StemCell Therapy

Further to my recent article about the 2020 Nobel Prize announcements, the winners of the 2020 Chemistry Nobel Prize were announced as Emmanuelle Charpentier and Jennifer Doudna on 7 October 2020 "for the development of a method for genome editing". This, of course, refers to the revolutionary genetic scissors technology, CRISPR/Cas9. For this article, Ive teamed up with my colleague Jamie Atkins, whose specialisms include prosecution of CRISPR-related patent applications at the EPO, to get into the details of the winning technology.

In this article, we explore:

Diversity in the Chemistry Nobel Prize;

The winning technology;

What is CRISPR and how does it work?;

How can CRISPR be used?;

CRISPR Patents; and

The future could CRISPR be used to combat COVID -19?

Diversity in the Chemistry Nobel Prize

Before looking at the patent side of things, it is worth noting that this is the first Nobel Prize awarded to two women. Charpentier commented shortly after the prize announcement that:

My wish is that this will provide a positive message to the young girls who would like to follow the path of science, and to show them that women in science can also have an impact through the research that they are performing This is not just for women, but we see a clear lack of interest in following a scientific path, which is very worrying.

While there is still a significant gender gap in the Laureates of the Chemistry Nobel Prize, it is encouraging that there are now an additional two female winners to add to the previous five: Marie Curie (1911), Irne Joliot-Curie (1935), Dorothy Crowfoot Hodgkin (1964), Ada Yonath (2009) and Frances H. Arnold (2018). We hope this figure continues to increase each year, along with wider recognition of other under-represented groups, for example in terms of BAME and LGBTQ+ representation.

The winning technology

At face value, CRISPR/Cas9 (CRISPR) seems to be more biological than chemical, but this only serves to highlight the breadth of chemistry as a field. As described in Nobels will, the Nobel Prize in Chemistry is to be awarded to the person who shall have made the most important chemical discovery or improvement, and this requirement is surely met by CRISPR.

What is CRISPR and how does it work?

The CRISPR/Cas9 editing tool developed by the Nobel Prize winners is based on the discovery of a naturally occurring system used by bacteria to defend against viral infection. When a virus is detected, the bacteria produce short RNA sequences that guide a DNA cutting enzyme (Cas9) to viral DNA matching the RNA sequence. Cas9 cuts the viral DNA, thereby disabling the virus. Doudna and Charpentier made several important discoveries leading to a better understanding of this bacterial system, developed a simplified version of the system and crucially showed that it could be programmed to target almost any DNA sequence of interest, as reported in the seminal Jinek et al. 2012 paper:

''Our study reveals a family of endonucleases that use dual-RNAs for site-specific DNA cleavage and highlights the potential to exploit the system for RNAprogrammable genome editing.

The basic components of the CRISPR/Cas9 system are the DNA cutting enzyme (Cas9) and the guide RNA based on the target DNA sequence, which directs the nuclease to the desired cutting location. Once the DNA in a cell is cut, the cell tries to fix the break using its own repair mechanisms. Due to the error-prone nature of such mechanisms, this fix can actually disable a gene. Alternatively, by supplying a template sequence together with the CRISPR machinery, the cells DNA repair mechanisms can be exploited to replace a section of DNA with the template sequence of choice.

Building on this foundational work of the Nobel Laureates, many complementary genome editing tools based on the CRISPR principle have been developed. For example, in a technique known as base editing, a deactivated Cas9 is fused to a cytidine deaminase enzyme, which allows targeted conversion of the cytidine base (C) to thymine (T) without cleaving the DNA (Komor et al, 2016). Another example is prime editing, in which deactivated Cas9 is fused to reverse transcriptase. This is coupled with a guide RNA that specifies the target site and encodes a desired replacement sequence, allowing new genetic information to be written into a specified DNA target site (Anzalone et al, 2019).

How can CRISPR be used?

There are innumerable exciting possibilities that stem from the ability to edit the genome of any living cell in a targeted manner using these basic principles. For example, CRISPR is already revolutionising genetic research by providing a quicker and easier way for researchers to knock out specific genes in order to investigate the function of those genes and their role in cellular pathways. There also important applications in agriculture, where it is being used to speed up the generation of improved crop varieties and could play an important role in food security.

Another key application is in the filed of diagnostics (more on that below), but perhaps one of the most exciting and lucrative CRISPR applications is in the field of medicine. Doudna is a co-founder of Intellia and Charpentier is a co-founder of CRISPR Therapeutics, both of which are developing CRISPR-based therapies, some of which are already in early stage clinical trials, e.g. for the treatment of sickle cell anaemia. Many current trials involve editing the genome of cells extracted from the body (e.g. hematopoietic stem cells) before reinserting the modified cells back into the patient. An alternative approach also being explored is delivering the CRISPR machinery directly into the body, for example to disable faulty disease-causing genes. This year saw the first delivery of CRISPR machinery to a patient in an attempt to treat an inherited form of blindness called Leber congenital amaurosis 10 (LCA10).

CRISPR patents

Any new technology with such a great potential for commercial application is an ideal candidate for patent protection. The European Patent Office (EPO) has published 32 European patent applications naming Doudna as an inventor and 7 European patent applications naming Charpentier as an inventor. Patent applications are published 18 months after their effective filing date, so there may be many more unpublished patent applications that have already been filed naming these Laureates as inventors.

CRISPR patents have also been at the centre of attention in both Europe and the US over recent years. In Europe, weve seen the high-profile CRISPR priority appeal, in which one of the Broad Institutes fundamental CRISPR patents (EP2771468, claiming an earliest priority date of 12 December 2012) was revoked for lack of novelty over some of the seminal CRISPR papers. These papers became prior art because the patent was found not to be entitled to its claimed priority dates (see our articles here, here and here from earlier this year for the details). Doudna and Charpentiers patents have also come under attack in Europe; their 2013 patent EP2800811 was opposed by seven parties, and maintained in amended form in May 2020.

In the US, high profile interference proceedings between University of California and others and the Broad Institute and others (Broad) before the US Patent Trial and Appeal Board culminated in a decision in favour of Broad, which was upheld in 2018 by the Court of Appeals for the Federal Circuit. Further such proceedings are currently in progress.

Stay tuned for a more in-depth discussion of the ongoing challenges relating to CRISPR patents.

The future could CRISPR be used to combat COVID -19?

Shortly after the Nobel Prize was announced, Charpentier was asked whether CRISPR could be used to make a vaccine for COVID-19. She indicated this was unlikely in a direct way, but that it could be useful indirectly by allowing researchers to understand the virus in ways that help them develop a vaccine (e.g. understanding what is important for the virus to replicate). The full Q&A with Charpentier is available here.

It has in fact already been deployed in a fast and accurate diagnostic test for Covid-19. This test, referred to as SARS-CoV-2 DNA Endonuclease-Targeted CRISPR Trans Reporter (DETECTR), harnesses the targeting function of the guide RNAs of the CRISPR system to bind to coronavirus sequences, and the cutting function of Cas12 (a nuclease related to Cas9) to cleave a reporter molecule, to confirm detection of the virus. Fittingly, Doudnas own lab recently announced its own CRISPR-based diagnostic test that can detect SARS-CoV-2 in just 5 minutes. This high processing speed is achieved by avoiding the need to amplify the viral genome (as required by earlier assay formats). Instead, the new test uses combinations of CRISPR RNA which target different parts of the virus RNA and activate multiple Cas nucleases (Cas13a) per piece of viral RNA, boosting the fluorescent signal generated when a reporter molecule is cut. Moreover, the researchers showed that the fluorescence could be measured with a mobile phone camera, demonstrating the simplicity and portability of the assay.

As mentioned above, clinical trials involving CRISPR-based approaches are already underway, and we look forward to seeing more success stories in the coming years. While these are no doubt exciting times, it is clear that extreme caution must be exercised to fully understand and mitigate the risk of CRISPR acting off-target. There are also ethical debates to be had about how far to take gene editing. Should scientists be permitted to introduce heritable changes into the genome even if this can be done safely and efficiently?

One thing is for sure, the work conducted by Doudna and Charpentier has revolutionised the field of genetic engineering, and for that work these inspirational inventors should be celebrated.

Link:
Nobel Prize in Chemistry 2020 Winners from a Patent Perspective - Lexology

In the ninth month of the COVID scourge which covered the land, the people lamented their fate and looked to the heavens for relief and succor.

That is, I imagine, how the Bible might recount the pandemic weve been in since February, if the Good Book were being written today.

Around here, at least, weve been spared the worst from this thing. But if you recall when it all started, and for several months hence, the hospital geared up for scores of deathly ill patients and local doctors and nurses were told to expect reporting for emergency duty. A mobile refrigerated morgue was brought in. They even retrofitted parts of Keene State College to handle the overflow. Main Street downtown was bereft of traffic; for a couple of months, it was always 6 a.m. Sunday morning down there. Planes, trains and buses stopped; there were no pedestrians. There was a mad rush for PPE (we all learned what that acronym meant), and ventilators.

No one knows for sure where this pandemic is headed, and those up here in the northern climes are wondering if it will get worse as the winter winds drive us all inside until April and May. What will our Thanksgiving and Christmas holidays look like this year?

Assessing the past nine months, Ive had a number of observations, and you may have had similar thoughts.

For starters, I think that society came unglued. And, I think I know why. We collided with something that all of our sophisticated science and technology couldnt handle, and we freaked out. Our new Apple phones, PET scans, 5G networks, genetic engineering all the kings horses and all the kings men were helpless in the face of one of the worlds oldest adversaries: pestilence, which is one of the Four Horsemen of the Apocalypse in the Book of Revelation, to use another biblical reference. While astronauts aboard the International Space Station circle the earth, ensconced in the most amazing science, they look down upon an earth stymied and suffering from a primordial disease.

Secondly, we learned that government has severe limitations. Like our belief in technology, we have come to think in the past century that the state and feds can come up with solutions and come to our rescue. Thats just not true, and never was. You can blame whoever you want, but governments response was and is severely flawed. Its not a failure of the Republicans or Democrats or career bureaucrats at the NIH or CDC its just the fact that government cannot solve our problems when the you-know-what hits the fan. Never could. If youve ever been through the aftermath of a severe hurricane or a strong earthquake, you know that there comes a time when youre just on your own. When a crisis hits, you learn immediately that the emperor lives very far away.

Thirdly, most people behaved, but enough didnt that it showed the sour side of humanity. Panic buying without cause, denying others of necessities. A refusal to wear masks in public. We can sometimes be a stupid bunch.

Fourth, our economy is very fragile, despite being the richest country in the world. That showed itself right away. Our weakest link proved to be our distribution network for goods and services. One of the correct responses by the federal government was the rapid carpet-bombing of cash to companies and individuals. Well have to pay that big bill later, but it saved us from a collapsed system.

Fifth, we have, in fact, dodged the bullet. Despite the number of hospitalizations and deaths, COVID-19 could have been worse, with a much higher mortality rate. If we didnt already possess a sophisticated medical system, the death rate might have been off the charts.

Sixth, instant communication and 24/7 media coverage is half good, half terrible. It disseminates at the speed of light erroneous theories, rumors, dubious statistics, malevolent gossip, wild statements from wrong-headed people parading as scientists, shoddy studies and surveys, and inflammatory rhetoric from politicians and bureaucrats. Cant change that; information and misinformation spread at the same rate, and people believe weird things. Well see that when a vaccine is finally developed, and millions refuse to take it.

Lastly, if there is a silver lining to all this, its that well be prepared for the next disaster, or disease, that comes our way. That is, if we remember what we did right and what we did wrong this time. Unfortunately, humans have a propensity to reinvent the wheel over and over.

John McGauley, an author and local radio talk-show host, writes from Keene. He can be contacted at mcgauleyink@gmail.com

Excerpt from:
We've learned much in this crisis including what we don't know, by John McGauley - The Keene Sentinel

The anti-GMO movement dominated the public discourse about crop biotechnology for decades. Led by committed activists who knew how to manipulate the media, they effectively steamrolled a scientific community that wasnt ready for the PR war that Greenpeace and other NGOs launched against frankenfoods in the mid-1990s. Thirty years later, were beginning to see that dynamic shift as plant breeding technology improves and experts successfully defend it against activist attacks.

In August, John Fagan, organic food champion, biologist and Raja of World Peace in the Maharishi organization, led a Greenpeace-funded study claiming that gene-edited crops developed with new breeding techniques (NBTs) like CRISPR can be detected.

This may seem unimpressive to most people, but the result is a big deal to anti-GMO activists like Fagan. Gene-edited crops may be essentially identical to conventionally bred plants; the only difference is that gene editing dramatically speeds up the breeding process, saving time, money and getting enhanced seeds into farmers fields much more quickly than was previously possibleall without inserting foreign DNA into the crops genome. This is the primary distinction between gene editing and transgenesis (GMO in the vernacular).

These facts aside, European law treats gene-edited and GMO crops the same. Commercial cultivation of both is effectively banned in the EU (farmers have access to only one transgenic corn variety), though political pressure is building to reform Europes strict regulations. Anti-biotech groups have been on a campaign to block these reforms since July 2018, just after the European Court of Justice first ruled on crop gene editing. Fagans paper was the latest contribution to this effort. If gene-edited and conventional crops can be distinguished, the argument goes, then the former should be regulated as GMOs.

But theres a problema big one in fact: Fagans study actually demonstrated that its not possible to detect most gene-edited plants, therefore destroying the EUs justification for regulating them as GMOs. Its the perfect example of what we fondly call an own goal. And it illustrates how anti-science groups flog disinformation with the help of gullible journalists who stenograph their questionable claims for wide distribution.

Given the onslaught of disinformation we face in a post-COVID world, Fagans paper offers us the perfect opportunity to review the activist playbook and immunize ourselves against bad science and its harmful consequences.

As gene editing becomes an increasingly effective tool for improving agricultural production and reducing its environmental impacts, many countries (the US, Canada, Brazil, Argentina among dozens more) have split from the European Union (EU) on NBTs, exempting them from the expensive and exhausting regulations that govern GMO crops.

This is not only scientifically sound, its pragmatic. There is no way to detect gene edits in most cases. These changes look just like natural mutations found in wild plants, or the genetic changes induced by old-fashioned and EU-approved practices like bathing seeds in mutagens or irradiating them, or changes that occur in plants produced via tissue culture. The tests at our disposal cannotI repeat, cannotdistinguish mutations caused by any of these techniques.

This creates a problem for Food Purity Rajas and other opponents of biotechnology. If these gene-edited crops gain public acceptance and dont count as GMO, the organic industry will be at a competitive disadvantage. How could they justify a premium price for Non-GMO Project-certified corn flakes in those circumstances? Naturally, they have to challenge the efficacy and safety of gene editing to prevent such an outcome. Fear is their go-to currency in this effort, as John Fagan explained almost six years ago in a mailing list for anti-GMO campaigners, run by Claire Robinson of the activist website GM Watch. Its part of a long-term plan to make people fear all engineered food.

Fagan recently gave credit for Americas rejection of GMOs to transcendental meditation (TM), which caused a sharp increase in coherence in U.S. collective consciousness, when a large permanent group of TM practitioners was assembled in Iowa, USA. I havent seen the evidence for that, though Id be happy to take a look at the research if anyone can locate it. What is more likely, and supported by data, is that a long-term misinformation campaign made up of bad science and shock marketing scared parents everywhere into buying organic fruit snacks to avoid scary GMOs.

Down to the last detail, this tried and true activism strategy was deployed to influence the current discourse around gene editing. Besides his enthusiasm for TM, John Fagan also has training in molecular biology and operates a non-profit lab with the necessary testing capacity (incidentally, he also started a company that certifies products for the Non-GMO Project). Greenpeace, meanwhile, has an effective, stunt-based PR machine that can churn out multimedia presentations and widely read press releases, which sympathetic NGOs can dutifully amplify. But things didnt turn out as intended this time.

Its impossible to know which came first: the idea for a campaign to attack gene-edited crops, which needed supporting science, or a study in need of the PR muscle Greenpeace could leverage. Someday an intrepid investigative journalist might be able to work this out. But in any case, the outcome on September 7, 2020 was the release of a paper in the peer-reviewed journal Foods, which claimed to reveal a test that could uniquely and specifically detect the first commercial gene-edited crop, a variety of herbicide-resistant canola developed by the seed company Cibus. With a press release, media blitz, and slickly produced website, Greenpeace and other funders launched the #NowhereToHide campaign to promote Fagans paper and encourage EU regulators to treat this herbicide-tolerant canola as a GMO.

Similar to the guy who claimed he invented email, Fagans team implied they developed a new test to identify this crop. Thats not the case; the qPCR (polymerase chain reaction) method used in the study is well established for canola. Fagans novelty claim is therefore quite erroneous, as one scientist noted on Twitter. Nobody disputes that you can find point mutations, changes to a single DNA base pair, with qPCR. The key is that its impossible to determine if a variation is naturally occurring or purposefully induced. Many experts have pointed this out in response to the paper. The test would likewise detect herbicide-resistant plants that have been known to scientists and regulators since in 2002, from wild populations with that same mutation. Etienne Bucher, a plant geneticist based in Switzerland, tried to help Greenpeace grasp this:

But heres the kicker: this canola is not gene edited. It is a somaclonal mutation that was found in the screenings for an herbicide-tolerant variety, one of those changes that occurs in tissue culture. So what Fagans team has, in fact, definitively proved: they cannot detect edited canola this way. Additionally, it appears this rapeseed could be classified as non-GMO in Europe, since it was developed with one of the grandfathered techniques not subject to the onerous EU GMO approval process.

Own. Goal. Reminds me of the time anti-vaxxers commissioned research that confirmed vaccines do not cause autism.

Let the goal-post moving commence!

After the scientific community made quick work of Fagans study, Greenpeace and activists like Claire Robinson at GMWatch began furiously backpedaling. Maharishi TM trainer and geneticist Michael Antoniou told the anti-GMO website that the method they have developed reliably detects a single DNA base unit change, regardless of how it came about. But he went on to assert that EU regulators should still rely on this test to detect the canola variety. This makes absolutely no sense, as the German Central Committee for Biosafety experts observed [automated Google translation]:

The publication by Chhalliyil et al does not add any new knowledge to the current state of science and technology. Rather, it proves that it is not possible to distinguish genome-edited plants from plants with spontaneously occurring mutations. Without prior knowledge of the manufacturing process [my emphasis], no statement can be made as to whether or not it is a GMO within the meaning of the ECJ [European Court of Justice] ruling.

GM Watch agreed, though it fell back on a legal argument to excuse the studys weakness:

What the test cannot do is detect the technique by which a mutation was brought about but under EU law it doesnt need to. The way that the law deals with proof of origin for all GMOs products of gene editing included is to require the developer to declare that their product is a GMO and provide a test method and reference material.

In other words, if Cibus tells regulators its canola is gene edited, then regulators can determine if the canola is gene edited.

The media blitz around Fagans study was designed to promote organic food, but ironically enough, all this talk about identifying the source of mutations dredged up a potentially serious problem for the organic industry. In 2014, the USDAs National Organic Standards Board investigated what kinds of genetic modifications led to many of the key organic crops, only to realize how difficult it would be to classify breeding and laboratory mutations:

Exploring this issue has brought to the attention of the subcommittee that engineered genetic manipulation of plant breeding materials has already occurred in many of the crop varieties that are currently being used in organic farming. A partial list:

Many of these techniques that were used in initial crosses that have now passed down through many generations may not be traceable any longer

The board realized that many of the crops in organic production right now were the result of laboratory processes (genetic engineering, one could say) that are undetectable with molecular testing. Why is this significant? Well, a cynical scientist could use Fagans test to detect mutations in organic tangerines just as well as Cibus canola, demonstrating the inanity of labeling the tangerine non-GMO and the canola genetically engineered.

Bungled though it was, this parallel science PR stunt helpfully illustrated how disinformation can sow confusion and lead to nonsensical policy. For example, Greenpeace celebrated when an Austrian health minister declared that Fagans test should be used to enforce the EUs GMO rules. Well-known anti-crop biotech German politicians also eagerly embraced the results of the study. If people with so much influence over food safety rules in their countries can be fooled, you can see why junk science poses the risk it does.

Still, Greenpeace clearly lost this round. The activist-media juggernaut went down in flames before it could do too much damageand GM Watch spent most of September explaining away Fagans study in the face of intense expert scrutiny. Expect the anti-science crusaders to fall back on these same tactics in the future, because its all they know how to do. But look forward to the fact that there are now scientists, battle hardened by years in the social media trenches, ready to blow air horns the next time an NGO launches a scheme like this.

Mary Mangan holds a PhD in cell, molecular, and developmental biology from the University of Rochester. She co-founded OpenHelix, a company that provides awareness and training on open source genomics software tools. Follow her on Twitter @mem_somerville

See original here:
Viewpoint: Greenpeace-funded study backfires, undermining case to treat gene-edited crops as GMOs - Genetic Literacy Project

First reported in 2012 in Saudi Arabia, Middle East Respiratory Syndrome (MERS) is a respiratory illness caused by a coronavirus with symptoms similar to the COVID-19 coronavirus, namely, fever, cough and shortness of breath with a range from none, to mild, to severe.

As of January 2020, about 2,500 cases of MERS have been reported worldwide. Human-to-human transmission typically requires close contact with an infected person, the spread being uncommon outside of hospitals.

In contrast to COVID-19, the death rate from MERS is about 35%.

MERS is believed to have originated in bats, was transmitted to camels as an intermediate host, then infecting humans, who had contact with the infected animals.

Although the COVID-19 virus has structural similarities to bat coronaviruses, its precise origin has yet to be identified.

The most distinguishing and unique structural feature of the COVID-19 virus is the furin polybasic cleavage site, a sequence of amino acids that interacts with human cell enzymes, which cut or cleave parts of the viral structure, thus contributing to the life cycle of the virus.

In the case of COVID-19, that sequence of amino acids is usually identified as proline-arginine-arginine-alanine or, in scientific notation, PRRA, which precedes an arginine-serine cleavage point, R-S.

It is unknown from where the PRRA sequence originated because it does not exist in any of the bat coronaviruses identified as close relatives of the COVID-19 virus.

A model for such a structure, however, does exist in the MERS coronavirus, which has a proline-arginine-serine-valine or PRSV sequence preceding the R-S cleavage point and having the following alignment:

COVID-19 PRRAR-S

MERS PRSVR-S

Both sequences begin with proline (P), both are polybasic having more than one arginine (R) and both have a non-polar amino acid in the fourth position, alanine (A) and valine (V), respectively, prior to the cleavage point, R-S.

It is important to note that COVID-19 and MERS are from two completely different families of coronaviruses, so one could not have evolved from the other.

According to the scientific article Structures and dynamics of the novel S1/S2 protease cleavage site loop of the SARS-CoV-2 spike glycoprotein," the presence of proline (P) is highly unusual.

Unlike other amino acids, proline produces structural rigidity in proteins and is found in only 5 out of 132 identified furin cleavage site sequences.

Likewise, alanine (A) located just prior to the R-S cleavage point exists in only 5 out of 132 furin cleavage site sequences.

In an early June scientific article, A novel bat coronavirus closely related to SARS-CoV-2 contains natural insertions at the S1/S2 cleavage site of the spike protein, the authors claimed to have identified a bat coronavirus, called RmYN02, that appears to have a precursor of the COVID-19 furin polybasic cleavage site.

RmYN02 has a proline-alanine-alanine (PAA) insertion roughly in a similar position to the COVID-19 virus, but PAA is chemically neutral, lacks any basic amino acids and has no R-S point to be cleaved.

RmYN02's PAA sequence, therefore, cannot be considered a precursor of the COVID-19 furin polybasic cleavage site.

So, the question remains, if no yet identified close relative of COVID-19 has a similar furin polybasic cleavage site, from where did such a unique structural feature with amino acids in unusual positions arise?

Furin polybasic cleavage sites are known to increase viral infectivity and pathogenicity. Genetic engineering techniques for inserting such cleavage sites have existed for at least fifteen years.

At present, no natural evolutionary pathway has been identified to explain the presence of COVID-19s furin polybasic cleavage site.

Those who may have manufactured the COVID-19 virus, could have been trying to mimic the cleavage site found in MERS.

Furthermore, the high rate of human-to-human transmission found for COVID-19, may have resulted from "pre-adapting" the virus for human infection by serial infection or passaging of the virus using animal models genetically-engineered to express the human coronavirus receptor.

There is now a preponderance of evidence that the COVID-19 virus was the product of laboratory experimentation rather than a natural infectious "jump" from bats to humans.

China still has a lot of explaining to do.

(Lawrence Sellin, Ph.D. is a retired U.S. Army Reserve colonel, who previously worked at the U.S. Army Medical Research Institute of Infectious Diseases and conducted basic and clinical research in the pharmaceutical industry. His email address is lawrence.sellin@gmail.com)

(Disclaimer: The opinions expressed above are the personal views of the author and do not reflect the views of ZMCL.)

The rest is here:
Was the MERS virus a model for the creation of COVID-19? - WION

Acute Lymphoblastic Leukemia (AML), also called acute myeloblastic leukemia, acute myelogenous leukemia, acute myeloid leukemia, or acute nonlymphocytic leukemia, is an aggressive, fast-growing, heterogenous group of blood cancers that arise as a result of clonal expansion of myeloid hematopoietic precursors in the bone marrow. Not only are circulating leukemia (blast) cells seen in the peripheral blood, but granulocytopenia, anemia, and thrombocytopenia are also common as proliferating leukemia cells interfere with normal hematopoiesis.

Approximately 40-45% of younger and 10-20% of older adults diagnosed with AML are cured with current standard chemotherapy. However, the outlook for patients with relapsed and/or refractory disease is gloomy. Relapse following conventional chemotherapy remains is a major cause of death.

The process of manufacturing chimeric antigen receptor (CAR) T-cell therapies. [1] T-cells (represented by objects labeled as t) are removed from the patients blood. [2] Then in a lab setting the gene that encodes for the specific antigen receptors is incorporated into the T-cells. [3] Thus producing the CAR receptors (labeled as c) on the surface of the cells. [4] The newly modified T-cells are then further harvested and grown in the lab. [5]. After a certain time period, the engineered T-cells are infused back into the patient. This file is licensed by Reyasingh56 under the Creative Commons Attribution-Share Alike 4.0 International license.Today, the only curative treatment option for patients with AML is allogeneic hematopoietic stem cell transplantation or allo-HSCT, which through its graft-vs.-leukemia effects has the ability to eliminate residual leukemia cells. But it is an ption for only a minority. And despite a long history of success, relapse following allo-HSCT is still a major challenge and is associated with poor prognosis.

In recent years, rresearchers learned a lot about the genomic and epigenomic landscapes of AML. This understanding has paved the way for rational drug development as new drugable targets, resulting in treatments including the antibody-drug conjugate (ADC) gemtuzumab ozogamycin (Mylotarg; Pfizer/Wyeth-Ayerst Laboratories).

CAR T-cell TherapiesChimeric antigen receptor (CAR) T-cells therapies, using a patients own genetically modified T-cells to find and kill cancer, are one of the most exciting recent developments in cancer research and treatment.

Traditional CAR T-cell therapies are an autologous, highly personalised, approach in which T-cells are collected from the patient by leukopheresis and engineered in the laboratory to express a receptor directed at a cancer antigen such as CD19. The cells are then infused back into the patient after administration of a lymphodepletion regimen, most commonly a combination of fludarabine and cyclophosphamide. Durable remissions have been observed in pediatric patients with B-ALL and adults with NHL.

CD19-targeted CAR T-cell therapies, have, over the last decade, yielded remarkable clinical success in certain types of B-cell malignancies, and researchers have made substantial efforts aimed at translating this success to myeloid malignancies.

While complete ablation of CD19-expressing B cells, both cancerous and healthy, is clinically tolerated, the primary challenge limiting the use of CAR T-cells in myeloid malignancies is the absence of a dispensable antigen, as myeloid antigens are often co-expressed on normal hematopoietic stem/progenitor cells (HSPCs), depletion of which would lead to intolerable myeloablation.

A different approachBecause autologous CAR T-cell therapies are patient-specific, each treatment can only be used for that one patient. Furthermore, because CAR T-cells are derived from a single disease-specific antibody, they are, by design, only recognized by one specific antigen. As a consequence, only a small subset of patients with any given cancer may be suited for the treatment.

This specificity means that following leukopheresis, a lot of work needs to be done to create this hyper personalised treatment option, resulting in 3 5 weeks of manufacturing time.

The manufacturing process of CAR T-cell therapies, from a single academic center to a large-scale multi-site manufacturing center further creates challenges. Scaling out production means developing processes consistent across many collection, manufacturing, and treatment sites. This complexity results in a the realitively high cost of currently available CAR T-cell therapies.

To solve some of the concerns with currently available CAR T-cell therapies, researchers are investigating the option to develop allogenic, off-the-shelf Universal CAR T-cell (UCARTs) treatments that can be mass manufactured and be used for multiple patients.

Allogeneic CAR T-cell therapy are generally created from T-cells from healthy donors, not patients. Similar to the autologous approach, donor-derived cells are shipped to a manufacturing facility to be genetically engineered to express the antibody or CAR, however, in contrast to autologous CAR T-cells, allogeneic CAR T-cells are also engineered with an additional technology used to limit the potential for a graft versus host reaction when administered to patients different from the donor.

One unique benefit ofn this approach is that because these therapies hey are premade and available for infusion, there is no requirement to leukopheresis or a need to wait for the CAR T-cells to be manufactured. This strategy also will benefit patients who are cytopenic (which is not an uncommon scenario for leukemia patients) and from whom autologous T-cell collection is not possible.

PioneersAmong the pioneers of developing allogeneic CAR-T therapies are companies including Celyad Oncology, Cellectis, Allogene Therapeutics, and researchers at University of California, Los Angeles (UCLA) in colaboration with Kite/Gilead.

Researchers at UCLA were, for example, able to turn pluripotent stem cells into T-cells through structures called artificial thymic organoids. These organoids mimic the thymus, the organ where T-cells are made from blood stem cells in the body.

Celyad OncologyBelgium-based Celyad Oncology is advancing a number of both autologous and allogeneic CAR T-cell therapies, including proprietary, non-gene edited allogeneic CAR T-cell candidates underpinned by the companys shRNA technology platform. The shRNA platform coupled with Celyads all-in-one vector approach provides flexibility, versatility, and efficiency to the design of novel, off-the-shelf CAR T-cell candidates through a single step engineering process.

In July 2020, the company announced the start of Phase I trials with CYAD-211, Celyads first-in-class short hairpin RNA (shRNA)-based allogeneic CAR T candidate and second non-gene edited off-the-shelf program. CYAD-211 targets B-cell maturation antigen (BCMA) for the treatment of relapsed/refractory multiple myeloma and is engineered to co-express a BCMA-targeting chimeric antigen receptor and a single shRNA, which interferes with the expression of the CD3 component of the T-cell receptor (TCR) complex.

During the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program in May 2020, the company presented updates from its allogeneic programs, including additional data from the alloSHRINK study, an open-label, dose-escalation Phase I trial assessing the safety and clinical activity of three consecutive administrations of CYAD-101, an investigational, non-gene edited, allogeneic CAR T-cell candidate engineered to co-express a chimeric antigen receptor based on NKG2D (a receptor expressed on natural killer (NK) cells that binds to eight stress-induced ligands and the novel inhibitory peptide TIM TCR Inhibitory Molecule), for the treatment of metastatic colorectal cancer (mCRC).

The expression of TIM reduces signalling of the TCR complex, which is responsible for graft-versus host disease.every two weeks administered concurrently with FOLFOX (combination of 5-fluorouracil, leucovorin and oxaliplatin) in patients with refractory metastatic colorectal cancer (mCRC).

The safety and clinical activity data from the alloSHRINK trial in patients with mCRC demonstrated CYAD-101s differentiated profile as an allogeneic CAR T-cell candidate. Furthermore, the absence of clinical evidence of graft-versus-host-disease (GvHD) for CYAD-101 confirms the potential of non-gene edited approaches for the development of allogeneic CAR-T candidates.

Interim data from the alloSHRINK trial showed encouraging anti-tumor activity, with two patients achieving a confirmed partial response (cPR) according to RECIST 1.1 criteria, including one patient with a KRAS-mutation, the most common oncogenic alteration found in all human cancers. In addition, nine patients achieved stable disease (SD), with seven patients demonstrating disease stabilization lasting more than or equal to three months of duration.

Based on these results, clinical trials were broadened to include evaluating CYAD-101 following FOLFIRI (combination of 5-fluorouracil, leucovorin and irinotecan) preconditioning chemotherapy in refractory mCRC patients, at the recommended dose of one billion cells per infusion as an expansion cohort of the alloSHRINK trial. Enrollment in the expansion cohort of the trial is expected to begin during the fourth quarter of 2020.

CellectisCellectis is developping a universal CAR T-cell (UCART) platform in an attempy to create off-the-shelf CAR T-cell therapies. The companys pipeline includes UCART123, a CAR T-cell therapy designed to targets CD123+ leukemic cells in acute myeloid leukemia (AML). The investigational agent is being studied in two open-label Phase I trials: AML123 studying the therapys safety and efficacy in an estimated 156 AML patients, and ABC123 studying the therapys safety and activity in an estimated 72 patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN).

UCART22Another investigational agent in clinical trials is UCART22 which is designed to treat both CD22+ B-cell acute lymphoblastic leukemia (B-ALL) and CD22+ B-cell non-Hodgkin lymphoma (NHL). Cellectis reported that UCART22 is included in an open-label, dose-escalating Phase I trial to study its safety and activity in relapsed or refractory CD22+ B-ALL patients.

UCART22 harbors a surface expression of an anti-CD22 CAR (CD22 scFv-41BB-CD3z) and the RQR8 ligand, a safety feature rendering the T-cells sensitive to the antibody rituximab. Further, to reduce the potential for alloreactivity, the cell surface expression of the T-cell receptor is abrogated through the inactivation of the TCR constant (TRAC) gene using Cellectis TALEN gene-editing technology.[1]

Preclinical data supporting the development of UCART22 was presented by Marina Konopleva, M.D., Ph.D. and her vteam during the 2017 annual meeting of the American Society of Hematology (ASH) meeting. [1]

Cellectis is also developing UCARTCS1 which is developed to treat CS1-expressing hematologic malignancies, such as multiple myeloma (MM). UCARTCLL1 is in preclinical development for treating CLL1-expressing hematologic malignancies, such as AML.

Cellectis and Allogene Therapeutics, another biotech company involved in the developmen t of CAR T-cell therapies, are developing ALLO-501, another CAR T-cell therapy which targets CD19 and is being developed for the the treatment of patients with relapsed or refractory NHL. Allogene Therapeutics is also developing ALLO-715, an investigational CAR T-cell therapy targeting the B-cell maturation antigen (BCMA) for treating relapsed or refractory multiple myeloma and ALLO-819, which targets CD135 (also called FLT3), for treating relapsed or refractory AML.

Allogene, in collaboration with both Cellectis, Pfizer (which has a 25% stake in Allogene) and Servier have numerous active open-label, single-arm Phase I trials for an off-the-shelf allogeneic CAR-T therapy UCART19* in patients with relapsed or refractory CD19+ B-ALL. Participating patients receive lymphodepletion with fludarabine and cyclophosphamide with alemtuzumab, followed by UCART19 infusion. Adults patients with R/R B-ALL are eligible.

The PALL aims to evaluate the safety and feasibility of UCART19 to induce molecular remission in pediatric patients with relapsed or refractory CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) in 18 pediatric patients.

The CALM trial is a dose-escalating study evaluating the therapys safety and tolerability in 40 adult patients; and a long-term safety and efficacy follow-up study in 200 patients with advanced lymphoid malignancies.

Allogene reported preliminary proof-of-concept results during the annual meeting of the American Society of Hematology (ASH) in December 2018.

Data from the first 21 patients from both the PALL (n=7) and CALM (n=14) Phase I studies were pooled. The median age of the participating patients was 22 years (range, 0.8-62 years) and the median number of prior therapies was 4 (range, 1-6). Sixty-two percent of the patients (13/21) had a prior allogeneic stem cell transplant.

Of the 17 patients who received treatment with UCART19 and who received lymphodepletion with fludarabine, cyclophosphamide and alemtuzumab, an anti-CD52 monoclonal antibody, 14 patients (82%) achieved CR/CRi, and 59% of them (10/17) achieved MRD-negative remission.

In stark contrast, the four patients who only received UCART19 and fludarabine and cyclophosphamide without alemtuzumab did not see a response and minimal UCART19 expansion.

Based on these results, researchers noted that apparent importance of an anti-CD52 antibody for the efficacy of allogeneic CAR-T therapies. In addition, safety data also looked promising. The trial results did not include grade 3 or 4 neurotoxicity and only 2 cases of grade 1 graft-versus-host disease (10%), 3 cases of grade 3 or 4 cytokine release syndrome which were considered manageable (14%), 5 cases of grade 3 or 4 viral infections (24%), and 6 cases of grade 4 prolonged cytopenia (29%).

Precision BiosciencesPrecision Biosciences is developing PBCAR0191, an off-the-shelf investigational allogeneic CAR T-cell candidate targeting CD19. The drug candidate is being investigated in a Phase I/IIa multicenter, nonrandomized, open-label, parallel assignment, dose-escalation, and dose-expansion study for the treatment of patients with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) or R/R B-cell precursor acute lymphoblastic leukemia (B-ALL).

The NHL cohort includes patients with mantle cell lymphoma (MCL), an aggressive subtype of NHL, for which Precision has received both Orphan Drug and Fast Track Designations from the U.S. Food and Drug Administration (FDA).

A clinical trial with PBCAR0191 Precision Biosciences is exploring some novel lymphodepletion strategies in addition to fludarabine and cyclophosphamide. Patients with R/R ALL, R/R CLL, R/R Richter transformation, and R/R NHL are eligible. Patients with MRD+ B-ALL are eligible as well. This trial is enrolling patients.

In late September 2020, Precision BioSciences, a clinical stage biotechnology amd Servier, announced the companies have added two additional hematological cancer targets beyond CD19 and two solid tumor targets to its CAR T-cell development and commercial license agreement.

PBCAR20APBCAR20A is an investigational allogeneic anti-CD20 CAR T-cell therapy being developed by Precision Biosciences for the treartment of patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) and patients with R/R chronic lymphocytic leukemia (CLL) or R/R small lymphocytic lymphoma (SLL). The NHL cohort will include patients with mantle cell lymphoma (MCL), an aggressive subtype of NHL, for which Precision BioSciences has received orphan drug designation from the United States Food and Drug Administration (FDA).

PBCAR20A is being evaluated in a Phase I/IIa multicenter, nonrandomized, open-label, dose-escalation and dose-expansion clinical trial in adult NHL and CLL/SLL patients. The trial will be conducted at multiple U.S. sites.

PBCAR269APrecision Biosciences is, in collaboration with Springworks Therapeutics, also developing PBCAR269A, an allogeneic BCMA-targeted CAR T-cell therapy candidate being evaluated for the safety and preliminary clinical activity in a Phase I/IIa multicenter, nonrandomized, open-label, parallel assignment, single-dose, dose-escalation, and dose-expansion study of adults with relapsed or refractory multiple myeloma. In this trial, the starting dose of PBCAR269A is 6 x 105 CAR T cells/kg body weight with subsequent cohorts receiving escalating doses to a maximum dose of 6 x 106 CAR T cells/kg body weight.

PBCAR269A is Precision Biosciencess third CAR T-cell candidate to advance to the clinic and is part of a pipeline of cell-phenotype optimized allogeneic CAR T-cell therapies derived from healthy donors and then modified via a simultaneous TCR knock-out and CAR T-cell knock-in step with the =companys proprietary ARCUS genome editing technology.

The FDA recently granted Fast Track Designation to PBCAR269A for the treatment of relapsed or refractory multiple myeloma for which the FDA previously granted Orphan Drug Designation.

TCR2 TherapeuticsTCR2 Therapeutics is developing a proprietary TRuC (TCR Fusion Construct) T-cells designed to harness the natural T cell receptor complex to recognize and kill cancer cells using the full power of T-cell signaling pathways independent of the human leukocyte antigen (HLA).

While succesful in hematological malignancies, CAR T-cells therapies have generally struggled to show efficacy against solid tumors. Researchers at TCR2 Therapeutics believe this is is caused by the fact that CAR T-cell therapies only utilize a single TCR subunit, and, as a result, do not benefit from all of the activation and regulatory elements of the natural TCR complex. By engineering TCR T-cells, which are designed to utilize the complete TCR, they have demonstrated clinical activity in solid tumors. However, this approach has also shown major limitations. TCR T-cells require tumors to express HLA to bind tumor antigens. HLA is often downregulated in cancers, preventing T-cell detection. In addition, each specific TCR-T cell therapy can only be used in patients with one of several specific HLA subtypes, limiting universal applicability of this approach and increasing the time and cost of patient enrollment in clinical trials.

In an attempt to solve this problem, researchers at TCR2 Therapeutics have developped a proprieatarry TRuC-T Cells which are designed to incorporate the best features of CAR-T and TCR-T cell therapies and overcome the limitations. The TRuC platform is a novel T cell therapy platform, which uses the complete TCR complex without the need for HLA matching.

By conjugating the tumor antigen binder to the TCR complex, the TRuC construct recognizes highly expressed surface antigens on tumor cells without the need for HLA and engage the complete TCR machinery to drive the totality of T-cell functions required for potent, modulated and durable tumor killing.

In preclinical studies, TCR2 Therapeutics TRuC T-cells technology has demonstrated superior anti-tumor activity in vivo compared to CAR T-cells therapies, while, at the same time, releasing lower levels of cytokines. These data are encouraging for the treatment of solid tumors where CAR T-cells have not shown significant clinical activity due to very short persistence and for hematologic tumors where a high incidence of severe cytokine release syndrome remains a major concern.

TCR2 Therapeutics product candidates include TC-210 and TC-110.

TC-210 is designed to targets mesothelin-positive solid tumors. While its expression in normal tissues is low, mesothelin is highly expressed in many solid tumors. Mesothelin overexpression has also been correlated with poorer prognosis in certain cancer types and plays a role in tumorigenesis. TC-210 is being developed for the treatment of non-small cell lung cancer, ovarian cancer, malignant pleural/peritoneal mesothelioma and cholangiocarcinoma.

The companys TRuC-T cell targeting CD19-positive B-cell hematological malignancies, TC-110, is being developed to improve upon and address the unmet needs of current CD19-directed CAR T-cell therapies. The clinical development TC-110 focus on the treatment of adult acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Preclinical data demonstrates that TC-110 is superior to CD19-CAR-T cells (carrying either 4-1BB or CD28 co-stimulatory domains) both in anti-tumor activity as well as the level of cytokine release which may translate into lower rates of adverse events. The development of TC-110 starts with autologous T-cells collection by leukopheresis. These T-cells undergo genetic engineering to create TRuC-T cells targeting CD19.

This strategy combines the best features of CAR T-cells and the native T-cell receptor. It is open for R/R NHL and R/R B-ALL.

AUTO1Auto1 is an autologous CD19 CAR T-cell investigational therapyis being developped by Autolus Therapeutics. The investigational drug uses a single-chain variable fragment (scFv) called CAT with a lower affinity for CD19 and a faster off-rate compared to the FMC63 scFv used in other approved CD19 CAR T-cell therapies. The investigational therapy is designed to overcome the limitations in safety while maintaining similar levels of efficacy compared to current CD19 CAR T-cell therapies.

Designed to have a fast target binding off-rate to minimize excessive activation of the programmed T-cells, AUTO1 may reduce toxicity and be less prone to T-cell exhaustion, which could enhance persistence and improve the T-cells abilities to engage in serial killing of target cancer cells.

In 2018, Autolus signed a license agreement UCL Business plc (UCLB), the technology-transfer company of UCL, to develop and commercialize AUTO1 for the treatment of B cell malignancies. AUTO1 is currently being evaluated in two Phase I studies, one in pediatric ALL and one in adult ALL.

CARPALL trialInitial results from the ongoing Phase I CARPALL trial of AUTO1 were presented during European Hematology Association 1st European CAR T Cell Meeting held in Paris, France, February 14-16, 2019.

Enrolled patients had a median age of 9 years with a median of 4 lines of prior treatment. Seventeen patients were enrolled, and 14 patients received an infusion of CAR T cells. Ten of 14 patients had relapsed post allogeneic stem cell transplant. Eight patients were treated in second relapse, 5 in > second relapse and 3 had relapsed after prior blinatumomab or inotuzumab therapy. Two patients had ongoing CNS disease at enrollment.

This data confirmed that AUTO1 did not induces severe cytokine release syndrome (CRS) (Grade 3-5). Nine patients experienced Grade 1 CRS, and 4 patients experienced Grade 2 CRS. No patients required tociluzumab or steroids. As previously reported, one patient experienced Grade 4 neurotoxicity; there were no other reports of severe neurotoxicity (Grade 3-5). The mean cumulative exposure to AUTO1 CAR T-cells in the first 28 days as assessed by AUC was 1,721,355 copies/g DNA. Eleven patients experienced cytopenia that was not resolved by day 28 or recurring after day 28: 3 patients Grades 1-3 and 8 patients Grade 4. Two patients developed significant infections, and 1 patient died from sepsis while in molecular complete response (CR).

With a single dose of CAR T cells at 1 million cells/kg dose, 12/14 (86%) achieved molecular CR. Five patients relapsed with CD19 negative disease. Event free survival (EFS) based on morphological relapse was 67% (CI 34-86%) and 46% (CI 16-72%) and overall survival (OS) was 84% (CI 50-96%) and 63% (CI 27-85%) at 6 and 12 months, respectively.

CAR T cell expansion was observed in all responding patients (N=12), with CAR T cells comprising up to 84% of circulating T cells at the point of maximal expansion. The median persistence of CAR T-cells was 215 days.

The median duration of remission in responding patients was 7.3 months with a median follow-up of 14 months. Five of 14 patients (37%) remain in CR with ongoing persistence of CAR T-cells and associated B cell aplasia.

Fate TherapeuticsFT819 is an off-the-shelf CAR T-cell therapy targeting CD19 being developed by Fate Therapeutics. The T-cells are derived from a clonal engineered master induced pluripotent stem cell line (iPSCs) with a novel 1XX CAR targeting CD19 inserted into the T-cell receptor alpha constant (TRAC) locus and edited for elimination of T-cell receptor (TCR) expression.

Patients participating in the companys clinbical trial will receive lymphodepletion with fludarabine and cyclophosphamide. Some patients will also receive IL-2. Patients with R/R ALL, R/R CLL, R/R Richter transformation, and R/R NHL are eligible. Patients with MRD+ B-ALL are eligible as well.

At the Annual Meeting of the American Societ of Hematology held in December 2019, researchers from Fate Therapeutics presented new in vivo preclinical data demonstrating that FT819 exhibits durable tumor control and extended survival. In a stringent xenograft model of disseminated lymphoblastic leukemia, FT819 demonstrated enhanced tumor clearance and control of leukemia as compared to primary CAR19 T-cells. At Day 35 following administration, a bone marrow assessment showed that FT819 persisted and continued to demonstrate tumor clearance, whereas primary CAR T cells, while persisting, were not able to control tumor growth. [2]

CAR-NK CD19Allogeneic cord blood-derived Natural Killer (NK) cells are another off-the-shelf product that does not require the collection of cells from each patient.

Unlike T-cells, NK-cells do not cause GVHD and can be given safely in the allogeneic setting. At MD Anderson Cancer Center, Katy Rezvani, M.D., Ph.D, Professor, Stem Cell Transplantation and Cellular Therapy, and her team broadly focuses their research on the role of natural killer (NK) cells in mediating protection against hematologic malignancies and solid tumors and strategies to enhance killing function against various cancer.

As part of their research, the team has developed a novel cord blood-derived NK-CAR product that expresses a CAR against CD19; ectopically produces IL-15 to support NK-cell proliferation and persistence in vivo; and expresses a suicide gene, inducible caspase 9, to address any potential safety concerns.

In this phase I and II trial researchers administered HLA-mismatched anti-CD19 CAR-NK cells derived from cord blood to 11 patients with relapsed or refractory CD19-positive cancers (non-Hodgkins lymphoma or chronic lymphocytic leukemia [CLL]). NK cells were transduced with a retroviral vector expressing genes that encode anti-CD19 CAR, interleukin-15, and inducible caspase 9 as a safety switch. The cells were expanded ex vivo and administered in a single infusion at one of three doses (1105, 1106, or 1107 CAR-NK cells per kilogram of body weight) after lymphodepleting chemotherapy. The preliminarry resilts of the trials confirmed that administration of CAR-NK cells was not associated with the development of cytokine release syndrome, neurotoxicity, or graft-versus-host disease, and there was no increase in the levels of inflammatory cytokines, including interleukin-6, over baseline.

The study results also demonstrated that of the 11 patients who were treated, 8 patients (73%) had a response. Of these patients, 7 (4 with lymphoma and 3 with CLL) had a complete remission ICR), and 1 had remission of the Richters transformation component but had persistent CLL. Noteworthy was that responses were rapid and seen within 30 days after infusion at all dose levels. The infused CAR-NK cells expanded and persisted at low levels for at least 12 months. The researchers also noted that a majority of the 11 participating patients with relapsed or refractory CD19-positive cancers had a response to treatment with CAR-NK cells without the development of major toxic effects.[3]

Note* Servier will hold ex-US commercial rights. Servier is the sponsor of the UCART19 trials.

Clinical trialsalloSHRINK Standard cHemotherapy Regimen and Immunotherapy With Allogeneic NKG2D-based CYAD-101 Chimeric Antigen Receptor T-cells NCT03692429Study Evaluating Safety and Efficacy of UCART123 in Patients With Relapsed/ Refractory Acute Myeloid Leukemia (AMELI-01) NCT03190278Study to Evaluate the Safety and Clinical Activity of UCART123 in Patients With BPDCN (ABC123) NCT03203369Study of UCART19 in Pediatric Patients With Relapsed/Refractory B Acute Lymphoblastic Leukemia (PALL) NCT02808442Dose Escalation Study of UCART19 in Adult Patients With Relapsed / Refractory B-cell Acute Lymphoblastic Leukaemia (CALM) NCT02746952Dose-escalation Study of Safety of PBCAR0191 in Patients With r/r NHL and r/r B-cell ALL NCT03666000.Dose-escalation Study of Safety of PBCAR20A in Subjects With r/r NHL or r/r CLL/SLL NCT04030195A Dose-escalation Study to Evaluate the Safety and Clinical Activity of PBCAR269A in Study Participants With Relapsed/Refractory Multiple Myeloma NCT04171843TC-110 T Cells in Adults With Relapsed or Refractory Non-Hodgkin Lymphoma or Acute Lymphoblastic Leukemia NCT04323657Phase 1/2 Trial of TC-210 T Cells in Patients With Advanced Mesothelin-Expressing Cancer NCT03907852CARPALL: Immunotherapy With CD19 CAR T-cells for CD19+ Haematological Malignancies NCT02443831Umbilical & Cord Blood (CB) Derived CAR-Engineered NK Cells for B Lymphoid Malignancies NCT03056339

Reference[1] Petti F. Broadening the Applicability of CAR-T Immunotherapy to Treat the Untreatable. OncoZine. October 24, 2019 [Article][2] Wells J, Cai T, Schiffer-Manniou C, Filipe S, Gouble A, Galetto R, Jain N, Jabbour EJ, Smith J, Konopleva M. Pre-Clinical Activity of Allogeneic Anti-CD22 CAR-T Cells for the Treatment of B-Cell Acute Lymphoblastic Leukemia Blood (2017) 130 (Supplement 1): 808. https://doi.org/10.1182/blood.V130.Suppl_1.808.808%5B3%5D Chang C, Van Der Stegen S, Mili M, Clarke R, Lai YS, Witty A, Lindenbergh P, Yang BH, et al. FT819: Translation of Off-the-Shelf TCR-Less Trac-1XX CAR-T Cells in Support of First-of-Kind Phase I Clinical Trial. Blood (2019) 134 (Supplement_1): 4434.https://doi.org/10.1182/blood-2019-130584%5B4%5D Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P, Basar R, Nassif Kerbauy L, Overman B, Thall P, Kaplan M, Nandivada V, Kaur I, Nunez Cortes A, Cao K, Daher M, Hosing C, Cohen EN, Kebriaei P, Mehta R, Neelapu S, Nieto Y, Wang M, Wierda W, Keating M, Champlin R, Shpall EJ, Rezvani K. Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors. N Engl J Med. 2020 Feb 6;382(6):545-553. doi: 10.1056/NEJMoa1910607. PMID: 32023374; PMCID: PMC7101242.

Featured image: T-cells attacking a cancer cell. Photo courtesy: Fotolia/Adobe 2016 2020. Used with permission.

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CAR T-cell Therapies for the Treatment of Patients with Acute Lymphoblastic Leukemia - OncoZine

A microscope photograph of a heart muscle cell. The regular green patterns show stained actin filaments.

By Tina Hilding, Voiland College of Engineering and Architecture

It might look like a little game at the molecular scale.

Filament-like proteins in heart muscle cells have to be exactly the same length so that they can coordinate perfectly to make the heart beat.

Another protein decides when the filament is the right size and puts a wee little cap on it. But, if that protein makes a mistake and puts the cap on too early, another protein, leiomodin, comes along and knocks the cap out of the way.

This little dance at the molecular scale might sound insignificant, but it plays a critical role in the development of healthy heart and other muscles. Reporting in the journal, Plos Biology,a WSU research team has proven for the first time how the mechanism works.

The finding could someday lead to improved diagnostics and medical treatments for serious and sometimes devastating hereditary heart conditions that come about from genetic mutations in the proteins. One of these conditions, cardiomyopathy, affects as many as one in 500 people around the world and can often be fatal or have lifetime health consequences. A similar condition called nemaline myopathy affects skeletal muscles throughout the body with often devastating consequences.

Mutations in these proteins are found in patients with myopathy, saidAlla Kostyukova, associate professor in the Gene and LindaVoiland School of Chemical Engineering and Bioengineeringand leader of the project. Our work is to prove that these mutations cause these problems and to propose strategies for treatment.

Heart muscle is made of tiny thick and thin filaments of proteins. With the help of electrical signals, the rope-like filaments bind and unbind in an intricate and precise architecture, allowing heart muscle to contract and beat.

The thin filaments are made of actin, the most abundant protein in the human body. Tropomysin, another protein, wraps itself around the actin filaments. Tropomyosin together with two other proteins, tropomodulin and leiomodin, at the end of the actin filaments act as a sort of cap and determine the filament length.

Its beautifully designed, said Kostyukova, whose research is focused on understanding protein structures.

And, tightly regulated.

To keep heart muscle healthy, the actin filaments, which are about a micron long, all have to be the exact same length. In families with cardiomyopathy, genetic mutations result in formation of filaments that are either too short or too long. Those affected can have significant heart problems that cause disability, illness and death.

In a project that spanned seven years, the researchers proved that leiomodin attaches to the end of the actin filament and kicks out the other protein, tropomodulin, to assure the actin filaments proper length.

This is the first time that this has been shown with the atomic-level precision, said Dmitri Tolkatchev, research assistant professor in the Voiland School and lead author on the paper. Previously, several laboratories attempted to solve this problem with very little success. With our data we finally have a direct proof.

The researchers used state-of-the-art approaches to make the key proteins and study them at the molecular and cellular level. The work entailed designing the molecules, constructing them at the gene level in a plasmid, and then producing them into bacterial or cardiac cells. The researchers used nuclear magnetic resonance, which works on the same physical principle as Magnetic Resonance Imaging (MRIs), to understand the proteins binding at the atomic level. They also used molecular dynamic simulation to model them.

The probability of being able to show this mechanism was not high, but the impact of the discovery is, said Tolkatchev, an expert in nuclear magnetic resonance. This was a very important problem to study and could have a significant impact in the field of muscle mechanics.

The researchers hope to continue the work, identifying additional components and molecular mechanisms that regulate thin filament architecture, whether diseased or healthy.

The multidisciplinary group included researchers from the University of Arizona led by Carol Gregorio, director of the Cellular and Molecular Medicine Department. WSUs group has expertise in protein structure, structural biochemistry, and properties of actin filaments and regulatory proteins, and UAs group has expertise in molecular, cellular and developmental biology of muscle assembly. The collaborative work was funded by the National Institutes of Health.

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TORONTO, Oct. 16, 2020 (GLOBE NEWSWIRE) -- Arch Biopartners Inc. (“Arch” or the “Company”) (TSX Venture: ARCH and OTCQB: ACHFF), announced today it has dosed the first patient in the Phase II trial of its lead drug LSALT peptide, targeting prevention of acute lung injury, acute kidney injury and other complications caused by inflammation in hospitalized patients with moderate to severe cases of COVID-19.

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First Patient Dosed in Phase II Trial to Treat Complications in COVID-19

MALVERN, Pa., Oct. 16, 2020 (GLOBE NEWSWIRE) -- Ocugen, Inc. (NASDAQ: OCGN), a biopharmaceutical company focused on discovering, developing, and commercializing transformative therapies to cure blindness diseases, today announced that Cantor Fitzgerald and Kristen Kluska will host a Management Fireside Chat Zoom Call on October 21 at 11 a.m. ET.

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MONTREAL, Oct. 16, 2020 (GLOBE NEWSWIRE) -- Theratechnologies Inc. (Theratechnologies) (TSX: TH) (NASDAQ: THTX), a biopharmaceutical company focused on the development and commercialization of innovative therapies, today announced the appointment of Mr. Andrew Molson and Mr. Alain Trudeau as new independent members to its Board of Directors.

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Theratechnologies Appoints Two New Board Members

SOUTH ORANGE, NJ, Oct. 16, 2020 (GLOBE NEWSWIRE) -- via NewMediaWire -- Nephros, Inc. (Nasdaq: NEPH) (“Nephros” or the “Company”), a commercial-stage company that develops and sells high performance water purification products and pathogen detection systems to the medical device and commercial markets, today announced the pricing of a registered direct offering of 833,333 shares of common stock at a price to the public of $6.00 per share.  The offering is expected to close on or about October 20, 2020, subject to the satisfaction of customary closing conditions.

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Nephros Announces Pricing of $5 Million Registered Direct Offering of Common Stock

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Novartis receives positive CHMP opinion for Leqvio®* (inclisiran), a potential first-in-class siRNA for the treatment of high cholesterol

Final European Commission Decision on Marketing Approval Anticipated in Q4 2020 Final European Commission Decision on Marketing Approval Anticipated in Q4 2020

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Aimmune Receives Positive CHMP Opinion on PALFORZIA® for the Treatment of Patients with Peanut Allergy in Europe

CHMP recommends approval of Dupixent® (dupilumab) for children aged 6 to 11 years with severe atopic dermatitis

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CHMP recommends approval of Dupixent® (dupilumab) for children aged 6 to 11 years with severe atopic dermatitis

GARDEN CITY, N.Y., Oct. 16, 2020 (GLOBE NEWSWIRE) -- Beyond Air, Inc. (NASDAQ: XAIR), a clinical-stage medical device and biopharmaceutical company focused on developing inhaled nitric oxide (NO) for the treatment of patients with respiratory conditions, including serious lung infections and pulmonary hypertension, and gaseous NO (gNO) for the treatment of solid tumors, today announced new in vitro and in vivo preclinical data that suggest the Company’s innovative gNO-based treatment may treat lung cancer locally and its metastases systemically, potentially via stimulation of an anti-tumor immune response. These data were included in a presentation by Hila Confino, PhD of Beyond Air at the International Association for the Study of Lung Cancer’s (IASLC) North America Conference on Lung Cancer 2020 (NACLC 2020), which is being held from October 16th to 17th.

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Beyond Air® Presents Positive New Preclinical Data for the Use of a Single Injection of Gaseous Nitric Oxide as a Novel In situ Cancer Vaccination

EMERYVILLE, Calif., Oct. 16, 2020 (GLOBE NEWSWIRE) -- Zogenix (NASDAQ: ZGNX), a global biopharmaceutical company developing rare disease therapies, today announced that the Committee for Medicinal Products for Human Use (CHMP), a part of the European Medicines Agency (EMA), has adopted a positive opinion recommending the marketing authorization of FINTEPLA® (fenfluramine) oral solution for the treatment of seizures associated with Dravet syndrome, a rare and devastating infant- and childhood onset epilepsy, as an add-on therapy to other antiepileptic medicines for patients two years of age and older. The European Commission (EC) is expected to make a final decision on the company’s Marketing Authorization Application (MAA) by the end of the year.

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Zogenix Receives Positive CHMP Opinion for FINTEPLA® (Fenfluramine) Oral Solution for the Treatment of Seizures in Patients with Dravet Syndrome

15 data presentations cover each of Spero’s three pipeline programs and include a late breaker oral presentation on the Phase 3 ADAPT-PO clinical trial 15 data presentations cover each of Spero’s three pipeline programs and include a late breaker oral presentation on the Phase 3 ADAPT-PO clinical trial

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Spero Therapeutics to Present Data for All Pipeline Programs at IDWeek 2020

NEW YORK, Oct. 16, 2020 (GLOBE NEWSWIRE) -- NetworkNewsAudio -- Cybin Corp. announces the availability of a broadcast titled, “Multi-Billion-Dollar Market Forecast in Psychedelic Therapeutics.”

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Psychedelics Experiencing Renaissance, Offer Tremendous Treatment Potential

NEW YORK, Oct. 16, 2020 (GLOBE NEWSWIRE) -- NetworkNewsAudio -- 180 Life Sciences Corp. announces the availability of a broadcast titled, “Blockbuster Year and Bright Horizons for SPACs.”

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SPACs Show Investors Faster, Simpler Way to Go Public

NEW YORK, Oct. 16, 2020 (GLOBE NEWSWIRE) -- Y-mAbs Therapeutics, Inc. (the “Company” or “Y-mAbs”) (Nasdaq: YMAB) a late-stage clinical biopharmaceutical company focused on the development and commercialization of novel, antibody-based therapeutic products for the treatment of cancer, today announced clinical updates on naxitamab for the treatment of relapsed/refractory high-risk neuroblastoma and omburtamab for CNS/leptomeningeal metastasis from neuroblastoma. Data was presented at the International Society of Pediatric Oncology (“SIOP”) Virtual Annual Congress held October 14 through October 17, 2020 in Ottawa, Canada. The naxitamab data was presented by Dr. Jaume Mora from SJD Barcelona Children's Hospital, and the omburtamab data was presented by Dr. Kim Kramer from Memorial Sloan Kettering Cancer Center (“MSK”).

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Y-mAbs Announces Update on Naxitamab and Omburtamab in Neuroblastoma

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German Federal Joint Committee (G-BA) Issues Nationwide Reimbursement Decision for EndoPredict® Breast Cancer Prognostic Test