--Focusing on neuroblastoma, the researchers used a multi-omics approach to identify tumor-specific peptides and then used genetic engineering to harness the immune system to destroy tumors--

PHILADELPHIA, Nov. 3, 2021 /PRNewswire/ -- In a breakthrough for the treatment of aggressive solid cancers, researchers at Children's Hospital of Philadelphia (CHOP) have developed a novel cancer therapy that targets proteins inside cancer cells that are essential for tumor growth and survival but have been historically impossible to reach. Using the power of large data sets and advanced computational approaches, the researchers were able to identify peptides that are presented on the surface of tumor cells and can be targeted with "peptide-centric" chimeric antigen receptors (PC-CARs), a new class of engineered T cells, stimulating an immune response that eradicates tumors.

Senior author John M. Maris, MD, pediatric oncologist and Giulio D'Angio Chair in Neuroblastoma Research at CHOP

The discovery, which was described today in Nature, opens the door to treating a broader array of cancers with immunotherapy as well as applying each therapy across a greater proportion of the population.

"This research is extremely exciting because it raises the possibility of targeting very specific tumor molecules, expanding both the cancers that can be treated with immunotherapy and the patient population who can benefit," said Mark Yarmarkovich, PhD, an investigator in the Maris Laboratory at Children's Hospital of Philadelphia and first author of the paper. "By using a multi-omics approach, we were able to identify peptides specific to neuroblastoma tumors, but this method could be used in any cancer, allowing for a more personalized approach to cancer treatment."

The development of CAR T cell-based cancer immunotherapy marked a breakthrough in the treatment of leukemia, but the approach has not yet made significant strides against solid tumors due, at least in part, to a lack of tumor-specific targets. In these cancers, most of the proteins responsible for tumor growth and survival are in the nuclei of tumor cells, not on the cell surface, where they would generally be accessible to CAR T cells. Instead, fragments of these proteins may be presented on the tumor cell surface through the presentation of peptides on the major histocompatibility complex (MHC), which evolved to present viral and bacterial peptides to the immune system. Cancer cells can also present intracellular proteins on MHC, and if these are mutant peptides, they may be recognized as foreign. However, all pediatric cancers and many adult malignancies have few mutations and are rather driven by other factors like dysregulated developmental pathways.

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Neuroblastoma is an explosively aggressive pediatric cancer that is driven by modifications of gene expression that promote uncontrolled tumor growth. Historically, neuroblastoma has been treated with chemotherapy, surgery, and radiation therapy, but patients often relapse with forms of the disease that are chemotherapy resistant. Additionally, the low mutational burden of the cancer, combined with its low MHC expression, have made it difficult to target with immunotherapies.

Despite these obstacles, the researchers hypothesized that some of the peptides presented on the surface of neuroblastoma tumor cells come from proteins that are essential for tumor growth and survival and could be targeted with synthetic CARs. These PC-CARs would allow for direct targeting and killing of tumor cells. The challenge was differentiating tumor-specific peptides from other, similar looking peptides or peptides that exist in normal tissues to avoid cross-reactivity and lethal toxicity.

To do so, the researchers stripped the MHC molecules off neuroblastoma cells and determined which peptides were present and at what abundance. They used a large genomic dataset that the Maris lab has generated to determine which peptides were unique to neuroblastoma and not expressed by normal tissues. They prioritized peptides that were derived from genes essential to the tumor and had characteristics required to engage the immune system. To weed out any potential antigens that might have cross reactivity with normal tissue, the researchers filtered the remaining tumor peptides against a database of MHC peptides on normal tissues, removing any peptide with a parent gene represented in normal tissue.

Using this multi-omics approach, the researchers pinpointed an unmutated neuroblastoma peptide that is derived from PHOX2B, a neuroblastoma dependency gene and transcriptional regulator that was previously identified and characterized at CHOP. The next major hurdle was developing a PC-CAR that specifically recognized just the peptide, which makes up 2-3% of the peptide-MHC complex. In collaboration with antibody-discovery company Myrio Therapeutics, the researchers developed a PC-CAR targeting this peptide and showed that these PC-CARs recognized the tumor-specific peptide on different HLA types, meaning the treatment could be applied to patients of diverse genetic lineages.

Taking the research a step further, the team tested the PC-CARs in mice and found that the treatment led to complete and targeted elimination of neuroblastoma tumors.

"We are excited about this work because it allows us to now go after essential cancer drivers that have been considered 'undruggable' in the past. We think that PC-CARS have the potential to vastly expand the pool of immunotherapies and significantly widen the population of eligible patients," said senior author John M. Maris, MD, pediatric oncologist and Giulio D'Angio Chair in Neuroblastoma Research at CHOP. "Thanks to the Acceleration grant we received through the Cell and Gene Therapy Collaborative at CHOP, we will bring our PHOX2B PC-CAR to a clinical trial at CHOP in late 2022 or early 2023."

Yarmarkovich et al. "Therapeutic Targeting of Intracellular Oncoproteins with Peptide-Centric CAR T Cells," Nature, November 3, 2021, DOI: 10.1038/s41586-021-04061-6

About Children's Hospital of Philadelphia:Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. In addition, its unique family-centered care and public service programs have brought the 595-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu

Contact: Jennifer LeeChildren's Hospital of Philadelphia(267) 426-6084LEEJ41@chop.edu

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Research from the nonprofit U.S. Right to Know has undergirded New York Times reporting on the food system, and outlets ranging from Vanity Fair to the National Review to the Washington Examiner to The Intercept have cited the groups inquiries into the origins of COVID-19.

But the Oakland-based truth and transparency organizations own provenance has gone largely unexamined, even as public interest and political furor over the controversial lab-leak theoryand the even more broadly disputed notion that the novel coronavirus was the result of engineeringhave steadily escalated. However, The Daily Beast found that public documents, including USRTKs own disclosures, show even as the group does not advocate against vaccines, its roots run into a vitriolically anti-vaccine organization that has promoted conspiracy theories about the Sept. 11 attacks and The Great Reset.

That theory posits that pandemic-safety protocols are a prelude to a new global regime of government and corporate control.

Filings with the Internal Revenue Service and the state of California show that USRTK launched in 2014 on a $44,500 grant from the Organic Consumers Association (OCA). For the first two years of USRTKs existence, the Minnesota-based OCA was its lone funder, with contributions swelling as years passed, and totaling more than $1 million in 2021, according to USRTKs own reporting.

While the self-described investigative research group has acquired other contributors, the Organic Consumers Association has far and away remained the largest, with its gifts to USRTK amounting to almost double the sum received from the next biggest donor. The Organic Consumers Association has also been the only organization to grant money to USRTK every year since its inception.

Like USRTK, the 23-year-old Organic Consumers Association began as a group preoccupied with pesticides and genetically modified organisms. But as it gained financial backing from ultra-rich backers in the wellness sectormost notably supplement kingpin Joseph Mercolait adopted their conspiratorial anti-vaccine views, as The Daily Beast previously reported.

Earlier this year, OCA founder Ronnie Cummins, who has also advanced 9/11 truther narratives, co-authored a book with Mercola which purported to expose The Great Reset, Lockdowns, Vaccine Passports, and the New Normal. The books footnotes included multiple citations of USRTK research on COVID-19s origins and, in promoting the book last month, Cummins referred to USRTK as a longtime ally. (Cummins did not respond to a request for comment.)

In late 2020, a USRTK researcher also participated in a Facebook Live event the Organic Consumers Association hosted. A lot of pieces dont fit the animal-origin story thats prevailing, the USRTK staffer asserted, citing what he described as the viruss unusual qualities.

Meanwhile, most scientistsand a recently declassified U.S. intelligence reporthave concluded that the virus was most likely not the product of deliberate genetic engineering.

USRTK co-founder Gary Ruskin, the only staffer at the organization who responded to The Daily Beasts queries, admitted that he had known Cummins for decades and launched the group with his support. But he insisted his group had nothing to do with his patrons more controversial views.

We wanted to start a new organization to stand up for the idea that people have the right to know what's in their food. Ronnie was supportive of this, Ruskin wrote in an email to The Daily Beast. We dont work on the issue of vaccines.

But Cummins is hardly the only anti-vaxxer operation with which the group has fraternized.

Public records show the organization has also received considerable financial contributions from the Westreich Foundation. That group, in turn, has bankrolled multiple anti-inoculation groups, including the National Vaccine Information Center, which experts have long called the most powerful anti-vaccine organization in America. Until last year, the Westreich Foundation maintained a Vaccine Safety page on its website that included false assertions that immunization is total nonsense and that vaccine safety is the greatest lie ever told.

The only phone number for the Westreich Foundation The Daily Beast could find was disconnected.

Further, though it has not echoed his notorious views on vaccines specifically, USRTK has repeatedly used its platforms to amplify Robert F. Kennedy Jr., perhaps Americas most infamous anti-vaxxer. He has in turn amplified themparticularly on the issue of COVID-19s origins. This Spring, USRTK research director Carey Gillam published excerpts of her recent book on agrochemical giant Monsanto on Kennedy Jr.s website, and in June she appeared on his podcast to discuss the issue.

All this time, Gillam has been a regular contributor to The Guardian, where her work has focused on environmental degradation and the food system. Neither Gillam nor Guardian U.S. editor John Mulholland responded to requests for comment, and Ruskin dodged questions about her decision to collaborate with Kennedy Jr., who the Center for Countering Digital Hate identified as one of the biggest purveyors of COVID-19 falsehoods on the Internet.

Robert Kennedy has lots of views about lots of things, Ruskin wrote. I dont really follow them all especially closely.

Dr. David Gorski of Wayne State University, who first identified USRTK as an arm of the Organic Consumers Association on the blog Science-Based Medicine in 2016, argued that the two nonprofits share a similar set of obsessions: namely, perceived tampering with nature. He argued USRTK took reasonable distrust of corporations and righteous calls for accountability to an extreme, tipping into pseudoscience and conspiracy theories.

"They started primarily as anti-GMO and anti-pesticide of any kind, and definitely into various conspiracy theories about Monsanto, [herbicide] glyphosate, etcetera. And that was primarily how I knew them, Gorski said. "Whats fascinating is how fast theyve pivoted to COVID nonsense.

But Gorski also posited the groups intensifying interest in the widely dismissed notion that COVID-19 sprang from so-called gain-of-function experiments at the Wuhan Institute of Virology was a natural evolution from USRTKs original mission.

"Think of it this way: if you come from a belief system where genetically manipulating organisms is dangerous, and its the goal of the corporations to exploit and harm and exploit us, he said, a group like that would be very much attracted to the idea that this horrible, deadly disease came from humans manipulating coronaviruses.

Dr. Kathleen Jamieson, professor of communication at the University of Pennsylvania and author of a recent article on conspiracists exploitation of uncertainty in COVID-19 science, noted USRTKs work flattens out crucial differences between the lab-leak theory with the notion that the virus was artificially modified. She pointed to a USRTK report that contrasted a scientific articles claimThere is currently no credible evidence to support the claim that SARS-CoV-2 originated from a laboratory-engineered CoVwith a private email the group obtained in which one of the same articles authors wrote, We cannot rule out the possibility that it comes from a bat virus leaked out of a lab.

The role of some of the players in that ecosystem is trying to maintain a more professional and trustworthy looking exterior.

Callum Hood

In fact, Jamieson noted, these claims do not contradict each other at all. Some versions of the lab-leak hypothesis have suggested that scientists at the Wuhan lab were studying a naturally occurring coronavirus in bats there, and failed to observe proper safety precautionsnot that they created the pathogen in a petri dish.

The difference between there being lab origin and the virus being genetically engineered in the lab is really important, she asserted. Theres some slippage across the materials you sent me between lab origin and the claim of it being genetically engineered.

Jamieson argued USRTKs work deserved scrutiny because of its funding and affiliations. But she also noted that the organizations published research stopped short of open conspiracy theorizing on the virus origins.

"Their language is not the traditional language of conspiracy theorists, Jamieson told The Daily Beast. My definition of a conspiracy theory is that there are powerful individuals of malign intent who are covering up.

But this may have to do with USRTKs role in what Callum Hood, research director at the Center for Countering Digital Hate, suggests amounts to a larger anti-science/anti-vaccine ecosystem. While Mercola and Cummins group may indulge in wild speculation about nefarious international plots, other organizations like Kennedys Childrens Health Defense and USRTK strive to maintain a respectable sheen.

The role of some of the players in that ecosystem is trying to maintain a more professional and trustworthy looking exterior, Hood said. "Childrens Health Defense is one of those which sort of goes to great lengths to look trustworthy, and U.S. Right to Know also appears to be trying to present itself as a trustworthy investigative organization.

The real target of proponents of the gain-of-function theory, Hood asserted, is Dr. Anthony Fauci. And, going by repeated explosive exchanges between Sen. Rand Paul (R-KY) and Fauci over government funding of groups engaged in gain-of-function research, they are hitting their target.

Some of Rands most recent verbal fusillades came after The Intercept published documents detailing U.S. grants to an organization that collaborated with the Wuhan lab. Although in this case USRTK did not provide the documents, as it had for past Intercept pieces, Ruskin himself donated a quote.

This is a road map to the high-risk research that could have led to the current pandemic, he told the left-leaning outlet.

The Intercepts reporters did not respond to requests for comment. Likewise most of the journalists or news organizations The Daily Beast contacted for this piece did not respond or declined to comment. Those who did requested anonymity in order to speak freely, and attested that they did not know about the depth USRTKs relationship with fringe groups when they accepted its assistance, and maintained they independently verified the authenticity of materials the group sent them.

Ruskin, for his part, denied promoting pseudoscience and conspiracies, and insisted his group had not conflated the lab-leak hypothesis with the bioengineering theory.

We stand by our work, he said, noting the group has published material in peer-reviewed journals. We talk with lots of people about our work, but we dont work on vaccines.

Meanwhile Jamieson, the communications professor and conspiracy theory expert, argued that uncertainty about COVID-19s originsand conspiracy theorieswill fester so long as Chinese authorities continue to resist an open investigation. What is necessary, she argued, is transparency from government actors and investigations that do not begin with presuppositions about how the virus emerged.

There are legitimate, important questions here that need to be answered, she said. "In the absence of certainty of the origins, not finding the host animal for example, or host entity, through which the virus jumped to the human population, you're going to have alternative causes posited, and those alternative causes are going to include some that will suggest malign intent by powerful actors who are covering up what they actually did."

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This Fave Mainstream Media Source Is Funded by Anti-Vaxxers - The Daily Beast

An international team of researchers has discovered genes linked to plant survival in one of the harshest environments on the planet: Chiles Atacama Desert. Their findings, published in the Proceedings of the National Academy of Sciences (PNAS), may aid scientists in developing resilient crops that can thrive in increasingly arid environments.

In an era of accelerated climate change, it is critical to uncover the genetic basis to improve crop production and resilience under dry and nutrient-poor conditions, said Gloria Coruzzi, Professor in the New York University (NYU) Department of Biology and Center for Genomics and Systems Biology, who co-led the study.

The researchers spent a decade studying Atacama plant life in 22 locations across the barren desert, carefully transporting plant and soil samples back to the lab. Later, they preserved them in liquid nitrogen for genomic analysis.

The study involved botanists, microbiologists, ecologists, evolutionary biologists, and genomic researchers worldwide. The teams unique skills allowed them to identify the plants, microbes, and genes that will enable Atacama plants to adapt to and thrive in harsh desert environments, potentially improving crop growth and reducing food shortages.

Overall, the transcriptomes of 32 of the deserts most dominant plants were sequenced and compared to the transcriptomes of 32 related species from other locations. None of them had genetic adaptations to the Atacama environment.

The goal was to use this evolutionary tree based on genome sequences to identify the changes in amino acid sequences encoded in the genes that support the evolution of the Atacama plant adaptation to desert conditions, Coruzzi says.

The researchers at NYU then used an approach called phylogenomics, which aims to reconstruct evolutionary history using genomic data to identify the genes whose protein sequences were adapted in the Atacama species.

Furthermore, 59 of these genes have been discovered in Arabidopsis, where they have been interconnected with physiological and molecular processes that can improve plant resilience in harsh environments.

In a nutshell, Arabidopsis has already been shown to withstand harsh radiation and temperature stress, regulate floral development and flowering time, aid in pathogen defense and nutrient uptake thanks to the genes positively selected in the Atacama desert plants.

It is a plants evolutionary survival mechanism in harsh and dry environments. Furthermore, some of the same genetics can be found in food crop species, giving us a better understanding of which crops to plant and how to reproduce, fine-tune, and future-proof them.

The study is directly relevant to regions around the world that are becoming increasingly arid, with factors such as drought, extreme temperatures, and salt in water and soil posing a significant threat to global food production, says senior author and plant systems biologist Rodrigo Gutirrez from the Pontifical Catholic University of Chile.

As some Atacama plants are closely related to staple crops, including grains, legumes, and potatoes, the candidate genes we identified represent a genetic goldmine to engineer more resilient crops, a necessity given the increased desertification of our planet.

The findings are reported in PNAS.

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This Genetic Goldmine In The Atacama Desert Could Be The Key To Feeding The Future - Wonderful Engineering

Some cases of heart failure have root causes surprisingly similar to diseases like Alzheimers, Huntingtons and ALS.

Over time, sometimes quite rapidly, the heart's thick strong muscle tissue becomes thin and weak, causing the left ventricle to swell like a balloon. This makes the heart less able to squeeze efficiently, which can lead to blood clots, irregular heartbeats, and sometimes sudden death when the malfunctioning heart simply stops beating. The origins of cardiomyopathy are diverse, including viral infections, autoimmune diseases, toxic drug exposures, and dozens of gene mutations.

Now, a multi-disciplinary team of clinicians and researchers has deciphered the function of a specific genetic mutation that causes cardiomyopathy. Their findings,published Nov. 3, 2021, in Nature Communications, were made possible by growing gene-edited human heart tissue from induced pluripotent stem cells and measuring the activity, location and binding of this mutant protein.

The team was led by co-corresponding authors Charles Murry, MD, PhD, a regenerative medicine expert at the University of Washington; Bruce Conklin, MD, a genetic engineering expert with the Gladstone Institutes in California, and Nathan Salomonis, PhD, a computational genomics expert at Cincinnati Children's.

"We hope this study will lead to broader insights that could lead to improved heart failure therapies," Conklin says.

Cutting-edge experiments expose more of the heart's inner workings

Over the last several decades, the research community has made many discoveries that have led to improved medications and medical devices that can dramatically extend life by slowing down the progression of heart failure. However, we still lack proven cures.

This study reveals a new mechanism of cardiomyopathy initiation by the RNA binding motif protein 20 (RBM20). This protein helps control RNA splicing in the heart, the process by which RNAs are sliced and diced to give rise to different proteins in different tissues. Normally, RBM20 splices RNAs to make proteins that enable the heart to adapt to stress and contract regularly throughout a person's entire life. But a class of mutations in RBM20 result in severe cardiomyopathy in adulthood.

"We and others had previously studied RBM20's function during heart development, but we had little to no clue of why it stops working in disease. We needed to step up our game if our research was to have a clinical impact," says Alessandro Bertero, PhD, who contributed to the work while at the University of Washington and now leads an Armenise-Harvard Laboratory at the University of Turin in Italy.

Discovering this protein's role was especially complex because knocking out this gene in animal models does not mimic the damaging effects seen in people. Instead, the work required editing the genome of healthy cells and engineering human heart tissue from these cells in a lab dish. Only by producing heart tissue similar to that found in humans could the authors understand the contractile defects and molecular mechanisms underlying this gene's function in a controlled manner.

"That was exactly what we intended when we started this project by genome-editing induced pluripotent stem cells," says co-leading author Yuichiro Miyaoka, PhD, of the Tokyo Metropolitan Institute of Medical Science.

First, the team observed that the engineered muscle tissue carrying the mutant form of RBM20 did not function like tissue engineered with normal RBM20 or lacking the protein all together. The mutated muscle fibers contracted with significantly less force and upstroke velocity, much like a heart affected by cardiomyopathy.

Then, at the single-cell level, the team detected another important clue. Normally, RBM20 is located exclusively within the cell nucleus. However, the mutated form localizes almost entirely out of the nucleus, in the cell's cytoplasm.

This, by itself, did not mean muchuntil the cell was exposed to heavy stress. When that occurred, the mutant protein was detected within tiny "stress granules" made of protein and RNA that cells rapidly produce as a reaction to stress. In contrast, RBM20 in healthy cells remained within the nucleus and distinct from stress granules. This suggests there are additional cellular mechanisms, along with changes in splice-activity, leading to RBM20 cardiomyopathy.

"When the RNA binding landscape of mutant RBM20 was revealed by a technology called enhanced CLIP, it mimicked the binding of other splicing factors that have been implicated in neurodegenerative diseases. These factors, when mutated, also change their activity from RNA splicing to RNA aggregation outside the nucleus," says co-author Gene Yeo, PhD, MBA, a member of the Department of Cellular and Molecular Medicine at the University of California San Diego.

"Over time, such aggregates play havoc with other cell functions, ultimately leading to the tissue-weakening of heart muscle during cardiomyopathy," Salomonis says.

"It is intriguing to note the parallels between our observations with RBM20 and recent findings in neuro-degeneration," the paper states. "Indeed, recent work has hypothesized cytoplasmic RBM20 may be similar to the cytoplasmic RNP granules associated with neurodegeneration (Schneider et al., 2020), such as TAU for Alzheimer s disease, Huntingtin for Huntington s disease, and FUS for amyotrophic lateral sclerosis (ALS)."

Next steps

Co-authors for this study also included scientists from the University of Cincinnati Department of Electrical Engineering and Computer Science, Sana Biotechnology, and the University of California San Francisco.

The co-authors say the 3D heart tissue model they've developed has the potential to be used to test new drugs to block the formation of cytoplasmic granules as a possible treatment for cardiomyopathy, even those without RBM20 mutations.

"RBM20 has been a frustrating protein to study, as animal models don't fully recapitulate human disease pathology," says lead author Aidan Fenix, PhD. "It's exciting to now have an in vitrohuman cell model of RBM20 cardiomyopathy that shows the major clinical feature of dilated cardiomyopathy--reduced contractile force. We hope these models will speed the discovery of therapies to treat RBM20 dilated cardiomyopathy."

About this study

This work was supported by grants from the National Heart, Lung, and Blood Institute (U01 HL099997, P01 HL089707, R01 HL130533, F32 HL156361-01, HL149734, R01 HL128362, R01 HL128368, R01 HL141570, R01 HL146868); the National Institute of Diabetes and Digestive and Kidney (U54DK107979-05S1); the National Science Foundation (NSF CMMI-1661730); a JSPS Grant-in-Aid for Young Scientists, and grants from NOVARTIS, the Mochida Memorial Foundation, SENSHIN Medical Research Foundation, Naito Foundation, Uehara Memorial Foundation, a Gladstone-CIRM Fellowship, and the A*STAR International Fellowship.

SOURCE Cincinnati Children's Hospital Medical Center

http://www.cincinnatichildrens.org

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Heart Tissue in a Dish Reveals New Links Between Neurodegeneration and Heart Disease - PRNewswire

CAMBRIDGE, Mass., Nov. 03, 2021 (GLOBE NEWSWIRE) -- Clade Therapeutics, a biopharmaceutical company focused on discovering and delivering scalable, off-the-shelf, next-generation stem cell-based medicines, today announced it has secured an $87 million Series A financing led by Syncona Ltd. with participation from LifeSci Venture Partners, Emerson Collective and Bristol Myers Squibb. Proceeds from this financing will support the development of the Companys proprietary platform, which enables the immune cloaking of induced pluripotent stem cells (iPSCs) and the differentiation of cloaked stem cells into therapeutic cells.

We have reached an era in medicine where insights across genetic engineering, regenerative medicine and immunology have enabled a revolution of cell medicines, said Chad Cowan, Ph.D., Chief Executive Officer of Clade Therapeutics. Clade was founded to overcome the clinical limitations of current cell therapies by addressing durability, patient compatibility, reproducibility and scalability to deliver on the transformative potential of this increasingly important therapeutic modality.

Jim Glasheen, Ph.D., President and Chief Business Officer of Clade Therapeutics, said, We feel very fortunate to partner with a world-class group of investors. The syndicates combination of industry insight, technical expertise, entrepreneurial zeal, and focus on patient impact brings incredible value to the Company.

Martin Murphy, Ph.D., Chief Executive Officer of Syncona Ltd., said, Clades inherent focus on developing therapies derived from a single engineered cell source has the potential to shift the paradigm of cell medicine with unprecedented scalability and standardization. We are thrilled to support Clades aggressive development of broadly accessible, off-the-shelf products with consistent pharmaceutical criteria to expand the reach of cell therapies across patients and indications.

Ryan Cinalli, Ph.D., Chief Scientific Officer of LifeSci Venture Partners, said, Clade has assembled a world-class team of scientific pioneers whose foundational discoveries are integral to the Companys immune cloaking technology platform. We are confident that Clades leadership will innovate the next generation of cell therapies that harness cloaking technology to overcome the immune barriers that have limited durability and redosing in the field.

Neil White, Investment Manager of Emerson Collective, said, The unparalleled expertise and novel approach to generating stem cell-derived adult T, NK and B cells positions Clade as leaders in developing widely accessible cell medicines. With differentiation and cloaking technologies in place, this funding round will accelerate the development of Clades immune cell-focused, cancer therapeutics.

About Clade TherapeuticsClade Therapeutics mission is to discover and deliver next generation cell medicines to improve the lives of patients in need. Our platform technology cloaks human pluripotent stem cells and their adult derivatives enabling the development of immune compatible cell transplantation therapies. Led by a world-class team of company builders and scientific innovators with an unparalleled expertise in generating stem cell-derived adult T, NK and B cells, Clade promises to become a leading innovator in developing widely accessible cell medicines. The company is initially focused on harnessing the potential of cloaked immune cells for cancer treatment. For further information, please visit the company's website athttps://www.cladetx.com/.

About SynconaSyncona's purpose is to invest to extend and enhance human life. We do this by founding and building a portfolio of global leaders in life science to deliver transformational treatments to patients in areas of high unmet need.

Our strategy is to found, build and fund companies around exceptional science to create a diversified portfolio of 15-20 globally leading healthcare businesses for the benefit of all our stakeholders. We focus on developing treatments for patients by working in close partnership with world-class academic founders and management teams. Our balance sheet underpins our strategy enabling us to take a long-term view as we look to improve the lives of patients with no or poor treatment options, build sustainable life science companies and deliver strong risk-adjusted returns to shareholders.

About LifeSci Venture PartnersFormed in 2017, LifeSci Venture Partners is the early stage investing arm of LifeSci Partners, a unique life sciences and healthcare consultancy. We focus on private institutional financing rounds of transformational healthcare companies managed by exceptional founder/entrepreneurs. Our most recent fund, LifeSci Venture Partners II, LP was launched in 2020 and has invested in more than 25 breakthrough biotechnology and healthcare technology companies. For further information, please visit the company's website athttps://www.lifesciventure.com/.

About Emerson CollectiveEmerson Collective deploys a wide range of tools from impact investing to philanthropy to advocacy in pursuit of a more equal and just society. We focus on creating systemic change in education, immigration, climate, and cancer research and treatment.

Forward Looking Statements

This press release contains forward-looking statements including, but not limited to, statements related to Clades iPSC immune cloaking and differentiation platform technology to address compatibility, durability, reproducibility and scalability of cell therapies, Clades ability to develop broadly accessible, off-the-shelf products with consistent pharmaceutical criteria and expand the reach of cell therapies across patients and indications, the funding round resulting in the acceleration of the development of Clades immune cell-focused, cancer therapeutics and the value that the investor syndicate adds to the Company. These forward-looking statements are based on our current expectations and inherently involve significant risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, without limitation, risks that Clades actual future financial and operating results may differ from its expectations or goals, Clades ability to commercialize and successfully launch its products, risks relating to Clades ability to successfully implement its business strategies, including potential competition, the ability to protect intellectual property and defend patents, regulatory obligations and oversight, including any changes in the legal and regulatory environment in which Clade operates and the effects of the COVID-19 pandemic on the business. We undertake no duty or obligation to update any forward-looking statements contained in this press release as a result of new information.

ContactLigia Vela ReidLifeSci AdvisorsTel: +4407413825310lvela-reid@lifesciadvisors.com

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Clade Therapeutics Raises $87 Million Series A Financing to - GlobeNewswire

Patients with nonsmall cell lung cancer (NSCLC), the most common lung cancer in humans, are frequently treated with an immunotherapy called immune checkpoint blockade (ICB). This therapy induces a population of tumor-infiltrating T cells called CD8 positive T cells to secrete interferon gamma which in turn induces the expression of programmed cell death ligand 1 (PD-L1).

PD-L1 expression in the tumor microenvironment indicates the T cells are poised to kill tumor cells and patients with PD-L1 positive T-cell infiltrated tumors are most likely to respond to ICB. However, only about 35% of NSCLC patients respond to ICB therapy. Not all CD8 positive T cells in lung tumors express PD-L1 and respond to ICB and little is known about the mechanisms that govern ICB resistance in T cells within NSCLC.

In a new study published in Science Immunologytitled, Lack of CD8+ T cell effector differentiation during priming mediates checkpoint blockade resistance in nonsmall cell lung cancer, Stefani Spranger, PhD, professor at the MIT department of biology, and her colleagues uncover what causes some T cells in animal models of NSCLC to fail to respond to ICB, offering a potential way around it.

Jeffrey Bluestone, PhD, professor of metabolism and endocrinology at the University of California, San Francisco, who was not involved with the paper said, The study provides a potential opportunity to rescue immunity in the NSCLC non-responder patients with appropriate combination therapies.

It has been generally held that the continuous fight against tumor cells exhausts T cells which causes them to stop working. The rationale behind ICB therapy, therefore, has been to reinvigorate the exhausted T cells that pass into the tumors microenvironment.

However, experiments conducted by Brendan Horton, PhD, postdoctoral fellow in Sprangers lab, showed some ICB-resistant T cells stop working before they even enter the tumor, indicating exhaustion is not the cause behind their dysfunction.

Instead, the authors found that gene expression in these T cells is altered during their activation in lymph nodes which causes them to stop functioning. Once activated, T cells specialize into different subtypes with distinct functions that can be detected by specific genetic signatures.

According to Spranger, the idea that the dysfunctional state leads to ICB resistance arises before T cells enter the tumor is quite novel.

We show that this state is actually a preset condition, and that the T cells are already nonresponsive to therapy before they enter the tumor, she said. As a result, she explained, ICB therapies that work by reinvigorating exhausted T cells within the tumor are less likely to be effective. This suggests that combining ICB with other forms of immunotherapy that target T cells differently might be a more effective approach to help the immune system combat this subset of lung cancer.

To determine why some tumors are resistant to ICB, the team studied T cells in mouse models of NSCLC. They sequenced mRNA from responsive and non-responsive T cells and used a technique called Seq-Well, developed in the lab of fellow Koch Institute member, J. Christopher Love, PhD, professor of chemical engineering, and a co-author of the study. The technique allows rapid gene expression profiling of single cells. T cells responsive and nonresponsive to ICB show different gene expression patterns at specialized functional states, the single-cell sequencing analysis showed. For instance, nonresponsive T cells express low levels of some cytokinesproteins that control immunity.

Armed with the differential gene expression pattern, the team sought to convert ICB-resistant T cells into ICB-responsive T cells. The researchers treated lung tumors in mouse models with cytokines IL-2 and IL-12. This led the previously nonresponsive T cells to fight cancer cells in the mouse NSCLC.

This is potentially something that could be translated into a therapeutic that could increase the therapy response rate in non-small cell lung cancer, Horton said.

Spranger and Horton suspect cytokine therapy could be used in combination with ICB, although current clinical practices avoid cytokine treatments due to potential adverse side effects, including a condition called cytokine storm that can be fatal.

Spranger feels this work will help researchers develop more innovative cancer therapies, refocusing their efforts from reversing T-cell exhaustion to earlier states of T-cell specialization.

If T cells are rendered dysfunctional early on, ICB is not going to be effective, and we need to think outside the box, she said. Theres more evidence, and other labs are now showing this as well, that the functional state of the T cell actually matters quite substantially in cancer therapies.

To Spranger, this means that cytokine therapy might be a therapeutic avenue for NSCLC patients beyond ICB.

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Lung Cancer Unresponsive to Immunotherapy and a Potential Solution - Genetic Engineering & Biotechnology News