CAR T-cell immunotherapy shows promising results for treating blood cancer patients

 Blood cancer patients, especially when they relapse, have a poor prognosis, and generally do not survive very long. The last five years have seen success in treating these patients with Chimeric Antigen Receptor (CAR) T-cells—a type of immunotherapy where T-lymphocytes are collected from patients, genetically modified in the laboratory to express a 'CAR' and infused back into patients where they multiply and specifically target and kill cancer cells.

CAR T-cells have had remarkable success in treating several types of blood cancers, including B-acute lymphoblastic leukemia (B-ALL), large B-cell lymphoma and multiple myeloma. However, this type of treatment is logistically challenging to deliver and it can take several weeks for the CAR T-cells to be manufactured, during which time the cancer can grow to a stage where it becomes too difficult to treat.

An alternative to using CAR-T cells derived from cancer patients is to use pre-manufactured 'off-the-shelf' Chimeric Antigen Receptor (CAR) T-cells. 'Off-the-shelf' CAR T-cells are generated from healthy volunteer donors and undergo an additional 'gene editing' step to remove their own T-cell receptor, allowing them to be given to any patient with minimal delay and without causing graft versus host disease.

The CALM clinical trial, initiated at King's in 2016, aimed to evaluate the therapeutic potential of UCART19—the first 'off-the-shelf' CAR-T cell product of its king against adult patients with B-ALL.

This multi-center trial was conducted in the UK, U.S. and Japan with much of the translational research carried out by the Cellular Immunotherapy Group at the Rayne Institute, School of Cancer & Pharmaceutical Sciences. The final results of this study were recently published in The Lancet Haematology and Cancer Research Communications, and build upon the preliminary data that were published in The Lancet in 2020.

A total of 25 adult patients with relapsed or treatment-resistant B-ALL who had no other treatment options were treated with chemotherapy drugs fludarabine and cyclophosphamide, with some additionally receiving an antibody called alemtuzumab. All patients were then given UCART19 'off-the-shelf' CAR T-cells and followed up for adverse events and disease response.

Side effects of the treatment were found to be manageable with no unexpected complications. 48% of treated patients achieved a complete remission lasting on average 7.4 months. Patients who showed signs of disease response had higher levels of UCART19 expansion than non-responders. Further analysis also found that alemtuzumab treatment was required for UCART19 expansion and disease response.

The findings from these two publications clearly highlight the therapeutic potential of UCART19 and 'off-the-shelf' CAR T-cell products more generally.

"The CALM Trial results are very promising and demonstrate, for the first time, the safety and feasibility of allogeneic 'off-the-shelf' CAR-T cells. Further work is underway to improve the persistence and long-term efficacy of these CARs," says Dr. Reuben Benjamin, Clinical Senior Lecturer at KCL and Chief Investigator for the CALM study.

More information: Reuben Benjamin et al, UCART19, a first-in-class allogeneic anti-CD19 chimeric antigen receptor T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia (CALM): a phase 1, dose-escalation trial, The Lancet Haematology (2022). DOI: 10.1016/S2352-3026(22)00245-9

Sandra Dupouy et al, Clinical Pharmacology and Determinants of Response to UCART19, an Allogeneic Anti-CD19 CAR-T Cell Product, in Adult B-cell Acute Lymphoblastic Leukemia, Cancer Research Communications (2022). DOI: 10.1158/2767-9764.CRC-22-0175

https://medicalxpress.com/news/2023-02-car-t-cell-immunotherapy-results-blood.html

New way to prevent common causes of vision loss

 UVA Health scientists have discovered an unknown contributor to harmful blood vessel growth in the eye that could lead to new treatments for blinding macular degeneration and other common causes of vision loss.

UVA's Jayakrishna Ambati, MD, and Shao-bin Wang, Ph.D., and their colleagues have identified a new target to prevent the formation of abnormal tangles of blood vessels associated with eye conditions such as neovascular age-related macular degeneration, proliferative diabetic retinopathy and ischemic retinal vein occlusion.

"Our study has opened up the possibility of mitigating aberrant blood vessel growth in eye diseases by targeting the epigenetic machinery," said Ambati, the founding director of UVA's Center for Advanced Vision Science and a member of the University of Virginia School of Medicine's Department of Ophthalmology.

"Through local targeting of the epigenetic regulator, we have gained a deeper understanding of how ocular immune cells can cause a loss of control over blood vessel growth under the retina. This approach also offers a new direction for the development of more effective, cost-efficient and accessible interventions, thereby avoiding issues such as drug resistance, which is a growing concern with conventional anti-VEGF therapies used in clinical treatments."

Understanding vision loss

Scientists have known that abnormal vessel overgrowth in the eye is fueled by excessive amounts of a substance called "vascular endothelial growth factor-A," or VEGF, that plays an important role in blood vessel formation. There are now treatments available that target VEGF to prevent vessel overgrowth, and they often provide dramatic benefits at first. Unfortunately, these benefits can fade with time. That leaves doctors in need of better treatments to help preserve patients' eyesight.

Ambati and Wang's new research identifies a key protein that determines VEGF levels. Blocking this protein in lab mice reduced their VEGF levels significantly, and it did so in a targeted way, without unwanted side effects. The scientists noted, for example, that they observed no toxic effects on the retina, the light-sensing portion of the eye where the vessel overgrowth occurs.

"This fat mass and obesity-associated (FTO) protein was previously shown to be correlated with obesity in humans. Unexpectedly, we found it also play important roles in regulating ocular neovascularization through an epigenetic mechanism," Ambati said. "This exciting discovery finally answers a longstanding question about how ocular immune cells, such as macrophages, contribute to abnormal blood vessel growth under the retina. This question was first investigated by our team 20 years ago, and we're thrilled to have found an answer."

In addition to identifying a promising target for the development of new treatments for vision loss, the discovery sheds important light on the fundamental mechanisms responsible for the blood vessel overgrowth that robs millions of people of their sight. Neurovascular age-related macular degeneration alone affects more than 200 million people worldwide. While much more research and testing will be needed before the new finding could be translated into a treatment, the UVA scientists are excited about the potential of the discovery.

"Current strategies for treating ocular neovascular disorders, which primarily focus on regulating the protein levels of VEGF, are not perfect. Therefore, it is imperative to identify more targetable candidates to develop alternative therapies," Wang said. "We are hopeful that our study will pave the way for the development of new treatments, ultimately reducing the burden of neovascular-related illnesses."

The researchers have published their findings in Signal Transduction and Targeted Therapy.

More information: Shao-bin Wang et al, Targeting the m6A mRNA demethylase FTO suppresses vascular endothelial growth factor release and choroidal neovascularization, Signal Transduction and Targeted Therapy (2023). DOI: 10.1038/s41392-022-01277-4

https://medicalxpress.com/news/2023-02-discovery-common-vision-loss.html

Cardio-behavioral responses associated with fear and anxiety

 Anxiety disorders are becoming increasingly common, with estimates suggesting that almost one in three people in the U.S. will experience high levels of anxiety at some point in their life. Anxiety is essentially a feeling of unease, worry or psychological discomfort, typically associated with catastrophic thoughts about a real or imagined future life event.

When they are anxious, humans experience the same sensations and physiological responses they would feel when they are afraid of a real and immediate threat, such as a lion chasing them, an ongoing natural disaster, and so on. To better support patients with anxiety disorders, neuroscientists and psychology researchers have been trying to understand the neural underpinnings of fear and anxiety for many years.

Ultimately, both fear and anxiety tend to promote defensive behaviors in response to real or imaginary threats, respectively. The most widely documented among these are the so-called freeze (i.e., staying still), flight (i.e., avoiding a feared situation or escaping), fight (i.e., arguing or becoming aggressive) and fawn (i.e., overpleasing or submitting to another human to avoid the escalation of conflict).

A team of researchers at University Hospital Wuerzburg in Germany, recently carried out a study concurrently investigating both cardiac and behavioral responses associated with anxiety and fear-based defensive states in mice. Their paper, published in Nature Neuroscience, introduces a new framework that could be used to characterize the complex cardio-behavioral defensive states experienced by animals and humans when they are feeling fearful or anxious.

"The defense reaction includes multiple interacting behavioral, autonomic and endocrine adjustments, but their integrative nature is poorly understood," Jérémy Signoret-Genest, Nina Schukraft and their colleagues wrote in their paper. "In particular, although threat has been associated with various cardiac changes, there is no clear consensus regarding the relevance of these changes for the integrated defense reaction."

The key objective of the recent work by Signoret-Genest, Schkraft and their colleagues was to gain a better understanding of anxiety and fear from a cardiac, physiological and behavioral standpoint. To do this, they analyzed a large dataset collected during experiments with mice, which included behavioral, heart-rate and thermal measurements.

During the experiments in which this data was collected, freely moving mice were implanted with electrocardiogram (ECG) electrodes and then exposed to a particular pattern of stimuli, namely a sound (i.e., a pure tone) and a mild electrical shock applied to their feet. The mice soon learned to associate the sound with the following painful stimulus, thus they exhibited anxious behaviors when they heard it.

Throughout this experiment, the mice's cardiac and physiological responses were recorded, to better understand its relation to the defensive behaviors they were performing. By analyzing collected measurements, the researchers were able to identify a cardio-behavioral microstate that occurred after the mice heard the sound, which was characterized by a lack of body movements (i.e., freezing or immobility) a decrease in heart rate, also known as bradycardia.

Interestingly, as the mice became more and more conditioned to fear the sound, or in other words the more times they had experienced the electrical shock following the sound, this cardio-behavioral state progressively increased. They then also identified other microstates in which the mice's behavior was consistently associated with a faster heart rate (i.e., tachycardia).

"We identify rapid microstates that are associated with specific behaviors and heart rate dynamics, which are affected by long-lasting macrostates and reflect context-dependent threat levels," Signoret-Genest and Schukraft explained in their paper. "In addition, we demonstrate that one of the most commonly used defensive behavioral responses—freezing as measured by immobility—is part of an integrated cardio-behavioral microstate mediated by Chx10+ neurons in the periaqueductal gray."

The recent study by this team of researchers offers new interesting insight about the cardiac, physiological and behavioral underpinnings of defensive states. Overall, it confirms previous hypothesis and observations suggesting that defensive states are marked by a series of concurrent and interdependent processes.

In the future, the framework they developed and the cardio-behavioral microstates they identified could be explored further, potentially paving the way towards an improved understanding of anxiety disorders and the body processes that characterize them. This could in turn inform clinical practices, for instance helping psychotherapists to better guide their patients in becoming aware of cardiac and physiological responses that occur when they are experiencing anxiety.

"Our framework for systematic integration of cardiac and behavioral readouts presents the basis for a better understanding of complex neural defensive states and their associated systemic functions," the researchers wrote in their paper.

More information: Jérémy Signoret-Genest et al, Integrated cardio-behavioral responses to threat define defensive states, Nature Neuroscience (2023). DOI: 10.1038/s41593-022-01252-w

https://medicalxpress.com/news/2023-02-framework-characterizing-cardio-behavioral-responses-anxiety.html

US Military Aid To Ukraine Exceeds The Costs Of Afghanistan

 Ukraine receives the most military aid from the United States: Since the beginning of the war and as of Jan. 15, 2023, $46.6 billion in financial aid for military purposes has flowed to the country now at war with Russia.

When calculating the average annual costs (in 2022 prices) of previous wars in which the United States has been involved in, the true magnitude of the country's Ukraine aid expenditure can be seen.

As Statista shows in the infographic below, the payments to Ukraine have already exceeded the annual military expenditure of the U.S. in the war in Afghanistan from 2001 to 2010. The U.S. military costs in the Vietnam War, the Iraq War and the Korean War were significantly higher - according to calculations by the Kiel Institute for the World Economy as part of its Ukraine Support Tracker.

In the Vietnam and Korean wars, the high usage rate of ammunition and other supplies cost a particularly large amount of money, in addition to the wear and tear of equipment and numerous other assets such as the care of the wounded. Further complicating matters in each case was the great distance to the theater of operations. Although the U.S. maintained a number of bases in Southeast Asia, the large weapons systems and the required replacement components all had to be shipped or flown across the Pacific. In addition, a large fleet of aircraft carriers was always deployed off the coast of Vietnam. The numerous missions of the air force also caused significant costs.

In the U.S., criticism of the scale of military aid to Ukraine is already coming from within the Republican ranks.

Some of the U.S. Republicans in Congress have announced that they intend to block aid to Ukraine.

Nevertheless, the day after his visit to Kyiv, U.S. President Biden underscored his country's commitment to continued support of the Ukrainian war effort. Speaking in Warsaw, Poland, he said:

"This is not just about freedom in Ukraine. It's about freedom of democracy in general".

In addition to the military aid detailed in this infographic, the U.S. has also supplied weapons and equipment worth over $5 billion.

https://www.zerohedge.com/geopolitical/us-military-aid-ukraine-exceeds-costs-afghanistan

Chiesi, Protalix: Positive CHMP Opinion for Pegunigalsidase Alfa for Treatment of Fabry Disease

 European Commission decision anticipated in beginning of May 2023 -

Chiesi Global Rare Diseases, a business unit of the Chiesi Group established to deliver innovative therapies and solutions for people affected by rare diseases, and Protalix Biotherapeutics, Inc.,  (NYSE American:PLX) (TASE:PLX), a biopharmaceutical company, announced today that the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending marketing authorization for PRX–102 (pegunigalsidase alfa), the first and only pegylated enzyme for the treatment of adult patients with Fabry disease.

https://www.biospace.com/article/releases/chiesi-global-rare-diseases-and-protalix-biotherapeutics-receive-positive-chmp-opinion-for-pegunigalsidase-alfa-for-treatment-of-fabry-disease/

Reata, Friedreich’s Ataxia Patients Await Potential First Approval

 There are currently no disease-modifying treatments for Friedreich’s ataxia (FA), a rare, degenerative neuromuscular disorder. That could change on Feb. 28, as the FDA is expected to make a decision about Reata Pharmaceuticals’ omaveloxolone. 

Touted as one of the top potential neurodegenerative approvals to watch in 2023, omaveloxolone activates Nrf2, a transcription factor that helps resolve inflammation by restoring mitochondrial function, reducing oxidative stress and inhibiting pro-inflammatory signaling.

In a registrational trial of 103 patients, a group of physicians and Reata representatives writing in the Annals of Neurology said omaveloxolone “significantly improved neurological function compared to placebo and was generally safe and well tolerated.”

Named after the German physician Nikolaus Friedreich, who first discovered it in the 1860s, Friedreich’s ataxia affects approximately 5,000 people in the U.S.

It is caused by a trinucleotide repeat expansion in the first intron of the frataxin (FXN) gene, which encodes the mitochondrial protein frataxin. This expansion leads to reduced frataxin expression, resulting in mitochondrial iron overload and uncoordinated muscle movement (ataxia).   

FA typically begins in childhood, with most patients succumbing to the disease by their mid-30s, often from cardiovascular problems.  

While Reata is up first with the FDA, several other companies are vying to be next.

PTC Therapeutics: Q2 Readout

PTC Therapeutics is expecting data from the Phase II/III MOVE-FA trial in the second quarter of 2023.

MOVE-FA is assessing vatiquinone, an experimental small molecule that inhibits 15-Lipoxygenase, a primary regulator of the oxidative stress and inflammation response pathways.

A key part of FA disease pathology, oxidative stress leads to chronic neural inflammation, where the inflammatory response can’t be turned off.

“When things go wrong with mitochondria, that can lead to disease states like FA,” Stuart Peltz, Ph.D., CEO, told BioSpace.

Adenosine triphosphate (ATP), the body’s primary energy source, is made in the mitochondria using an electron transfer chain. But these electrons need to be carefully regulated. If released from the mitochondria, they can interact with proteins and DNA and can cause loss of activity, Peltz said.

The 15-Lipoxygenase enzyme plays a key role in regulating neuroinflammation.  

“If the 15- Lipoxygenase pathway is activated as a consequence of dysregulation of the mitochondrial electron transfer pathway, then you’ve got a problem,” Peltz said. “The inflammatory system is chronically on and instead of protecting the body, you have this inflammatory milieu that starts to cause damage.” 

In a previous Phase II trial, vatiquinone demonstrated what the company called “a statistically significant effect” at the 24-month mark. It also had a “favorable” safety profile in more than 500 patients. 

Patients typically lose about two points per year on the modified Friedreich’s Ataxia Rating Scale (mFARS), which measures disease progression, Peltz said. “If you can stabilize the patient, you're doing a good thing.” 

Targeting the Root Cause

Pennsylvania-based Larimar Therapeutics expects topline data from a Phase II trial of CTI-1601 during the second half of 2023. The company’s sole clinical-stage product, CTI-1601, is a recombinant fusion protein intended to deliver human frataxin into the mitochondria of FA patients.

In healthy people, a small protein sequence attached to frataxin carries the frataxin molecule across the mitochondrial membrane. It is cut off by an enzyme once in the mitochondria.

“[CTI-1601 has a cell-penetrating peptide attached to the frataxin molecule. The cell-penetrating peptide is a short sequence that's intended to get the molecule across the cell membrane and across the mitochondrial membrane,” Carole Ben-Maimon, M.D., president and CEO, told BioSpace. 

It also contains a cleavage site that enables the cell-penetrating sequence and mitochondrial targeting sequence to be removed so the frataxin stays where it’s supposed to.  

When the Phase II data reads out, Larimar will be looking for safety pharmacokinetics and changes in frataxin levels. Ben-Maimon hopes to repeat Phase I data that showed daily injections of CT1-1601 given at 50 mg or 100 mg led to increased levels of frataxin in buccal cells in the skin, which are correlated to FA disease burden. 

She said CTI-1601’s differentiator is that it gets at the root cause of the disease, replacing the frataxin of which FA patients don’t make enough.

Conversely, Reata’s omaveloxolone activates Nrf2, which stimulates the production of certain proteins. Therefore, the drug works as an antioxidant, she said.

While omaveloxolone will not be curative, “I think the different mechanisms could potentially be synergistic. I don't think it's one or the other.”

Regulatory Precedent

PTC and Larimar are both following the upcoming Reata decision closely.

While Peltz would not comment directly on omaveloxolone’s chances of approval, he said it would be interesting to see the point of view taken by the FDA’s neurology division.   

Ben-Maimon agreed that it is a precedent-setting decision.

‘If omaveloxolone is approved, that will set the gold standard from the standpoint of what FDA is willing to accept or not accept,” she said.

To date, the expectation has been a double-blind, placebo-controlled trial, and Larimar expects to have to do the same. Though, Ben-Maimon added that her company might be able to use frataxin levels as a surrogate endpoint in addition to clinical outcomes.

Reata’s NDA for omaveloxolone was granted priority review in May 2022. The PDUFA date was later extended until Feb. 28, 2023, to allow the FDA additional time to review confirmatory evidence submitted by Reata in response to concerns raised by the regulator.

“If it gets approved, it's really good for patients,” Ben-Maimon said. “These patients have nothing.”  

https://www.biospace.com/article/reata-friedreich-s-ataxia-patients-await-potential-first-approval/

Brooklyn Dem floats ban on ‘poison’ sodium nitrite linked to youth suicides across US

 New legislation in Albany would ban retailers like Amazon from selling sodium nitrite, a common meat preservative linked to youth suicides across the country.

“It’s basically like the suicide poison of choice,” state Sen. Andrew Gounardes (D-Brooklyn) told The Post Friday.

“There are whole websites – whole corners of the dark web, where people are like: ‘Here’s how you do it. Here’s how you take your life. You have to just go online and order x amount of sodium nitrite, mix it with water and drink it.'”

The bill Gounardes plans to officially introduce Monday would bar both online retailers and brick-and-mortar stores from selling the salt-like substance “without proof of its intended use for institutional or scientific purposes.”

Only people 21 years old and up would be able to purchase sodium nitrite under the bill, which also establishes a right for individuals to sue violators of the ban.

State Sen. Andrew Gounardes is proposing legislation to restrict sales of sodium nitrite to the general public in order to prevent the toxic substance from being used by people committing suicide.

LightRocket via Getty Images

“I think we’ll get a lot of support for it,” Gounardes said.

Amazon has faced criticism in recent years for resisting efforts by bereaved families to limit the sale of the toxic compound — which has been tied to the deaths of at least 10 people who bought it from the site, according to The New York Times. In all, several dozen deaths nationwide have been linked to the chemical.

Sodium nitrite can be fatal in high amounts with producers sometimes dying the white substance pink in order to differentiate it from common products like table salt.

Amazon

“They know it’s killing people,” Ruth Scott, a Texas resident whose 18-year-old son committed suicide, told the Times last year. “They are fully aware. They just don’t care.”

An attorney tied to Scott, who has filed a class action lawsuit against the e-commerce giant, eventually brought their fight to the attention of Gounardes.

The Brooklyn legislator told The Post Friday that he had personally seen sodium nitrite for sale on Amazon with purity levels way above the 6.25% allowed for commercial use.

“It shouldn’t be for sale on the open market. You should not be able to log on to Amazon and purchase sodium nitrite at levels that can kill you,” Gounardes said. “And this is really not a novel thing. I mean, Etsy and eBay have both banned the sale of any form of sodium nitrite over 6.25% purity globally, because there’s no use for it for anyone outside of like a commercial meat processor.”

Amazon enacted a policy in Oct. 22 restricting sales of high concentrations sodium nitrite to its business customers.

Getty Images

A Post review of Amazon on Friday did not find any sales of sodium nitrite – a different substance than its chemical cousin sodium nitrate – in concentrations above 6.25% though other sites offered the chemical with purity rates as high as 98%.

An Amazon spokesperson told The Post Friday that the company began limiting sales of high-concentration nitrite, which is 95% or more pure, to its business customers in Oct. 2022 though members of the general public can still buy it with less than 10% purity.

But the company declined to comment on the bill proposed by Gounardes.

A spokesperson said “customer safety is a top priority” while expressing “deepest condolences to families who lost loved ones to suicide.

“We are committed to a safe shopping experience and require our selling partners to follow all applicable laws and regulations when listing items in our store,” the spokesperson said before adding: “High concentration sodium nitrite is not intended for direct consumption, and unfortunately, like many products, it can be misused.”

https://nypost.com/2023/02/24/nys-sen-andrew-gounardes-floats-sales-ban-on-sodium-nitrite-tied-to-youth-suicides/