cell pool expansion in Fanconi anemia." Nat Commun. Online February 29, 2024. DOI: 0.1038/s41467-024-46159-1.

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Scientists Uncover Cause of Inherited Bone Marrow Failure - Mirage News

Collagen hydrogel can boost survival of precursor neurons to brain – Parkinson’s News Today

Encapsulating precursor nerve cells in a collagen hydrogel can enhance the efficacy of stem cell transplantation to the brain, a potential treatment to replace dopamine-producing nerve cells that are lost in people with Parkinsons disease, according to a preclinical study.

Our hydrogel nurtures, supports and protects the cells after they are transplanted into the brain, and this dramatically improves their maturation and reparative ability, Eils Dowd, PhD, study lead at the College of Medicine, Nursing and Health Sciences at the University of Galway, in Ireland, said in a university press release.

Ultimately, we hope that continued development of this promising gel will lead to a significant improvement in brain repair approaches for people living with Parkinsons, Dowd said.

The study, Survival and maturation of human induced pluripotent stem cell-derived dopaminergic progenitors in the Parkinsonian rat brain is enhanced by transplantation in a neurotrophin-enriched hydrogel, supported by research grants from The Michael J. Fox Foundation for Parkinsons Research (MJFF), was published in the Journal of Neural Engineering.

Parkinsons symptoms are caused by the progressive loss of dopaminergic neurons, the specialized nerve cells that produce dopamine, a chemical messenger in the brain.

Cell-based brain repair is a promising therapeutic approach for Parkinsons disease, whereby the lost dopaminergic neurons are replaced by the transplantation of healthy neurons. Such neurons can be derived from induced pluripotent stem cells, or iPSCs, that are reprogrammed from adult cells, such as skin cells, and converted into dopaminergic neurons.

In fact, stem cell-based therapies have already started clinical testing, including a trial evaluating bemdaneprocel, which demonstrated sustained efficacy 1.5 years after treatment, and another called STEM-PD.

However, iPSCs need to be transplanted into the brain very early in their maturation from stem cells to fully functional neurons. Even so, most transplanted cells do not fully mature into dopaminergic neurons once they are inside the brain.

Thus, it is imperative to continue rigorous preclinical studies to identify methods to improve their outcome to maximise their reparative/reconstructive potential, Dowd and her colleagues wrote.

Encapsulating cells in hydrogels made with collagen, the most abundant protein in connective tissue, has the potential to address many limitations of transplantation. These hydrogels act as a scaffold, shielding cells from immune responses, and can be infused with neurotrophic factors, proteins that induce the survival, development, and function of neurons.

Ultimately, we hope that continued development of this promising gel will lead to a significant improvement in brain repair approaches for people living with Parkinsons.

In previous work, Dowds team encapsulated primary dopaminergic neurons in a collagen hydrogel loaded with a neurotrophic factor called GDNF. Transplantation with the specialized gel dramatically increased the survival and function of these cells in a rat model of Parkinsons.

In this new study, the researchers tested the gel method using dopaminergic precursor cells (DAPs) derived from iPSCs (iPSC-DAPs). Cells were transplanted into the brain of a Parkinsons rat model, with or without the gel, and with or without the neurotrophic factors GDNF and BDNF.

Surviving iPSC-derived cells were visible in all four groups as early as one week after transplantation. Still, the graft cells were significantly larger in the two groups treated with iPSC-DAPs in the hydrogel, with or without neurotrophic factors, than in the two groups without the hydrogel.

This suggested not only was the hydrogel cytocompatible with these cells, the beneficial effects of the gel were already manifesting shortly after transplantation, the researchers wrote.

Although the cells transplanted with the hydrogel stimulated a broader immune response, the researchers noted this was likely a reflection of the larger graft size in the hydrogel groups.

As assessed 20 weeks, or 4.6 months, after transplantation, neurotrophic-enriched iPSC-DAPs in the hydrogel were larger and more dispersed within the brain compared with cells transplanted alone, which were small and compact. When transplanted with the neurotrophic-enriched hydrogel, cell survival increased eightfold, and dopaminergic neuron maturation improved 16 times higher.

Comparably, significantly more iPSC-DAPs matured into dopaminergic neurons with the enriched hydrogel than without (11.2% vs. 2.1%). Furthermore, one in six rats given cells alone reached a dopaminergic maturation level of more than 5%, whereas all seven rats treated with enriched cells in the hydrogel achieved this outcome.

This suggests that the neurotrophin-enriched hydrogel is having a beneficial effect on dopaminergic differentiation and maturation over and above the effect on progenitor survival, the team wrote.

Given the beneficial effects of this hydrogel on human iPSC-derived brain repair in this Parkinsonian rat model, further development of such hydrogel carriers is warranted to improve the survival, differentiation and overall outcome of stem cell-derived brain repair in Parkinsons patients, the researchers concluded.

Further development of the hydrogel, specifically to understand how the immune system in the brain reacts upon transplantation, is being supported by a $300,000 award from the MJFF.

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Collagen hydrogel can boost survival of precursor neurons to brain - Parkinson's News Today

Notoginsenoside R1 promotes Lgr5+ stem cell and epithelium renovation in colitis mice via activating Wnt/-Catenin … – Nature.com

Chemicals and reagents

Notoginsenoside R1 (NGR1, BP1010, C47H80O18, purity 98%, CAS No 80418-24-2, MW: 933.13Da) was purchased from Chengdu Purifa Technology Development Co. Ltd (Chengdu, China). Dextran sulfate sodium salt (DSS, 0216011010, MW: 36kDa50kDa) was purchased from MP Biomedicals (Shanghai, China). Salicylazosulfapyridine (SASP, S0883, C18H14N4O5S, CAS No 599-79-1, MW: 398.39Da) and FITC-dextran (FD4, CAS No 60842-46-8) was purchased from Sigma-Aldrich (Darmstadt, Germany). ICG-001 (T6113, C33H32N4O4, purity 98%, CAS No 780757-88-2, MW: 548.64Da) was acquired from TOPSCIENCE (Shanghai, China). Water-DEPC treated (693520) and DMSO (D8418) were obtained from MilliporeSigma (Burlington, MA, USA).

NCM460 human intestinal epithelial cells and CT26 murine colon carcinoma cells were obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA). NCM460 and CT26 cells were cultured in Roswell Park Memorial Institute (RPMI)-1640 culture medium (11875085, Gibco, NY, USA) supplemented with 10% fetal bovine serum (10099158, Gibco, NY, USA). The culture conditions included a humidified atmosphere containing 5% CO2, with a constant temperature maintained at 37C.

The Laboratory Animal Center of Shanghai University of Traditional Chinese Medicine provided female C57BL/6 mice weighing 202g. These mice were housed in a specific pathogen-free facility under meticulously controlled conditions, including a temperature range of 2325C, humidity maintained at 60%70%, and a well-regulated 12-h light-dark cycle. The Animal Experimentation Ethics Committee of Shanghai University of Traditional Chinese Medicine granted approval (PZSHUTCM2307310004) for experimental procedures conducted on the animals. All experiments were conducted in accordance with institutional animal care guidelines and protocols approved by the committee.

According to the method reported by Yue [26], we established the acute colitis mouse model. Briefly, female C57BL/6 mice were divided randomly into four groups: Control, DSS, DSS+SASP, and DSS+NGR1. Acute colitis was induced by administering 3% DSS in the drinking water of mice for a period of 8 days. Mice in the DSS+SASP group were treated orally with SASP (260mg/kg) once per day for the same duration. The DSS+NGR1 group received NGR1 (25, 50, 125mg/kg) by oral gavage once per day for 10 days. Mice in the Control and DSS groups were administered the same volume of Control. Daily monitoring of body weight and rectal bleeding was conducted throughout the 10-day period. At the end of the experiment, mice were euthanized, and the colon was collected for further analysis.

Female C57BL/6 mice were randomly divided into four groups: DSS, DSS+ICG-001, DSS+NGR1 and DSS+ICG-001+NGR1. To establish an acute enteritis model, mice were subjected to the protocol described above. Mice in the DSS+NGR1 and DSS+ICG-001+NGR1 group were given NGR1 (25mg/kg) orally once daily for 10 consecutive days. Meanwhile, mice in the DSS+ICG-001 and DSS+ICG-001+NGR1 groups were given ICG-001 (20mg/kg) via intraperitoneal injection three times per week. The DSS and DSS+NGR1 groups received the same volume of Control.

Male BALB/c mice were acclimated for 1 week in a specific pathogen-free environment. Subsequently, CT26 cells (2105 cells/mouse) were subcutaneously transplanted into the left axillary region of each mouse. Once the tumor size reached 200mm3, the mice were randomly assigned to the vehicle group or the NGR1 group based on tumor size. Throughout the 18-day experiment, mice in the vehicle group received 0.5% CMC-Na, while those in the NGR1 group were administered 25mg/kg NGR1. Tumor volume=0.5length (mm)width (mm)2.

C57BL/6 mice were fasted for 4h before execution. Mice were then orally administered 60mg/100g body weight of FITC-dextran in 200L of sterile saline. After 4h, blood samples were collected via retro-orbital bleeding, and serum was separated by centrifugation. The serum FITC-dextran levels were measured at an excitation wavelength of 485nm and an emission wavelength of 528nm using a fluorometer (VARIOSKAN FLASH, Thermo Fisher, MA, USA).

Colonic tissues were collected from mice and fixed in 4% paraformaldehyde. Tissues were then dehydrated, embedded in paraffin, and sectioned into 4m thick slices. The sections were then stained with hematoxylin and eosin (H&E) using standard protocols. Stained sections were analyzed under a light microscope (BX61VS, Olympus, Tokyo, Japan), and images were captured for further analysis.

The concentrations of DAO (CSB-E10090m) and LPS (CSB-E13066m) in mouse serum samples were determined using the respective ELISA kit (Wuhan Huamei Biological Engineering Co., Ltd, Wuhan, China). Specifically, serum samples were added to a 96-well plate coated with DAO or LPS-specific antibodies, followed by incubation with detection reagents and substrate solution. Absorbance was measured at 450nm, and concentrations were calculated using standard curves.

Colonic tissues were fixed in 4% paraformaldehyde, embedded in OCT compound, and sectioned into 5-m slices. After permeabilization and blocking, sections were incubated with primary antibodies against ZO-1 (#13663, Cell Signaling Technology, CST, MA, USA) and Occludin (#91131, CST, MA, USA), followed by secondary antibodies conjugated to fluorophores (9300039001, ABclonal, Wuhan, China). Nuclei were counterstained with DAPI (#4083, CST, MA, USA), and images were obtained using a fluorescence microscope (BX61VS, Olympus, Tokyo, Japan). Quantification of ZO-1 and Occludin expression was performed using ImageJ software (NIH, Bethesda, MD, USA).

Colonic tissue samples were obtained from mice, fixed, dehydrated, embedded in paraffin blocks, sectioned, and stained with Alcian blue using a commercial kit. Under a light microscope (BX61VS, Olympus, Tokyo, Japan), the stained sections were examined and images were captured for subsequent analysis.

RNA was extracted using the TRIzol method, and RNA quantity and purity were measured by NanoDrop spectrophotometer (Thermo Fisher Scientific). The RNA was then reverse-transcribed using an Evo M-MLV RT Premix for qPCR kit (AG11706, Accurate Biotechnology Co., Ltd., Chengdu, China), and qPCR was performed using a SYBR Green Premix Pro Taq HS qPCR Kit (AG11718, Accurate Biotechnology Co., Ltd., Chengdu, China) (Table1). The amplification was carried out using an ABI Prism 7900HT Sequence Detection System (Life Technologies, CA, USA), and data were analyzed using the 2Ct method.

Colonic tissues were extracted and homogenized, and protein was obtained using RIPA lysis buffer with phosphatase and protease inhibitors. Protein concentration was measured using a BCA assay kit (20201ES76, Yeasen Biotech Co., Ltd, Shanghai, China). Equal amounts of protein were loaded onto SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis) gels and separated by electrophoresis. Subsequently, the separated proteins were transferred onto PVDF membranes (000025736, Milipore, MA, USA). The membrane was then blocked with 5% BSA solution for 2h. After blocking, the membrane was incubated with primary antibodies overnight at 4C, followed by incubation with HRP-conjugated secondary antibodies for 1h at room temperature. Protein bands were visualized using ECL reagents (WBKLS0500, Millipore) and imaged with a GS-700 imaging densitometer (Bio-Rad, CA, USA). Protein expression levels were quantified using ImageJ software (NIH, Bethesda, MD, USA). The following primary antibodies were used: rabbit anti--Catenin (1:1000, #8480, CST, MA, USA), rabbit anti-p-GSK-3 (1:1000, #5558, CST, MA, USA), rabbit anti-GSK-3 (1:1000, #12456, CST, MA, USA), rabbit anti-Cyclin D1 (1:1000, #2922, CST, MA, USA), rabbit anti-c-Myc (1:1000, #5605, CST, MA, USA) and rabbit anti--actin (1:1000, #4970, CST, MA, USA).

Colonic tissue sections were fixed in 4% paraformaldehyde, embedded in paraffin, and sliced into 5m thick sections. Antigen retrieval was performed using citrate buffer solution (pH=6.0) and heating in a microwave oven. Non-specific binding was blocked with 5% goat serum for 30min. Sections were incubated overnight at 4C with primary antibodies, followed by incubation with a secondary antibody and staining with DAB (3,3-diaminobenzidine). Hematoxylin was used for counterstaining before the sections were examined microscopically and images were captured.

Total RNA was extracted from mouse intestinal tissues using TRIzol reagent according to the manufacturers instructions. The extracted RNA was evaluated for quality using a NanoDrop spectrophotometer (Thermo Fisher). RNA sequencing libraries were then constructed with the NEBNext Ultra RNA Library Prep Kit for Illumina, and sequencing was performed on an Illumina HiSeq platform. The differential gene was carried out on the cloud platform of majorbio (https://www.majorbio.com/).

Caco-2 cells were seeded in Millicell inserts of 24-well plates at a density of 5104 cells/400L per well. The outer chamber was filled with 600L DMEM medium (2323012, Gibco, NY, USA) and replaced every other day. TEER values were measured using a MERS00002 volt-ohm meter system (Milipore), and the electrode was sterilized with 70% ethanol and rinsed with sterile phosphate-buffered saline (PBS) before each measurement. Monolayer formation was assumed at TEER values of 400/cm2. Measurements were taken at regular intervals using the same electrode and recorded.

The intestinal crypts were isolated from the small intestine of C57BL/6 mice (6- to 8-week-old). The small intestine was removed and flushed with ice-cold PBS. The intestine was opened longitudinally and cut into 2- to 3-mm pieces. The pieces were then washed with ice-cold PBS and incubated in 3mM EDTA solution at 4C for 20min with gentle shaking. After incubation, the crypts were released by vigorously shaking the tubes. The supernatant containing the crypts was collected and filtered through a 70-m cell strainer. The crypts were then centrifuged at 1200r/min for 5min and resuspended in Matrigel (Corning, NA, USA). The crypt-Matrigel mixture was plated in 24-well plates and incubated at 37C for 30min to allow the Matrigel to solidify. The IntestCultTM OGM Mouse Basal Medium (#06005, STEMCELL, Vancouver, Canada) was then added to the wells and changed every other day.

After cultured 2 days in a 24 well plate, the intestinal crypts were randomly divided into control, DSS model group and DSS+NGR1 group. Then, the organoids were administered DSS (20g/mL), DSS (20g/mL) plus NGR1 (100M) for 4 days. The organoid growth conditions were recorded by the microscope (Olympus CKX4, Tokyo, Japan). IHC assay was conducted to examine the fluorescent protein expression of Lgr5 and -Catenin (refer to the above method of IHC).

The molecular docking was performed using AutoDock Vina software. The 3D crystal structure of -Catenin protein (PDB: 1JDH) was obtained from the Protein Data Bank (PDB) database. The structure of NGR1 was drawn and optimized using ChemDraw software and converted to a PDB file using Open Babel software. The protein and ligand files were prepared using AutoDock Tools. Docking simulations were performed and the conformation with the lowest binding energy was selected as the final docking result. The docking results were analyzed using PyMOL software.

The TOPFlash assay was performed as previously described with slight modifications [27]. HEK293T cells were seeded in 24-well plates and cultured overnight. The cells were transfected with the 500ng TOPFlash luciferase reporter plasmids (Beyotime Biotechnology, Shanghai, China) and 50ng Renilla luciferase (Promega GmbH, Mannheim, Germany) using Lipofectamine 3000 (Thermo Fisher). After 24h, the cells were treated with NGR1 (50M) and BIO (0.5M) for 24h, separately. Subsequently, cells were lysed in 150L/well passive phenylbenzothiazole (PPBT) buffer, and the luciferase activity was measured using a Dual-LuciferaseTM Reporter Assay System (Promega Corporation, WI, USA). The firefly luciferase activity was normalized to Renilla luciferase activity.

A scratch wound was created using a plastic pipette (10L) tip. NCM460 cells were then washed with PBS to remove any debris and treated with either DSS (20g/mL) or DSS (20g/mL)+NGR1 (100M) for 24h. The width of the scratch was measured using microscopy at 0 and 24h post-dosing, and the percentage of wound closure was calculated by comparing the scratch width at 24h to the initial scratch width.

NCM460 cells were treated with either DSS (20g/mL) or DSS (20g/mL)+NGR1 (100M) for 24h. Then, NCM460 cells were harvested and washed with PBS after experimental treatment. Cells were then suspended in a binding buffer containing Annexin V-fluorescein isothiocyanate (FITC) and propidium iodide (PI), and incubated in the dark at room temperature for 15min. Flow cytometry analysis was performed to detect apoptotic cells. The data were analyzed using Guava software, and the percentage of apoptotic cells was expressed.

Statistical analysis was performed using GraphPad Prism 9.0 software. Data were presented as meanstandard deviation (SD). Differences between groups were analyzed using one-way analysis of variance (ANOVA). P<0.05 was considered statistically significant. All experiments were repeated at least three times.

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Notoginsenoside R1 promotes Lgr5+ stem cell and epithelium renovation in colitis mice via activating Wnt/-Catenin ... - Nature.com

Lawsuit over League City stem-cell treatment headed for trial – Galveston County Daily News

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Lawsuit over League City stem-cell treatment headed for trial - Galveston County Daily News

Developing Stem Cell Therapy to Halt Critical Limb Amputations – Mirage News

Critical limb ischemia is a condition in which the main blood vessels supplying blood to the legs are blocked, causing blood flow to gradually decrease as atherosclerosis progresses in the peripheral arteries. It is a severe form of peripheral artery disease that causes progressive closure of arteries in the lower extremity, leading to the necrosis of the leg tissue and eventual amputation. Current treatments include angioplasty procedures such as stent implantation and anti-thrombotic drugs, but there is a risk of blood vessel damage and recurrence of blood clots, which is why there is a strong interest in developing a treatment using stem cells.

A research team led by Dr. Sangheon Kim of the Center for Biomaterials Research at the Korea Institute of Science and Technology (KIST) announced that they have developed a three-dimensional stem cell therapy to treat critical limb ischemia through a self-assembling platform technology using a new material microgel. By using collagen microgels, a new biocompatible material, the researchers were able to easily transplant stem cells into the body and increase cell survival rate compared to 3D stem cell therapies made of cells alone.

Stem cell therapies have high tissue regeneration capabilities, but when stem cells are transplanted alone, hypoxia at the site of injury, immune responses, and other factors can reduce cell viability and prevent the desired therapeutic effect. Therefore, it is necessary to develop a material that delivers stem cells using biodegradable polymers or components of extracellular matrix as a support to increase cell viability.

The team processed collagen hydrogels to micro-scale to create porous, three-dimensional scaffolds that are easy to inject in the body and have a uniform cell distribution. Collagen, a component of the extracellular matrix, has excellent biocompatibility and cellular activity, which can induce cell self-assembly by promoting interactions between the microgel particles and collagen receptors on stem cells. In addition, the spacing between microgel particles increased the porosity of the three-dimensional constructs, improving delivery efficiency and cell survival.

The microgel-cell constructs developed by the researchers expressed more pro-angiogenic factors and exhibited higher angiogenic potential than cell-only constructs. When microgel-cell constructs were injected into the muscle tissue of mice with critical limb ischemia, blood perfusion rate increased by about 40% and limb salvage ratio increased by 60% compared to the cell-only constructs, confirming their effectiveness in increasing blood flow and preventing necrosis in the ischemic limb.

The new stem cell therapy is expected to provide a new alternative for patients with critical limb ischemia who have limited treatment options other than amputation due to its excellent angiogenic effect. Furthermore, since angiogenesis is an essential component of various tissue regeneration processes, it can be extended to other diseases with similar mechanisms to peripheral arterial disease.

"The collagen microgel developed in this study is a new biomaterial with excellent biocompatibility and high potential for clinical applications," said Dr. Sangheon Kim of KIST. "We plan to develop technologies for administration methods required in the medical field, as well as conduct follow-up research to clarify the clear mechanism of action of the treatment and discover target factors."

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Developing Stem Cell Therapy to Halt Critical Limb Amputations - Mirage News

Cell therapy for retinal degenerative disorders: a systematic review and three-level meta-analysis – Journal of … – Journal of Translational…

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Trends in Stem Cell Transplantation Refusal for Myeloma Treatment – Targeted Oncology

Determining the right path for multiple myeloma treatment is often complex as various decisions can significantly impact patient outcomes. Among these decisions, the consideration of autologous hematopoietic stem cell transplantation (HSCT) stands as a cornerstone, offering hope for improved progression-free and overall survival. However, recent research from Chakra Chaulagain, MD, showed that a small yet significant percentage of patients are refusing this potentially life-saving procedure.

An analysis of National Cancer Database (NCDB) data presented at the 2023 American Society of Hematology Annual Meeting showed that of 43,653 patients with newly diagnosed multiple myeloma recommended for HSCT, 98.05% proceeded with the procedure. However, the remaining 2% opted out. Some of the key factors influencing the patient's decision regarding HSCT related to socioeconomic, racial, and geographic disparities.

According to Chaulagain, director of the multiple myeloma and amyloidosis program at Cleveland Clinic Florida, older patients with multiple myeloma, those with comorbidities, and those lacking robust insurance coverage are more likely to decline HSCT. Furthermore, Black patients exhibited higher rates of refusal compared with White patients (OR, 1.38; P =.0022).

These findings underscore the need for future studies and policy changes to address socioeconomic and racial disparities in access to transplantation.

In an interview with Targeted OncologyTM, Chaulagain discussed the trends of rates of autologous HSCT refusal among patients with multiple myeloma.

Targeted Oncology: What led to your research on autologous HSCT refusal rates among patients with multiple myeloma?

Chaulagain: There is minimal data on real-world findings about refusal of a standard-of-care, for example, stem cell transplantation in [patients with] multiple myeloma. We wanted to explore some ideas about what are the factors that are contributing to the refusal transplant, which is the current standard-of-care, and it is known to improve both progression-free and overall survival based on randomized clinical trials. But there is limited real-world data around this subject, so we decided to investigate the NCDB.

Tumor microenvironment background with cancer cells, T-Cells, nanoparticles, molecules, and blood vessels. Oncology research concept: ratatosk - stock.adobe.com

What were the methods and design of this analysis?

This is a retrospective analysis of a very large number of [patients with] multiple myeloma that were treated by a commission of cancer-accredited cancer centers throughout the United States. There are at least 1500 of these types of cancer centers, and they report to this NCDB, where they have all of this data collected. NCDB captures about 70% of all cancer cases in the United States. We decided to get those data and analyze them just for multiple myeloma with the purpose of finding what are the variables and clinical factors that are responsible for refusal of autologous stem cell transplantation in [patients with] myeloma.

What were the key findings regarding the utilization of autologous HSCT in patients with multiple myeloma?

We had 43,600 patients [with] newly diagnosed multiple myeloma, and they were recommended to undergo a stem cell transplantation after completing their initial induction therapy by their doctors. Ninety-eight percent of the patients did go and do the stem cell transplantation, but 2% refused. We analyzed the various socioeconomic, racial, ethnic, and geographic factors about what made them refuse the stem cell transplantation.

Did the study identify any patient subgroups who were more likely to refuse?

We did find that older patients had a higher odds of refusing essential transplantation. Male [patients] had higher odds of accepting transplantation and females had higher odds of refusing it. Patients with more major medical comorbidities had higher odds of refusing it. Patients without insurance, or Medicare and Medicaid, had higher odds of refusing stem cell transplantation compared with patients who had private insurance. Median household income was also a significant predictor of whether the patient will go for a stem cell transplant or not. Those who were earning less than $63,000 annually had a higher odds of refusing autologous stem cell transplantation. Black patients, for example, had a higher odds of refusing transplantation, and Hispanic [patients] had a lower odds of refusing transplantation.

Were there any significant trends in the refusal rates over this time period?

The study time point was from 2004 until 2020. Patients who were diagnosed and treated closer to 2020 had a higher odds of refusing transplantation, and patients who were diagnosed closer to 2004 had a higher odds of accepting transplantation or lower odds of refusing transplantation, and we think it may have to do with advancement in novel therapies, particularly monoclonal antibody therapies in multiple myeloma in the current years.

What are the potential reasons as to why patients refused more than others?

The higher age, decreased income, not having strong private insurance, and also, the facility type did matter. For example, patients who were treated at nonacademic facilities had a higher odds of refusing transplant compared with patients that were treated at academic centers. There was also regional variation on whether the patient would refuse or accept transplant. For example, in South Atlantic states in the United States, patients had higher odds of refusing transplantation.

What are the implications of these findings?

We found that there was significant variation across the United States in terms of racial, economic, and geographic variation, and this data can and should be used for designing future clinical studies in a prospective basis.

How have recent advancements in the multiple myeloma space such as the emergence of novel therapies impacted transplantation?

Based on our studies, the emergence of novel therapies and immunotherapy, particularly anti-CD38 monoclonal antibodies like daratumumab [Darzalex], have led to decrease utilization of transplant, and it will probably further evolve down the road because of the availability of even more effective novel therapies such as [chimeric antigen receptor] T-cell therapy, and bispecific T-cell engager therapy. The role of transplant will continue to evolve and will probably continue to diminish down the road.

What barriers still need to be addressed regarding transplant?

These are bigger decisions at the policy and procedure and legislation [levels], like increasing incidence coverage, increasing socioeconomic aspects for all of our patients, particularly those who are marginalized or who are minorities. This is a bigger, national goal and the legislator has to act on it,

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Trends in Stem Cell Transplantation Refusal for Myeloma Treatment - Targeted Oncology