Enhancing Stem Cell Tracking with Nanoparticle Imaging Agents – AZoNano

Sponsored by MerckJan 23 2024Reviewed by Emily Magee

Stem cell therapies show promise in tissue engineering, regenerative medicine, and their homing effect. They offer hope for treating numerous incurable diseases like Parkinsons disease, liver failure, ischemic heart disease, and cancer.

However, understanding the cell distribution, migration behaviors, and functionality post-engraftment remains challenging due to the absence of effective in vivo tracing methods. This lack impedes the clinical progress of stem cell therapies.

To overcome this hurdle, it is crucial to develop advanced imaging strategies that can label and track transplanted stem cells without disrupting their normal functions. These strategies are necessary to uncover therapeutic mechanisms and assess safety before clinical trials.

Imaging techniques suited for stem cells should prioritize non-toxicity, high resolution, longevity, and the dynamic provision of cell fate information. Over recent years, several bioimaging approaches have emerged.

One particularly promising tactic involves leveraging well-designed nanoparticles as contrast agents to monitor stem cells. These nanoparticles boast unique physicochemical properties and offer versatility and customizability.

However, existing imaging methods still fall short of meeting all the necessary in vivo stem cell tracking demands.

This article provides a concise examination of the four commonly utilized nanoparticle-based imaging techniques for the tracking of stem cells: magnetic resonance imaging (MRI), fluorescence imaging, ultrasound imaging (USI), and photoacoustic imaging (PAI) (Figure 1).

Emphasis is placed on the design of contrast nanoagents, the corresponding imaging mechanisms, and the specific challenges these nanoagents have addressed.

The objective is to illuminate potential pathways for future advancements in contrast agent development, aiming to create more sophisticated solutions for the in vivo tracking of transplanted stem cells.

Figure 1.Various contract nanoagents designed for magnetic resonance imaging, fluorescence imaging, ultrasound imaging, and photoacoustic imaging modalities in stem cell trackingin vivo.Image Credit:Merck

The preferred method for in vivo stem cell imaging is MRI, owing to its distinctive attributes such as unrestricted penetration depth, exceptional spatial (ranging from 40 to 100 m), and temporal (ranging from minutes to hours) resolution, and safe operational nature.1

MRI operates in two main categories: T1/T1* and T2/T2*-weighted MRI. These categories are determined by the relaxation time of the longitudinal (T1) and transverse (T2) components of the magnetization vector towards equilibrium below the applied magnetic field.

MRI contrast agents, such as gadolinium (III) chelates and superparamagnetic iron oxide nanoparticles (SIONPs), are introduced to heighten resolution and amplify signal intensity by influencing the relaxation times of nearby water protons.2

Gadolinium (III) chelates are efficient T1 contrast agents as they accelerate the longitudinal relaxation rate (T1), thereby enhancing positive contrast in T1-weighted MRI sequences.

SIONPs function as T2 contrast agents and have found widespread application in MRI-based cell tracking by producing negative contrast through the reduction of T2/T2* relaxation times.

The subsequent section reviews nanoparticle-based contrast agents that have demonstrated clinical or commercial validation for their utility in stem cell tracking applications.

Nanoparticle-based stem cell labeling agents necessitate specific criteria: colloidal stability, non-toxicity, strong magnetism, and efficient labeling. Achieving colloidal stability in aqueous solutions typically involves utilizing hydrophilic polymer coatings like chitosan, dextran, and PEG, among others.

A preclinical study by Margarita Gutova et al. demonstrated the transplantation of neural stem cells (NSCs) labeled with dextran-coated ferumoxytol (FDA-approved SIONPs) into patients with brain tumors.3 The distribution of NSCs was consistently monitored over 12 weeks at various intervals, followed by surveillance serial MRI scans.3

Enhanced labeling efficiency can be achieved by modifying particle surfaces to carry a positive charge or specific ligands.

For instance, compared to ferumoxytol, self-assembling ferumoxytol nano-complexes altered with heparin and protamine sulfatewhich reversed the original particle's negative chargeexhibited increased labeling efficiency and a threefold rise in T2 relaxivity.

This modification approach demonstrated in vivo MRI detection of a minimum of 1000 HPF-labeled cells implanted within rat brains.4

Clinically approved Gd-DTPA enclosed within cationic liposomes ensured highly efficient uptake of Gd and exceptional intracellular retention in mesenchymal stem cells.

The Gd-DTPA-liposomes complex contrast agent rendered 500000 labeled stem cells distinctly visible for a minimum of two weeks on a 3.0 T clinical scanner, effectively overcoming the relatively low MRI sensitivity of Gd-DTPA.5

Monitoring the migration and survival of stem cells is crucial for both therapeutic efficacy and safety evaluations.

For investigating stem cell migration, Lili Jiang et al. observed that T2*-weighted MRI successfully tracked the migration of implanted pluripotent stem cells labeled with SIONPs (from Merck KGaA, Darmstadt, Germany) from the injection site to the injured brain areas for more than four weeks.6

In assessing cell survival, Ashok J. Theruvath et al. observed significant changes in ferumoxytol-labeled apoptotic matrix-associated stem cell implants (MASIs), indicating a substantial loss of iron signals and an extended T2 relaxation time, which persisted up to two weeks post-implantation during a cartilage repair process.7

When coupled with histopathologic examination, a ferumoxytol-based contrast agent could serve as an indicator distinguishing between living and deceased stem cells.

The duration for tracking stem cells varies depending on specific tissues, organs, and diseases, spanning from several days to months. An effective strategy for in vivo stem cell tracking involves evaluating cell distribution, migration, and differentiation, as well as assessing the efficacy and safety of cell implantation.

Despite the rapid advancements in nanoparticle-based MRI for stem cell tracking, certain challenges persist. These include imaging the differentiation and functionality of stem cells, integrating MRI contrast agents with reporter genes, and combining MRI with other noninvasive imaging tools.

Fluorescence imaging, a traditional optical imaging method, is affordable and highly sensitive, but its effectiveness is limited by poor tissue penetration (<1 cm) in comparison to MRI technology.

One potential solution involves fine-tuning fluorophores or fluorescent proteins to be responsive within the near-infrared (NIR) range, enabling deeper tissue penetration. However, challenges like severe photo-bleaching and light scattering restrict tracking efficiency and duration.8

The evolution of fluorescent nanoparticles (NPs) has significantly enhanced the capability of fluorescent imaging for long-term stem cell tracing in vivo.

Quantum dots (QDs), a set of classic inorganic semiconductor NPs used for cell labeling,9 rely on the transition behaviors of excited electrons across various energy levels. These transitions can be adjusted by manipulating material components or compositions, enabling the realization of NIR emission.

For instance, CdSe/ZnS core/shell structures were developed specifically to label and track adipose tissue-derived stem cells (ASCs) in C57BL/6 mice models using NIR emission.10

Modifying the bandgap of materials significantly enhances the optical properties of QDs.11

Wang et al. coupled NIR-II fluorescence QDs of Ag2S with the traditional bioluminescence red firefly luciferase (RFLuc) to label human mesenchymal stem cells (hMSCs).

Using a wide spectrum spanning from 400 to 1700 nm, the researchers investigated the dynamic tracking of survival and osteogenic differentiation of the transplanted hMSCs in a mouse model with calvarial defects.12

Up-conversion nanoparticles (UCNPs) have also been employed to label and track mouse MSCs. UCNPs utilize the anti-Stokes process, absorbing multiple NIR photons to generate a single short-wavelength photon.13,14

Despite this, rare earth metal ions doped in UCNPs and heavy metal ions in QDs pose potential safety risks for tracing clinical stem cells. Aggregation-induced emission (AIE) fluorophores offer a secure method to track stem cells, boasting excellent photostability in comparison to inorganic NPs.15-18

AIE fluorophores remain non-emissive when dispersed but emit robust fluorescence when in an aggregated state due to limited intramolecular rotation, unlike aggregation caused by quenching (ACQ). This unique property makes Dots or AIE NPs present enduring and robust fluorescent signals.

For example, AIE Dots derived from tetraphenyl ethylene have demonstrated the ability to trace the journey of adipose-derived stem cells (ADSCs) over an extended period, outperforming green fluorescent proteins (FPs) and other bioluminescent molecules.18

It is also easy to adjust the AIE monomer for NIR or even NIR-II emission. The advancement of AIE Dots is an encouraging option for in vivo stem cell tracking, offering prolonged stability and reliability.

Due to its remarkable temporal and spatial resolution and substantial tissue penetration depth, ultrasound imaging stands as a potent method for noninvasive and long-term cell tracking in stem cell therapies.19

However, its effectiveness is hindered by the limited contrast between implanted cells and neighboring soft tissues. To address this, ultrasound contrast agents (UCAs), a type of echogenic material, are deployed in clinical settings to enhance contrast and amplify detection signals.20

Traditional UCAs are micro-sized gas-filled bubbles, made of a bioinert heavy gas enveloped by stabilizing shells like proteins, lipids, and biocompatible polymers.21 The potential of these microbubbles for tracking stem cells is curbed by their inadequate structural stability, big microscale size, and short half-life.

Recent research has directed its attention toward scaling down UCAs, leading to the development of nanoscale UCAs such as nanobubbles, silica nanoparticles, and nanotubes tailored for ultrasound imaging.22

Achieving stability in the shell structure is crucial for nanobubbles. Leon et al. described a highly stable nanobubble type by employing a bilayer shell design with varying elastic properties akin to bacterial cell envelopes.23

These ultrastable nanobubbles exhibit minimal signal loss under continuous ultrasound exposure in vitro and boast a prolonged lifespan when tested in vivo. However, due to their small size, nanobubbles might lack sufficient ability to efficiently scatter ultrasonic waves.

To address this, a "small to large" transformation approach has been proposed. This strategy involves nanoscale UCAs transforming into microbubbles upon exposure to ultrasound, thereby amplifying the resulting echo signals.24 Gas-generating nanoparticles exemplify this concept.25,26

Min et al. reported a carbonate copolymer nanoparticle featuring a distinctive gas-generating mechanism. These nanoparticles undergo hydrolysis, yielding microscale CO2 bubbles that effectively absorb ultrasonic energy.27

Silica nanoparticles and similar glass-based nanomaterials significantly boost ultrasound signals due to tissue irregularities caused by the rigid characteristics of these nanoparticles, creating high impedance differences at tissue interfaces.28

Chen et al. detailed an innovative exosome-like silica (ELS) nanoparticle with high ultrasound impedance mismatches designed specifically for stem cell labeling and tracking using ultrasound.29

The researchers found that the nanoparticles' discoid shape, coupled with a positive charge, facilitated cellular uptake, and inherently heightened echogenicity. Silica nanoparticles with varied structures, like hollow and mesoporous configurations, also exhibited substantial ultrasound contrast.30

These silica-based nanoparticles show promise as UCAs for real-time stem cell tracking through ultrasound imaging due to their relatively robust structural integrity, low toxicity, and adaptable size and structure.

Biosafety and precise imaging are crucial for tracking cells in vivo over extended periods. PAI emerges as a promising biomedical imaging technique, based on the principle of the photoacoustic effect.

When a pulsed laser is introduced, it generates heat. The intermittent heat results in expansion, which is identified by PAI as a mechanical wave. This imaging method couples the strong contrast of optical imaging with the deep tissue penetration capabilities of ultrasonic imaging, offering real-time and high-resolution data in vivo.

PAI contrast nano agents are extensively used in vivo for imaging stem cells due to their exceptional capacity for photothermal conversion and the nanoparticles' biocompatibility

Various PAI contrast nano agents have been developed to absorb light across a spectrum, stretching from visible light to the NIR II region. This aims to minimize light absorbance and scattering within tissues.

Tracking methods that solely provide physical information, such as the whereabouts of labeled stem cells, do not meet the demands of studying stem cell engraftment. There is a pressing need for new platforms that can indicate real-time cell function and viability, crucial for clinical applications.

By focusing on the design of contrast nanoagents, new studies of PAI-based stem cell tracking were outlined in the following aspects: shape, component, size, and surface modification, shedding light on the essential factors that require consideration in the design of PAI contrast agents (Table 1).

Gold nanoparticles stand out among the various PAI contrast agents due to their notable advantages, including outstanding photothermal conversion efficiency, stable imaging capabilities, and high biosafety. The inert feature of gold nanoparticles has little effect on cell function.32

The Suggs group employed gold nanospheres of different sizes (20 nm, 40 nm, and 60 nm) in vivo to label and monitor MSCs.33

This study demonstrated the possibility of loading gold nanoparticles into MSCs for imaging purposes while preserving cell functionality post-loading. The research showed that gold nanoparticles remained detectable within stem cells for up to fourteen days, highlighting the potential for long-term and noninvasive cell tracking via PAI.

Anisotropic gold nanoparticles exhibit superior photothermal conversion efficiency. Jokerst et al. highlighted that applying a silica coating notably boosted the uptake rate of gold nanorods into stem cells by up to five times, achieving a minimum detection limit of 100000 labeled cells in vivo.34

The intricate transplant microenvironment in vivo poses challenges. Ricles et al. utilized a dual gold nanoparticle system, comprising gold nanorods and gold nanospheres, to track transplanted stem cells and image infiltrated macrophages.35

These studies introduced a novel approach to differentiate delivered stem cells from infiltrating immune cells, offering insights into the mechanisms of injury healing. Researchers also combined PAI with other imaging techniques to enhance tracking accuracy.

Nam et al. merged PAI with ultrasound imaging to monitor MSCs labeled with citrate-stabilized gold nanospheres.36 This combined approach offered both morphological insights through ultrasound imaging and functional information via photoacoustic imaging, allowing for spatial visualization of labeled MSCs.

Qiao et al. employed magnetic resonance and PAI techniques to track iron oxide (IO)@Au core-shell structure-labeled MSCs for imaging brain tumors.

This system exhibited potential for mapping cell trajectories and visualizing stem cell migration toward brain tumors in real time.37 Additionally, nanoparticles with NIR absorption capabilities were developed for stem cell tracking via PAI due to the superior penetration depth of NIR light.

Kim et al. utilized Prussian blue nanoparticles with robust light absorption at 740 nm for tracking stem cells.38

In vivo, these nanoagents demonstrated detection limits of 200 cells/L, enabling monitoring for up to fourteen days post-injection, attributed to the excellent bio-stability and NIR-I detectability. Yin et al. developed a NIR-II organic semiconductor polymer specifically for stem cell tracking via PAI.39

The researchers observed a significant 40.6-fold and 21.7-fold enhancement in subcutaneous and brain imaging, respectively, primarily due to the deep tissue penetration of NIR-II light.

To monitor stem cell activity post-transplantation, Dhada et al. engineered a ROS-sensitive dye (R775c) coated onto gold nanorods.

The strategy leveraged the fact that stem cells release ROS to degrade dying cells in vivo, enabling the measurement of stem cell viability. Consequently, they could simultaneously visualize cell viability and location in vivo using PAI.40

Table 1.The design of nanoparticle-based contrast agents for PAI.Source:Merck

Table 2. Comparison of different imaging modalities. Source:Merck

Nano agents offer key advantages over organic molecules in PAI imaging, primarily in terms of photostability, water solubility, and biocompatibility.

The limitations of PAI hinge on the penetration depth and photothermal conversion efficiency of contrast nano agents. Therefore, future advancements in PAI imaging are likely to focus on developing nanomaterials with enhanced NIR-II responsiveness and improved biocompatibility.

Advancing stem cell-based therapies heavily relies on the progress of stem cell tracking techniques. Current imaging technologies present both strengths and limitations (Table 2).

Consequently, the choice of imaging modalities depends on specific tissue requirements and imaging depth.

A range of nanoparticles, including iron oxide nanoparticles, quantum dots, aggregative-induced emission nanoparticles, silica nanoparticles, and gold nanoparticles, have been employed for stem cell tracing due to their distinct physical-chemical properties. These properties enhance imaging signals upon irradiation.

By elaborately designing the structures and compositions, nanoparticles play a pivotal role in improving the performance of existing imaging modalities concerning imaging resolution, stability, and lifespan. However, tracking stem cells in vivo remains a significant challenge in the biomedical field.

The amplitude of the image signal typically correlates linearly with contrast nanoagent concentration, but as contrast agents within cells dilute through cell division, challenges arise. This fuels the necessity for a new generation of contrast agents that resist dilution or prompt cells to self-synthesize these agents, addressing this issue.

Additionally, apart from cell division, studies indicate that nanoparticle levels within cells achieve equilibrium via endocytosis and exocytosis, potentially leading to false positive detections in vivo.

Moreover, few contrast agents can capture a cell's live state and normal functional abilities, severely limiting the exploration of stem cell therapy mechanisms. Therefore, concerted efforts are crucial to design multifunctional contrast agents that address these concerns.

Lastly, the advancement of both imaging devices (the "hardware") and imaging contrast agents (the "software") is urgently needed. This development aims to enable precise, long-term, and dynamic tracking of transplanted stem cells, a critical aspect of the field.

This information has been sourced, reviewed, and adapted from materials provided by Merck.

For more information on this source, please visit Merck.

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Enhancing Stem Cell Tracking with Nanoparticle Imaging Agents - AZoNano

1st-of-its-kind therapy blocks immune attack after stem-cell transplant – Livescience.com

A new treatment may be able to prevent a common immune-related complication of lifesaving bone-marrow transplants, a midstage clinical trial shows.

In patients with blood cancer, high doses of chemotherapy or radiation therapy are used to kill the cancerous cells, but these treatments also damage the patients' healthy, blood-forming stem cells. To rectify this, doctors may perform a type of bone-marrow transplant known as an allogeneic hematopoietic stem cell transplant (HSCT), in which blood-forming stem cells from a healthy donor are transplanted into the cancer patient.

But there's a potential catch: Immune cells in the donor's tissue can sometimes attack the recipient's tissue, because the cells see it as foreign. A short-term form of this condition, called graft-versus-host disease (GVHD), affects around 40% of bone-marrow transplant patients, while different studies estimate that between 6% and 80% develop a chronic form of GVHD.

There are ways to reduce a patient's risk of this reaction, for example, by prescribing immune-suppressing drugs, but this reduces their ability to fight pathogens. There are also treatments that target a type of immune cell called T cells in the donor tissue. Although these therapies can be effective, they may come with an increased risk of cancer relapse or infection, the scientists behind the new trial wrote in a study published Jan. 4 in the journal Blood.

Related: Zika virus could potentially treat cancer, another early study hints

In contrast, the new treatment, called CD24Fc, derails the immune response at an earlier stage, by inhibiting the response of the cells responsible for activating T cells.

Specifically, the treatment prevents so-called antigen-presenting cells from activating donor T cells that would go on to attack the cancer patient's cells that have been damaged by radiation and chemotherapy before transplantation. These antigen-presenting cells can differentiate between the damaged host cells and pathogens, such as viruses, so CD24Fc only quietens the unwanted inflammation tied to GVHD and not other, helpful immune activity. As such, CD24Fc has also been trialed as a treatment for other conditions that are exacerbated by an off-the-rails immune response to tissue damage, such as severe COVID-19.

"The molecular targets of the intervention are new and original," Dr. Ivan Maillard, a professor of medicine at the University of Pennsylvania who was not involved in the research, told Live Science in an email. CD24Fc kicks in right as the body senses the tissue damage associated with the transplant procedure, rather than later on, he said.

The new trial included 26 patients with blood cancer who received three doses of CD24Fc in the month before they underwent an allogeneic HSCT. They also received the standard, post-transplant immunosuppressive treatment. Of these patients, only one developed moderate-to-severe GVHD within six months of their surgery.

The researchers cross-referenced the trial participants' data to that of 92 patients who underwent the same procedure but without CD24Fc. These patients' results were pulled from a database, and 68 of the patients, or 74%, developed GVHD within six months.

Related: 'Bionic breast' could restore sensation for cancer survivors

The trial's results are "impressive," Dr. Javier Bolaos Meade, a professor of oncology at Johns Hopkins Medicine who was not involved in the research, told Live Science in an email. However, after a year, the researchers found no significant difference in overall survival rates, risk of chronic GVHD, or relapse rates between the two groups, which was "disappointing," he said.

CD24Fc caused minimal side effects in most patients, the authors wrote in the paper. However, two of the 26 patients developed a rare-but-serious skin disorder called Stevens-Johnson syndrome, which is normally caused by an adverse immune reaction to certain medications.

"Whether this rare complication was related to administration of CD24Fc cannot be excluded and will require careful monitoring and evaluation in future trials," Dr. Paul Martin, a professor emeritus of clinical research at the Fred Hutchinson Cancer Center in Seattle who was not involved in the research, wrote in a commentary accompanying the study.

The authors highlighted several limitations of the study, including that it was small and that the conclusions about CD24Fc's effectiveness stem from comparisons to historic data, rather than to a typical control group you'd expect in a gold-standard trial. This may have skewed the reliability of the findings for several reasons; for instance, the trial patients and historic patients may have differed from each other in key ways that weren't flagged or accounted for.

Nevertheless, Bolaos Meade and Maillard anticipate that there will be more studies testing this approach to GVHD prevention, which could provide more robust data about its effectiveness.

This article is for informational purposes only and is not meant to offer medical advice.

Ever wonder why some people build muscle more easily than others or why freckles come out in the sun? Send us your questions about how the human body works to community@livescience.com with the subject line "Health Desk Q," and you may see your question answered on the website!

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Oral Stem Cells Genome Map Revolutionizes Regenerative Medicine – Mirage News

Cambridge, Mass., Jan. 16, 2024 - A team of researchers from the ADA Forsyth Institute and University of North Carolina (UNC), Chapel Hill used single-cell transcriptomic analysis to successfully map dental pulp stem cells (DPSC) and periodontal ligament stem cells (PDLSC) and found remarkable differences between them. The study, which appeared in the Journal of Dental Research, provides the most detailed analysis of these stem cells to date, identifying the entire genome of the stem cells and their potential differentiation trajectories.

"Dental pulp and periodontal ligament stem cells both have the potential to develop into any type of cell in the body," explained ADA Forsyth Scientist, Alpdogan Kantarci, DDS, MSc, PhD who led the study with UNC biostatistician, Di Wu, PhD. "We wanted to discover how they were different and whether there were differences in their capacity to differentiate into other cell types."

The team discovered that both types of stem cells have seven different gene clusters, with different categories of genes reflecting different stages in the process of differentiation. Four of those gene clusters were similar when comparing the two types of stem cells. Three of the clusters were uniquely different. While PDLSC's were more like fibroblasts (cells that can become connective tissue) because of an increased proportion of certain clusters, DPSCs had higher differentiation potential and converted more easily into bone cells.

"This new information on the specific genetic composition and mechanisms of differentiation in dental pulp and periodontal ligament stem cells will generate a new era of work in regenerative medicine" said Dr. Kantarci. "We could potentially select a stem cell based on its distinct properties to create targeted regenerative dental tissue repair and other regenerative therapies."

ADA Forsyth scientists obtained the stem cells from extracted teeth without culturing them (unlike other studies of these stem cells) and sent them unfrozen to UNC for single-cell transcriptomic analysis. Meanwhile, they also took the same cells and differentiated them into known cell types such as fibroblasts (cells that can become connective tissue) and osteoblasts (bone cells). The team then used advanced bioinformatics to compare and document the capacity of the two populations of stem cells to differentiate into osteoblasts or fibroblasts. The results of the bulk RNA sequencing validated the findings of the single-cell transcriptomics.

"Prior to this study, people believed that stem cells were either very similar to each other, or very different from one another," said Dr. Kantarci. "Now we have enough information to see the huge potential for using specific features of these stem cells to create more effective and targeted regenerative therapies."

Additional collaborators on the project included T. Van Dyke, H. Hasturk, and Y.C. Wu of ADA Forsyth; Y. Yang, T. Alvarez, M.Z. Miao and G. Li of UNC Chapel Hill; and, J. Lou of University of Washington, Seattle.

Funding:

This work was funded by NIH/NIA (AG062496) and NIH/NIDCR (DE025020) grants, and the University of North Carolina Computation Medicine Program Award 2020. T. Alves holds a J. William Fulbright Scholarship (CAPESfinance code 001). M.Z. Miao is supported by the Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research ZIA DE000719 and ZIE DE000727.

Paper cited:

"Single-Cell Transcriptomic Analysis of Dental Pulp and Periodontal Ligament Stem Cells," Journal of Dental Research. DOI: 10.1177/00220345231205283

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Oral Stem Cells Genome Map Revolutionizes Regenerative Medicine - Mirage News

Cancer Mutations in 22% of Stem Cells: Concern for Regenerative Medicine – BNN Breaking

Cancer-Related Mutations Found in 22% of Human Pluripotent Stem Cells: A Cause for Concern in Regenerative Medicine

A recent study conducted by the Hebrew University of Jerusalem has raised significant concerns in the rapidly evolving field of regenerative medicine. The study, focusing on human pluripotent stem cells (hPSCs)known for their capacity to self-renew and differentiate into various human cell typeshas unearthed a disturbing revelation. A staggering 22% of hPSC samples were found to carry at least one cancer-related mutation. These cells, despite their remarkable potential for tissue regeneration, disease modeling, and drug discovery, might harbor hidden dangers.

The majority of these mutations, accounting for approximately 70%, were discovered to be acquired during cell propagation in culture. This finding emphasizes the need for increased vigilance in the use of stem cell derivatives in both research and clinical applications. It underscores the importance of regular evaluations of cell cultures to ensure accurate conclusions and safe therapeutic practices.

The research was led by Prof. Nissim Benvenistys laboratory at the Azrieli Center for Stem Cell and Genetic Research. The team used a bioinformatic algorithm to analyze over 2,200 samples from more than 140 different hPSC lines. The study, published in the esteemed Nature Biotechnology, found that the most common mutation was in the P53 gene, a well-known tumor suppressor.

The high prevalence of mutations poses a serious challenge to the safety standards in research and clinical applications. Moreover, these mutations affect not only the growth advantage in culture but also influence the cell fate transition during differentiation. This raises considerable concerns for the future direction of the field, particularly in clinical settings. The findings of the study merit urgent attention and pave the way for more comprehensive safety protocols in regenerative medicine.

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Cancer Mutations in 22% of Stem Cells: Concern for Regenerative Medicine - BNN Breaking

Opinion | A Rejected A.L.S. Drug Made Me Rethink the Role of Hope in Medicine – The New York Times

Of all the ways the body can go wrong, A.L.S. is one of the most frightening. It begins subtly a twitching muscle, a cough when you swallow or a clumsy hand. But then it progresses. Motor neurons degenerate and die. You lose the ability to talk, to eat and ultimately to breathe. There is no cure. Treatment will slow progression somewhat, but not enough.

A diagnosis of A.L.S., or amyotrophic lateral sclerosis, begins a race against the clock. What do you do to make yourself heard before you are rendered voiceless? How do you find a trial or a treatment to extend time long enough to be there for the next scientific advance?

I rarely have time to probe the answers to these questions when I take care of people with A.L.S. in the intensive care unit or long-term hospital ward. But the faces stay with me. I remember a woman who just wanted to go to the beach once more, to eat a lobster roll before she could no longer swallow. I remember a young man with an elaborate sound system in his hospital room whose wife had left him; there was no one to take care of him at home, and so he would live out his days in a nursing facility.

In contrast to the experience of those with cancer, for whom there is often the promise of a new drug around the bend, there are relatively few therapies for A.L.S. Perhaps that is why I became so interested recently in the vigorous debate over the possible approval by the Food and Drug Administration of a new treatment for A.L.S.: a stem cell therapy called NurOwn developed by BrainStorm Cell Therapeutics. Some patients who had early access to the drug described improvement like being able to pick up a remote control for the first time in months or being able to walk through the grass.

But the data did not bear out these experiences. Ultimately, the F.D.A. advisory committee that evaluated NurOwn recommended against approving the therapy, a decision that devastated many A.L.S. patients and their family members.

This is the latest in a sequence of controversial drug approval decisions from Alzheimers to muscular dystrophy that see educated and impassioned patient advocates pleading their case before regulatory authorities. These debates extend beyond the quality of scientific evidence. The decision of whether to approve a drug for a lethal disease gets to complex, deeply human questions. How far do you go when the alternative is certain death? What level of proof is good enough, and who gets to decide? And when someone is facing a terminal illness, what is the cost and benefit of hope, even hope for an outcome that might never be realized?

A few years ago, I began to follow a man named Brian Wallach on social media. It was some time after his A.L.S. diagnosis in 2017, back when his voice was still audible and he could ride his Peloton stationary bicycle. He was around my age, in his late 30s at the time, with a wife and two young daughters. He described his disease, somewhat hopefully, as currently fatal.

After all, when he was diagnosed on the day his newborn daughter came home from the hospital a new drug for A.L.S. had recently been approved. Surely there were more in the pipeline. The first neurologist he saw had told him that he would be dead in six months, and that he should go home and eat whatever he wanted and be with his family. But the specialists he went on to see pointed him in the direction of clinical trials.

Mr. Wallach knew that A.L.S. is a terminal illness. That knowledge was with him every moment of every day. But if there was a hope for a different outcome, he wanted to grab hold of it. So Mr. Wallach and his wife, Sandra Abrevaya, researched the existing data for drugs that had been proven safe and had some evidence of benefit. They knew that no one drug would offer a magic bullet. But perhaps in combination, the available treatments could help slow the progression of Mr. Wallachs A.L.S. enough so that he would still be alive when the next drug became available. There was no time to wait.

They drew on their skills and connections Mr. Wallach is a lawyer while Ms. Abrevaya has headed nonprofit organizations, and both worked in the Obama White House to build what has been described as the most successful patient advocacy campaign in decades. They catalyzed new research, helped pass a bill to allocate millions in federal money to A.L.S. studies and improved access to promising investigational drugs for patients who are not eligible for clinical trials. (The nonprofit that Mr. Wallach and Ms. Abrevaya founded, I AM ALS, provided a $100,000 grant to BrainStorm for its research into NurOwn.) Mr. Wallach would be among the first generation to survive A.L.S., he wrote on the social media platform X.

I want to believe this. Though he is nearly completely paralyzed and his voice is so weak that his wife serves as his translator, he is alive six years after his diagnosis, still breathing on his own. That itself is remarkable.

And yet as doctors particularly those of us working in places like the I.C.U. we are trained to tread cautiously when it comes to hope. We applaud families for being realistic, which generally means that they do not ask for outcomes we consider to be impossible. We guard carefully against what we think of as false hope or hope for an outcome that we believe cannot come to pass. If hope even false hope is a kind of medicine, it is not one that we are comfortable with.

That said, maybe hope despite long odds is not always the worst thing, especially when the alternative is no hope at all. For many A.L.S. patients, that is what NurOwn represented. According to BrainStorm, the treatment involves stem cells harvested from patients bone marrow and engineered in a lab to prevent nerve damage and cell death associated with A.L.S. Those cells are then given back to the patients through injections into the spine. The science was exciting, the early data promising.

But the data from the companys largest trial, enrolling nearly 200 patients, were negative the treatment was no better than placebo in the full patient population. Further analyses suggested those with a milder form of A.L.S. may benefit, but the subgroup population was small and these improvements fell short of consistently meeting the bar of statistical significance.

Patients offered impassioned testimony, describing how NurOwn had given them back a bit of their autonomy and stilled the relentless pace of this disease. The drug would not work for everyone. But for patients facing certain death, the idea that it might help some of them was enough, even if that had not been borne out in a rigorous scientific study.

Unconvinced, and despite the F.D.A.s promise to be more flexible when it comes to approving drugs for fatal diseases, the advisory committee nearly unanimously voted against recommending NurOwn for approval. I cant know if that was the right decision. Maybe a larger trial would have proven NurOwn to be beneficial and maybe not. BrainStorm is now working with the F.D.A. to design another trial. But for patients whose disease is rapidly progressing, now, those results might come too late.

There is a narrative that desperate patients would try anything, and the role of the F.D.A. and the health care system more broadly is to protect those patients against themselves. That is flawed. Mr. Wallach and Ms. Abrevaya are indeed desperate. Their lives have been ravaged by this disease. But their judgment is still intact. Their decisions are not influenced by the nihilism that comes from despair. They simply want the ability to decide for themselves whether to take drugs that might be helpful.

Of course, no one wants the F.D.A. to approve drugs that are useless or, worse still, dangerous. And the F.D.A. has made decisions in recent years that demonstrate a willingness to make available drugs for lethal diseases based on imperfect data, most controversially with the Alzheimers drug Aduhelm, but also with other A.L.S. treatments. But where does this flexibility end? Where do we draw that line?

One worry is that increasing flexibility will mean the F.D.A. is influenced by the loudest voices to put drugs on the market that are expensive and possibly ineffective. But isnt it also dangerous, maybe more so, to be wrong in the other direction to withhold a drug that might actually be beneficial, when the alternative is certain death? The treatments may not cure us, but they have a chance to help us, Mr. Wallach said. And that chance is everything, when you know what is behind door number two.

I thought of this conversation and of the NurOwn debate recently, as I walked through the long-term acute care hospital. I was taking care of a man in his 40s with a debilitating disease that had caused his muscles to shrink and atrophy, leaving him on the ventilator. From the bed, he mouthed to me that he was hoping to try to breathe on his own for at least part of the day. Looking at him, I was fairly sure that would be impossible.

I felt myself start to explain to him how unlikely that outcome was. Surely I should prepare him and guard him against false hope. But then I paused. The time might come for that. But for the moment, we would try.

Daniela Lamas is a contributing Opinion writer and a pulmonary and critical-care physician at Brigham and Womens Hospital in Boston.

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Stem cell technology developed at UWMadison leads to new understanding of Autism risks – University of Wisconsin-Madison

RosetteArrays, developed at UWMadison, grow fields of neural rosettes embroynic versions of down-scaled, simplified brain structures from stem cells, giving scientists the opportunity to study the development of disorders like autism, spina bifida and epilepsy. Image courtesy of Neurosetta

Technology developed at the University of WisconsinMadison to grow rosettes of brain and spinal tissue gives scientists new ways to study the growing human brain, including a recent study of how genetic mutations linked to autism affect early stages of human brain development.

Its the latest discovery using RosetteArray technology, a screening tool that uses stem cells to generate embryonic forebrain or spinal cord tissue structures called neural rosettes. Neural rosettes are the starting material for generating human stem cell-derived neural organoids clusters of cells that resemble larger, more complex organs and can be used to assess whether different genetic makeups or exposure to chemicals increase the risk of neurodevelopmental disruptions.

Randolph Ashton

This technology gives us access to an embryonic model of human central nervous system development that we would otherwise not have access to, says Randolph Ashton, a UWMadison professor of biomedical engineering and associate director of the Stem Cell and Regenerative Medicine Center. This is useful, because not only can we now understand more about human development, but we can get an understanding of when it goes wrong.

Ashton and Gavin Knight, a scientist at the Wisconsin Institute for Discovery who earned his doctorate in Asthons lab, developed the technology behind RosetteArrays, which are marketed by Neurosetta, a company they co-founded with support from UWMadison Discovery to Product and the Wisconsin Alumni Research Foundations (WARF) Accelerator Program.

RosetteArray technology played an important role in a study published recently in Nature Neuroscience. The study, led by University of Southern California stem cell biologist Giorgia Quadrato, with Ashton and Knight as co-authors, investigated mutations of a gene called SYNGAP1.

SYNGAP1 mutations have long been associated with risk factors for autism spectrum disorder, epilepsy, neurodevelopmental disability and more, but until now the gene has mainly been studied in animal models and focued on the impact of SYNGAP1 on synapses, the structure at the tips of long brain cells called neurons that allow them to pass signals to neighboring cells.

In their new SYNGAP1 autism study, Quadrato and her lab used RosetteArray technology to grow neural rosettes from healthy human cells as well as from the cells of a patient with a disease-causing variant in SYNGAP1. By analyzing these young, developing neural organoids, Quadrato determined that human radial glia cells the cells responsible for producing all the neurons in the outer layer of the brain called the cerebral cortex can express SYNGAP1. When SYNGAP1 is mutated, it leads to disrupted organization of the cortical plate, an early brain structure that gives rise to the cerebral cortex. This shows that SYNGAP1-related brain disorders can arise through non-synaptic mechanisms.

Quadrato Lab and Neurosetta plan to partner on further studies to explore the extent of autism spectrum disorder genetic backgrounds that can be modeled using RosetteArray technology, which Ashton hopes will eventually lead to new precision medicine approaches.

Simply being able to model early human development, in this case brain and spinal cord formation, gives you a very powerful platform to try to improve human health, says Ashton. Weve been surprised to see the effects of neurological disease-causing mutations in the earliest stages of these tissues formation. RosetteArrays model approximately four to six weeks post conception, and were learning that you can start to see markers for autism then, which is a disease that people typically arent diagnosed with until post 2 years of age. So, the fact that we can see this very early in our model of human development is amazing.

Ashton says researchers using technologies like the RosetteArray are finding that the risk factors for autism spectrum disorder are boiling down to a couple of core pathways, that seem to have roles very early in human brain development, which is helpful information as researchers work on treatments.

While this paper focused on studying brain tissue, Ashton has used the RosetteArray platform in his own lab to study defects in neural tube formation.

(The neural tube) is a structure that goes from the head of the embryo all the way down through the back of the spinal cord. All brain, spinal cord and eye tissue comes from this neural tube, says Ashton. It so happens that a lot of things can disrupt that process, and if that formation is disrupted early enough, then it causes lots of issues. It can cause congenital birth defects known as neural tube defects, for example spinal bifida, which is when the lower spine doesnt fully close. Or, if you have a failure of closure higher in the neural tube that leads to a failed pregnancy, so understanding this process is crucial.

Ashton and his lab members have been using RosetteArrays to investigate what may be causing spina bifida defects and how they can be mitigated.

There are examples of known chemicals we use in our food supply, pesticides, and anti-cancer drugs that have historically been correlated with causing neural tube defects. So, its important that we have a way to test new chemistries and chemical processes to make sure they dont have these effects on human development, says Ashton. Weve used rodent models but theres a difference between animals and humans. The RosetteArray provides a way to test these chemicals on early human brain and spinal cord development.

The RosetteArray platform may also be used for individualized medicine, as it can be used to screen individual patients cell lines to better understand how mutations in a persons genomic background can lead to a disorder as well as how the interaction between a persons genomic background and the chemicals that theyre exposed to may lead to a health risk.

We think this platform will be highly useful for both commercial applications for screening for chemicals that can cause neurodevelopmental risk, as well as for clinical application, Ashton says. And I think the real power of the tool is for precision medicine and drug discovery.

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Stem cell technology developed at UWMadison leads to new understanding of Autism risks - University of Wisconsin-Madison

Casgevy and Lyfgenia: Two Gene Therapies Approved for Sickle Cell Disease – Yale Medicine

Until recently, the only possible cure for sickle cell disease, an inherited genetic blood disorder most common in people with African ancestry, was a bone marrow transplant, which has its own set of challenges.

Now, people with sickle cell disease (SCD)which affects an estimated 100,000 Americans and can cause chronic pain, organ damage, strokes, and shortened life expectancyhave additional, potentially curative options. In early December, the Food and Drug Administration (FDA) approved two gene therapies for SCD, one of which is the first approved medication that uses the gene-editing tool CRISPR.

Both treatmentsCasgevy, which is made by Vertex Pharmaceuticals and CRISPR Therapeutics, and Lyfgenia, by Bluebird Bioare for people 12 and older. Sickle cell disease is a red blood cell disorder that affects hemoglobin, the protein that carries oxygen throughout the body. These two therapies work in different ways, but both are intended to be a one-time fix, although that will require years of follow-up to know for sure.

With Casgevy, an edit (or cut) is made in a particular gene to reactivate the production of fetal hemoglobin, which dilutes the faulty red blood cells caused by sickle cell disease (more on that below). Lyfgenia, on the other hand, uses a viral envelope to deliver a healthy hemoglobin-producing gene.

The therapies are hailed as groundbreaking as they represent the first-ever gene therapies to potentially cure a hereditary condition.

For many years, we only had one treatment for sickle cell disease, and then medicine advanced to the point where we could offer bone marrow transplant, the first potential cure for sickle cell disease, says Cece Calhoun, MD, MBA, a Yale Medicine hematologist-oncologist. But trying to find a good match for a transplant is a big barrier. This new technology uses gene therapy to allow patients to be their own match.

This is significant, she notes, because a sickle cell crisisthe pain the disease causesis unpredictable and intense, akin to how it feels to have a long bone fracture.

But, says Dr. Calhoun, the pain sickle cell disease causes is not the only problem faced by people with the condition.

Sickle cell disease impacts every organ. Children are having strokes, and young adultspeople in their 30sare experiencing kidney failureall because of sickle cell disease. If we can intervene and prevent these complications and let these patients live full lives, that is huge, Dr. Calhoun says.

Lakshmanan Krishnamurti, MD, chief of Yale Medicine Pediatric Hematology & Oncology, agrees.

Many cant have bone marrow transplantation because only about 15% of patients have a matched sibling, and we can find an unrelated donor for only another 10% to 12%. That means we are only helping 25% of patients, says Dr. Krishnamurti, who was an author on the Lyfgenia study published in The New England Journal of Medicine. This is a big step forward.

However, the gene therapies are time-intensivetaking about a year to complete the processand grueling. As with bone marrow transplants, they require high-dose chemotherapy to kill the faulty stem cells before they are replaced with modified stem cells.

The gene therapies will be available only at large, authorized medical centers because they require advanced care. They are also expensive (estimates put it at $2 to $3 million per patient), and its yet to be determined if or how insurance companies, including Medicaid, will cover the treatment.

Dr. Krishnamurti says both treatments will be available at Yale and that anyone interested in learning more should speak to their physician.

Below, Drs. Calhoun and Krishnamurti answer common questions about sickle cell disease and these new gene therapies.

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Casgevy and Lyfgenia: Two Gene Therapies Approved for Sickle Cell Disease - Yale Medicine

Paralyzed B.C. man has hopes in stem cell treatment for recovery journey – Global News

A paralyzed B.C. man has hopes that stem cell treatment will help him regain sensation and movement in his body.

On July 21, 2021, Cameron Thompson, 25, was swimming at Puntledge River in Courtenay, B.C., on Vancouver Island. He dove into the water head first and ended up severing his spinal cord.

That day when I dove into the water, I knew instantly that I had become paralyzed, he told Global News.

I just thought, I dont want to choke on water so I just held my breath thinking I would hold it until I passed out.

Thompsons friends then were able to pull him out of the water and called 911.

I remember everything until I got into the ambulance, he said. And then I woke up the next day in Vancouver.

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Thompson had lost the majority of the functions of his body, except partial movement to his shoulders and arms.

Super thankful for my friends without them I would have floated down the river, Thompson said.

The Thompson family has created an online fundraiser, hoping to raise $50,000 for stem cell treatment at BioXcellerator.

According to BioXcellerator, the company is recognized as a global leader in treating a wide range of conditions based on 25 years of clinically-based research with stem cell therapy.

2:00 B.C. communities rank high on list of Canadas most generous cities

With the stem cell treatment, Thompson hopes to reduce his nerve pain which will boost his immune system and could help him regain sensation and movement in his body.

Thomson said his recovery journey so far has been a tough road to travel but he has not let the injury affect his mindset and outlook on life.

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I have the same outlook on life I have hard days thinking about what life could have been. But, day by day, things get easier. I understand there will always be struggles with life. Other people have it worse so you just deal with what you got, he said.

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In terms of a possible future career, Thompson said he is focusing on investments and the stock markets.

I want other people that have spinal injuries to know there are things that can help them and there are people that understand what they are going through, Thompson said.

Reaching out and talking can make a really big difference.

Global News spoke with Camerons mother who said the road has been tough, but she is very hopeful for the stem cell treatment.

Even if it partly works, it will be amazing, said Christina Thompson

Its a blessing. The fundraiser is just for the treatment. If we could raise the money it would be a godsend.

She said none of the costs would be covered by the government.

1:42 Friends and family set up fundraiser for Pitt Meadows boy killed in crash

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Stem cell study reveals how infantile cystinosis causes kidney failure and how to cure it – EurekAlert

image:

This image, produced by a fluorescence microscope,shows a normal renal proximal tubule, the specific nephron segment in the kidney that is impaired in the rare disease infantile cystinosis. The red, green and yellow regions indicate the presence of different proteins in the tubule and the blue indicates the presence of nuclei. The UB researchers generated the tubule in the image from stem cells derived from an individual who does not have the disease.

Credit: Alexandra Kojac

BUFFALO, N.Y. University at Buffalo research has identified how a misstep in the genesis of a key component of the kidney causes infantile cystinosis, a rare disease that significantly shortens the lifespan of patients. Published Nov. 30 in theInternational Journal of Molecular Sciences, the work reveals that the mechanisms that cause the disease could be addressed and potentially cured through the genome-editing technique CRISPR. That could make kidney transplants, the most effective treatment currently available for these patients, unnecessary.

Infantile cystinosis, the most common and most severe type of cystinosis, occurs as the result of an accumulation in the bodys cells of cystine, an amino acid. The buildup damages cells throughout the body, especially the kidneys and the eyes. Treatment consists of medications that work to lower the level of cystine in the body, as well as therapies that address the impaired growth of these children due to the inability to properly absorb nutrients. Some children require feeding tubes. Eventually, patients with infantile cystinosis, also called nephropathic cystinosis, will require dialysis and a kidney transplant.

Promise of stem cells

Human-induced pluripotent stem cells (hiPSCs) are stem cells that can differentiate into many different cell types. They hold tremendous potential for studying genetic diseases; the drawback has been that differentiation into certain cell types has been problematic. Such is the case with many cell types found in the kidney.

But a new protocol developed by this research team was successful.

When our normal human-induced pluripotent stem cells were subjected to the differentiation protocol we developed, we were able to demonstrate extensive expression of physiologically important markers of the renal proximal tubule, the specific nephron segment that is altered in this disease, saysMary L. Taub, PhD, senior author on the paper and professor of biochemistry in the Jacobs School of Medicine and Biomedical Sciences at UB.

Ramkumar Thiyagarajan, PhD, assistant professor of geriatric studies at the University of Kansas and formerly a postdoctoral fellow at UB, is first author on the paper.

The protocol involved extracting stem cells from a healthy individual and an individual with infantile cystinosis. The researchers developed a culture medium to grow stem cells that included a small number of defined components present in blood, including insulin, specific proteins, growth factors and others. Conducting the differentiation protocol under these conditions occurred in a timely manner, says Taub, we didnt have to wait for weeks on end, and it occurred in a reproducible manner.

The researchers were able to efficiently differentiate the hiPSCs into the kidney proximal tubule, the type of nephron in the kidney that is impaired in infantile cystinosis, as well as in other kidney diseases.

Unlike in other studies, we were able to retain a number of markers in the tubule that are physiologically important in the kidneys reabsorptive functions, says Taub. Although these markers were expressed in both the normal and the cystinosis-derived hiPSCs, the genesis of the tubule was impaired in the cystinosis-derived cells, mimicking what happens in infantile cystinosis.

A potential cure

That finding means that the CRISPR genome-editing technique could be used to repair the defective genome and potentially cure the disease. The normal gene can be introduced in the genome of cystinotic hiPSCs, which can then be injected in the kidney to replace the defective proximal tubules of individuals with infantile cystinosis, Taub says.

In cystinotic individuals, it is the renal proximal tubule that degenerates, presumably due to programmed cell death, explains Taub, so the entire kidney would not need to be replaced. The defective renal proximal tubules of individuals with this disease can be replaced with normal tubules following the introduction of the normal gene into cystinotic hiPSCs obtained from the patient. And because these tubules are from cells derived from the patient, there should be no problem with tissue rejection.

The findings are applicable to other kidney diseases where the renal proximal tubule is damaged, including acute kidney injury that can lead to chronic kidney disease and renal failure, and can be fatal.

Initial studies will need to be conducted with animal models as well as with in vitro tissue culture cells.

The research was funded byUBs WNYSTEM and The Cystinosis Research Foundation.

International Journal of Molecular Sciences

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Orca-Q Demonstrates Early Efficacy, Tolerable Safety in Haploidentical Stem Cell Transplant Without PTCy – Targeted Oncology

Bone marrow: 7activestudio - stock.adobe.com

The high-precision cellular product Orca-Q showcased early signals of clinical activity and an acceptable safety profile in patients receiving a haploidentical stem cell transplantation (haplo-SCT) without posttransplant cyclophosphamide (PTCy), according to findings from a phase 1 trial (NCT03802695) presented during the 2023 ASH Annual Meeting.1

Results showed that both the graft-vs-host disease (GVHD) relapse-free survival (GRFS) rate and overall survival (OS) rate at 1 year was 82% (95% CI, 65%-94%) with Orca-Q. This is in comparison to historical data with conventional PTCy for haplo-SCT, with recent 1-year GRFS rates of 46%.

These findings show promising safety and efficacy outcomes using Orca-Q cell therapy for haploidentical transplant, said Samer A. Srour, MB ChB, MS, lead study author and assistant professor in the Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center in Houston, in an oral presentation during the meeting. No safety signals in this haploidentical setting were identified.

Standard allogeneic SCT can be a curative approach for patients across many high-risk hematologic cancers, although access to this therapy was previously limited to those who have a fully matched donor. The introduction of PTCy as prophylaxis for GVHD increased the utility of haploidentical donors; however, it has also increased relapse rates and toxicity issues such as cytokine release syndrome (CRS), delayed engraftment and T-cell reconstitution, mucositis, infections, cardiac events, and non-relapse mortality, Srour added.

However, GRFS rates in this patient population remain low. Through allograft optimization, Orca-Q improves haplo-SCT with its fully defined stem and immune cells, which consist of hematopoietic stem and progenitor cells, invariant natural killer cells, regulatory T cells, and CD4+/CD8+ T-cell subsets.

Orca-Q is derived from granulocyte colony stimulating factor that is mobilized during peripheral blood apheresis and is manufactured centrally at a Current Good Manufacturing Practice Manufacturing Facility in Sacramento, California. Its administration involves a vein-to-vein time of less than 72 hours across the United States, Srour noted, adding that the vein-to-vein time was within 60 hours for most cases on the study.

The multicenter, dose-expansion trial enrolled patients aged 18 to 65 years with the following high-risk hematologic cancers: acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), very high or high-risk myelodysplastic syndrome, or myelofibrosis. Patients were required to be undergoing a haplo-SCT with negative donor-specific antibodies and were eligible for myeloablative chemotherapy with a Hematopoietic Cell Transplantation-specific Comorbidity Index 4 or lower, a Karnofsky performance score of at least 70, and adequate organ function.

Orca-Qs regimen begins with myeloablative conditioning on days -10 to -2, followed only by single-agent tacrolimus on day -1no PTCy or additional immunosuppressive therapies are administered. A fresh Orca-Q infusion is given on day 0, and tacrolimus is tapered on day +60 (posttransplant).

The studys primary end points are dose-limiting toxicities and primary graft failure.

Off the 33 patients enrolled onto the study, the median age is 43 years (range, 21-63) and 27% of patients were female; a total 30.3% of patients identified as Hispanic or Latino. Patients were Asian (15.2%), Black or African American (21.2%), White (42.4%), or other (21.2%). Their primary disease was ALL (30.3%), AML (63.3%), or chronic myeloid leukemia (6.1%). Additionally, patients had high-/very highrisk disease (18%), intermediate-risk disease (79%). Disease risk index was not applicable for 3% of patients.

Patients disease status at time of transplant encompassed those who achieved their first complete remission (CR1; 73%), second CR (CR2; 24%) and CML accel phase (3%). Patients either had a total body irradiation (TBI)-based conditioning regimen (51.5%) or busulfan-based one (48.5%). Donor characteristics showed that there were more male donors (73%) vs female donors (27%), and the CMV status was positive (30.3%), negative/not detected (36.3%), or not available (33.3%).

Rapid engraftment with Orca-Q was observed in the patients. The median engraftment time with neutrophils was 12.0 days (range, 8-25) and 15.5 days with platelets (range, 8-79). Two patients experienced secondary graft failure, and grade 1/2 CRS occurred in 3 patients (grade 1, n = 2; grade 2, n = 1).

Additional data showed a low incidence of severe Common Terminology Criteria for Adverse Events grade 2 (CTCAE; n = 9) and CTCAE grade 3 (n = 15) infections. There were 5 events (15%) of acute grade 2 to 4 GVHD and 1 event of grade 3 acute GVHD. At a median follow-up of 375 days (range, 73-1384), no patients have developed moderate to severe chronic GVHD. This in comparison to historical cohorts with PTCy, which show 1-year chronic GVHD rates of 24% to 33%.2

The phase 1 trial is continuing to enroll patients across the United States. Srour stated that there are plans to increase the age criteria to 75 years and provide less-intensive conditioning therapy.

Editors Note: Dr Srour disclosed research funding from Orca Bio for this study.

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