Category Archives: Gene Medicine

Recent allergy research has focused on a family of cells in the immune system proven to play a critical role in allergic responses.

Known as innate lymphoid cells, or ILCs, they can kill or regulate various cell types to fight pathogens and protect against infections but at the same time may exacerbate allergies by over-responding and causing inflammation.

Now, researchers have discovered a protein in the bone marrow that drives production of these influential immune cells, according to findings led by the Mary H. Weiser Food Allergy Center at Michigan Medicine that appears in Science Immunology.

We have identified a regulatory molecule that controls the production of cells that are critical to mediating allergic responses, says lead author Chang Kim, Ph.D., Michigan Medicine pathologist and researcher with the allergy center.

A better understanding of how these cells are made and regulated brings us closer to a novel target to treat inflammatory and allergic diseases through new therapies in the future.

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Researchers found that this protein (BATF) regulates the gene expression required for the differentiation of the ILCs immune cells in the bone marrow.

ILCs are counterparts to T-cells that contribute to immune responses. In addition to their role in allergy responses, ILCs protect from diverse pathogens such as bacteria, viruses and parasites like tapeworms. They also help regulate fat mass, metabolism and microbiome.

The study found that animals deficient in the expression of BATF are highly susceptible to infection and are unable to mount an effective immune response to allergy-inducing cytokines.

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Animals deficient in this molecule are protected from allergic responses, Kim says. This tells us that our research may provide useful information regarding mechanisms of allergic immune responses.

Kims lab continues research on the molecular details in the regulation of ILC production that may lead to novel targets of intervention.

Study cited: BATF regulates innate lymphoid cell hematopoiesis and homeostasis, Science Immunology, DOI: 10.1126/sciimmunol.aaz8154

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Uncovering Key Molecule that Drives Production of Cells Critical to Allergic Reactions - Michigan Medicine

rBIO launched last week with technology that can reduce the cost of insulin by 30 percent, making U.S. manufacturing cost-effective for insulin and several other drugs.

This new method is an enhancement of the recombinant DNA (rDNA) processes that have been used since the 1980s to produce insulin.

Forty years later, were taking it to the next level, Cameron Owen, rBIO co-founder and CEO, told BioSpace. It is akin to expediting billions of years of evolution.

The company genetically modified E. coli to cause it to hyper-produce peptide hormones initially, insulin thereby creating more product from the same quantity of material. Those bacteria will then manufacture the product at scale using standard vat fermentation processes.

The idea emerged when Owen was a graduate student at Johns Hopkins Universitys Carey Business School.

I had started another biotech company (Aevus Precision Diagnostics) that looked at the pharmacogenomics of diabetes medications, so I got to know the diabetes space really well, he said.

As he learned, Insulin is too expensive for many people who depend on it, and its supply chain is vulnerable because like most drugs used in the U.S. a large percentage of insulin is manufactured offshore. With 30 million diabetics in the U.S. now, and an expected 60 million by 2030, keeping up with demand is a significant challenge.

In 2016, the J. Craig Venter Institute determined the minimum number of genes bacteria needed to survive.

If you can take those minimal genes and add to them, youve eliminated a lot of processing waste, Owen said.

Therefore, rBIO is rewriting E.colis genetic code, eliminating the unnecessary genes and coding the genome so the bacteria hyper-expresses the maximum quantities of insulin but does not produce the products needed for the bacterias normal metabolic function.

rBIOs goal is to increase production to the cells theoretical limits. In this case, thats 100 molecules of insulin.

We havent achieved 100% theoretical maximum yield, he said, but production rates are approximately double that of todays generally accepted insulin production methods.

Whats different about this approach, beyond its high yield, is how the genetic code as devised. Were now at the point in genetics where the genetic code can be not only manipulated, but written, Owen said.

Rather than cut and paste genes in or out of organisms, rBIO actually designs the DNA, he said.

Were writing the DNA code from scratch, the way a computer programmer would, and translate it to biology, he said. Rather than use ones and zeros, we use ACGT the bases found in DNA molecules. We can manipulate those letters to write anything you want.

The rBIO team doesnt start entirely from scratch, of course. There are set sequences that we know work, so we are using those sequences, and designing others, Owen said. We wrote three different genetic codes for the bacteria during the past several months and put them into a lab setting to determine if they first and foremost grew and divided, and secondly whether they produced the product we wanted.

Two of the three bacteria strains were successful, and optimization is continuing.

Once rBIO determines the genetic code it wants, it outsources the actual gene assembly. rBIO has produced several milligrams of insulin this way in the lab.

The next stage, Owen said, is to scale up the company. That means bringing in management with the skills to take the organization to the next level and to help shape its direction.

This early in its existence, all the options are open.

My goal is to become a manufacturer, Owen said, but, realistically, this is more of an out-licensing opportunity to a company with the existing infrastructure for mass manufacturing already in place.

rBIO is still developing a platform technology, Owen pointed out. The company is focused on insulin, but also is considering eight other drugs for its pipeline, including erythropoietin and epinephrine. They each have a projected compound annual growth rate (CAGR) of 12 percent for the next decade, he said, so represent significant opportunities for the company.

Owen said the companys technology also has the potential to make reshoring attractive for several drugs that currently are produced offshore.

The COVID-19 pandemic put the spotlight on the risks of off-shoring pharmaceutical products. According to the FDA, only 21% of the drugs on the World Health Organizations Essential Medicines List are manufactured in the U.S.

Medicine security shouldnt be allowed to be affected by the fluctuations of international trade policies, he said. Having the manufacture of life-saving medicines offshore is a major national security issue. Imagine what would happen if 30 million American diabetics couldnt access insulin. Wed be in a world of hurt.

Whether or not such drastic trade wars happen, rBIOs hyperproduction technology may offer significant benefits to therapeutic manufacturers and customers alike. He isnt overly concerned about competition. Instead, he sees potential allies.

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rBIO Launches with Technology to Hyper-Produce Insulin Cost-Effectively, at Scale - BioSpace

Humans seem to be more prone to developing carcinomas (cancers starting in the skin or tissue lining organs), in comparison to our closest evolutionary relatives chimpanzees.

We are prone to developing advanced carcinomas even without known risk factors such as smoking and genetic predisposition being present.

Researchers at the University of California School of Medicine and Moores Cancer Center conducted a study aimed at explaining why this may be the case.

Findings of the study suggest that distinct genetic mutations that happened during the course of our evolution may be part of the reason why we are prone to developing these cancers.

SIGLEC 12 is a primate protein-coding gene that harbours specific mutations in humans.

According to senior author of the study, Ajit Varki, At some point during human evolution, the SIGLEC12 gene and more specifically, the Siglec-12 protein it produces as part of the immune system suffered a mutation that eliminated its ability to distinguish between 'self' and invading microbes, so the body needed to get rid of it.

He went on to say the gene is not completely gone from the body and it appears that this dysfunctional form of the Siglec-12 protein went rogue and has now become a liability for the minority of people who still produce it.

When the researchers studied normal tissues and compared them to cancer tissues, they found that the risk of developing advanced cancer was more than double in people who produce a SIGLEC-12 compared to those who don't.

The majority of the global population no longer produce the SIGLEC-12 protein because dysfunctional encoded proteins are normally erased over time, and the protein is only functional in chimpanzees.

It was believed that the gene had no relevance in cases where it was still present in humans, but the researchers found that it is in fact significant because of its prevalence in the majority of advanced cancer samples.

"These results suggest that the minority of individuals who can still make the protein are at much greater risk of having an advanced cancer," said corresponding author, Nissi Varki.

The researchers went on to say that such a discovery is beneficial as it can be used in future for diagnostics and treatments, and the team already made progress by developing a urine test that can detect the presence of the dysfunctional protein.

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Evolution may be to blame for humans susceptibility to a certain cancer - News24

SAN FRANCISCO--(BUSINESS WIRE)--Audentes Therapeutics, an Astellas genetic medicines company, today announced that the U.S. Food and Drug Administration (FDA) has lifted the clinical hold for the ASPIRO clinical trial evaluating AT132 in patients with X-linked myotubular myopathy (XLMTM). XLMTM is a serious, life-threatening neuromuscular disease characterized by extreme muscle weakness, respiratory failure, and early death.

We are grateful for the efforts of our team and investigators who have worked tirelessly to answer the FDAs questions and we now look forward to resuming this study, said Natalie Holles, President and Chief Executive Officer of Audentes. We want to again extend our deepest sympathies to patients families impacted by the events earlier this year. We are deeply committed to the continued safe development of AT132 for the families and patients living with XLMTM, a disease with no existing treatments.

The company is now working to complete all clinical and regulatory activities necessary to resume dosing and plans to have discussions at a future date with the regulators on the path forward toward global registration filings for AT132.

About X-linked Myotubular MyopathyXLMTM is a serious, life-threatening, rare neuromuscular disease that is characterized by extreme muscle weakness, respiratory failure and early death. Mortality rates are estimated to be 50 percent in the first 18 months of life. For those patients who survive past infancy, there is an estimated additional 25 percent mortality by the age of 10. XLMTM is caused by mutations in the MTM1 gene that lead to a lack or dysfunction of myotubularin, a protein that is needed for normal development, maturation and function of skeletal muscle cells. The disease affects approximately 1 in 40,000 to 50,000 newborn males.

XLMTM places a substantial burden of care on patients, families and the healthcare system, including high rates of healthcare utilization, hospitalization and surgical intervention. More than 80 percent of XLMTM patients require ventilator support, and the majority of patients require a gastrostomy tube for nutritional support. In most patients, normal developmental motor milestones are delayed or never achieved. Currently, only supportive treatment options, such as ventilator use or a feeding tube, are available.

About the ASPIRO StudyASPIRO is a two-part, multinational, randomized, open-label ascending dose trial to evaluate the safety and preliminary efficacy of AT132 in XLMTM patients less than five years of age. Primary endpoints include safety (adverse events and certain laboratory measures) and efficacy (assessments of neuromuscular and respiratory function). Secondary endpoints include the burden of disease and health-related quality-of-life, and muscle tissue histology and biomarkers.

About AT132 for the treatment of X-linked Myotubular MyopathyAudentes is developing AT132, an AAV8 vector containing a functional copy of the MTM1 gene, for the treatment of XLMTM. AT132 may provide patients with significantly improved outcomes based on the ability of AAV8 to target skeletal muscle and increase myotubularin expression in targeted tissues following a single intravenous administration. The preclinical development of AT132 was conducted in collaboration with Genethon (www.genethon.fr).

AT132 has been granted Regenerative Medicine and Advanced Therapy (RMAT), Rare Pediatric Disease, Fast Track, and Orphan Drug designations by the U.S. Food and Drug Administration (FDA), and Priority Medicines (PRIME) and Orphan Drug designations by the European Medicines Agency (EMA).

About Audentes Therapeutics, Inc.Audentes Therapeutics, an Astellas company, is developing genetic medicines with the potential to deliver transformative value for patients. Based on our innovative scientific approach and industry leading internal manufacturing capability and expertise, we have become the Astellas Center of Excellence for the newly created Genetic Regulation Focus Area. We are currently exploring three gene therapy modalities: gene replacement, exon skipping gene therapy, and vectorized RNA knockdown, with plans to expand our focus and geographic reach under Astellas. We are based in San Francisco, with manufacturing and laboratory facilities in South San Francisco and Sanford, North Carolina.

About AstellasAstellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. We are promoting the Focus Area Approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on Biology and Modality. Furthermore, we are also looking beyond our foundational Rx focus to create Rx+ healthcare solutions combine our expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of healthcare change to turn innovative science into value for patients. For more information, please visit our website at https://www.astellas.com/en

Cautionary NotesIn this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on managements current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas intellectual property rights by third parties.

Information about pharmaceutical products (including products currently in development) which is included in this press release is not intended to constitute an advertisement or medical advice.

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Audentes Therapeutics Announces FDA Lifts Hold on ASPIRO Clinical Trial of AT132 for Treatment of X-Linked Myotubular Myopathy (XLMTM) - Business Wire

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Genes (Basel). 2020 Dec 25;12(1):E19. doi: 10.3390/genes12010019.

ABSTRACT

The human serine protease serine 2 TMPRSS2 is involved in the priming of proteins of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and represents a possible target for COVID-19 therapy. The TMPRSS2 gene may be co-expressed with SARS-CoV-2 cell receptor genes angiotensin-converting enzyme 2 (ACE2) and Basigin (BSG), but only TMPRSS2 demonstrates tissue-specific expression in alveolar cells according to single-cell RNA sequencing data. Our analysis of the structural variability of the TMPRSS2 gene based on genome-wide data from 76 human populations demonstrates that a functionally significant missense mutation in exon 6/7 in the TMPRSS2 gene is found in many human populations at relatively high frequencies, with region-specific distribution patterns. The frequency of the missense mutation encoded by rs12329760, which has previously been found to be associated with prostate cancer, ranged between 10% and 63% and was significantly higher in populations of Asian origin compared with European populations. In addition to single-nucleotide polymorphisms, two copy number variants were detected in the TMPRSS2 gene. A number of microRNAs have been predicted to regulate TMPRSS2 and BSG expression levels, but none of them is enriched in lung or respiratory tract cells. Several well-studied drugs can downregulate the expression of TMPRSS2 in human cells, including acetaminophen (paracetamol) and curcumin. Thus, the interactions of TMPRSS2 with SARS-CoV-2, together with its structural variability, gene-gene interactions, expression regulation profiles, and pharmacogenomic properties, characterize this gene as a potential target for COVID-19 therapy.

PMID:33375616 | DOI:10.3390/genes12010019

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Structural Variability, Expression Profile, and Pharmacogenetic Properties of TMPRSS2 Gene as a Potential Target for COVID-19 Therapy - DocWire News

Without a doubt, the top topic of 2020, pretty much for any news outlet, was the COVID-19 pandemic. BioSpace ran its first story about the virus on January 22, titled, China Coronavirus Update: What it is, How Dangerous it is, What is Being Done. At that time, it had infected more than 440 people and killed nine in China and the first reported case in the U.S. had been the day before.

By March, the pandemic had begun to dominate our coverage and we designated a space for general COVID-19 coverage every day. That eventually dropped to three times a week and then just once a week, although almost every day since then has included multiple stories about the pandemic and biopharmas efforts to test and/or develop therapies or vaccines for the disease. Keeping in mind that this has dominated the news cycle, here are the top 10 stories of 2020 in no particular order.

At the beginning of 2020, nobody knew how bad COVID-19 would be or that Gilead Sciences remdesivir, which had failed to work in Ebola, would turn out to be the first drug granted Emergency Use Authorization (EUA) for COVID-19 in Spring 2020 and then full approval on October 22, 2020. At the time of the EUA, it was really the only available treatment, but few physicians or analysts were particularly impressed with the drugs effectiveness.

Back in April 2020, when the world was desperate for any drug that might help, Gilead reported encouraging results from its clinical trial of Veklury in COVID-19, with topline results from the Phase III SIMPLE trial evaluating 5-day and 10-day dosing in hospitalized patients with severe disease. It also reported positive data from the National Institute of Allergy and Infectious Diseases (NIAID) trial.

The results were promising, but not dazzling. One of the bigger takeaways was that the 5-day regimen appeared to have similar results to the 10-day regimen, which was good news because supply of the drug was limited. In terms of clinical improvement, the trial showed the time to clinical improvement for 50% of patients was 10 days in the 5-day cohort and 11 days in the 10-day cohort.

But a clinical trial by the World Health Organization (WHO) reported that the drug does not have any particular effect on a patients survival. The WHO has since taken remdesivir off their list of recommended treatments for COVID-19. Despite that, Veklury, which is far better known by its scientific name, remdesivir, is still a go-to drug to treat COVID-19.

On December 10, 2020, the U.S. Food and Drug Administration (FDA) granted Emergency Use Authorization (EUA) to the first vaccine against COVID-19. It was an mRNA vaccine created by Germanys BioNTech and co-developed and manufactured with Pfizer. Within days the vaccine was distributed around the U.S., the U.K. and shortly after, in Europe. It was authorized for individuals ages 16 and above. On December 23, the U.S. government reached a deal with Pfizer for an additional 100 million doses by July 31, 2021.

A week after Pfizer-BioNTech received EUA, Moderna received authorization for its own very similar mRNA COVID-19 vaccine and began distributing it in the U.S. on December 21. Unlike Pfizer-BioNTech, Modernas vaccine was developed in partnership with the U.S. National Institute of Allergy and Infectious Diseases (NIAID) and with funding from the U.S. governments Operation Warp Speed, a program that threw money at the problem of COVID-19 vaccinations, and is overseeing distribution around the U.S. with the U.S. Centers for Disease Control and Prevention (CDC), McKesson, and partnerships with Walgreens and CVS.

On November 9, 2020, the FDA granted Eli Lillys neutralizing antibody bamlanivimab EUA for mild to moderate COVID-19 in adults and pediatric patients 12 years and older who are at high risk for progressing to severe COVID-19 and/or hospitalization. The EUA was based on data from BLAZE-1, a Phase II trial in patients with recently diagnosed mild to moderate COVID-19 in the outpatient setting.

On November 22, the FDA granted Regeneron Pharmaceuticals antibody cocktail casirivimab and imdevimab, together REGN-COV2, EUA for mild to moderate COVID-19 in adults and pediatric patients at least 12 years of age and weighing at least 40 kg.

Operation Warp Speed (OWS) is a public-private partnership launched by the U.S. government to help and accelerate the development, manufacturing, and distribution of COVID-19 vaccines, therapeutics and diagnostics. It was first announced on April 29, 2020, then officially launched on May 15. It was initially funded with approximately $10 billion from the CARES Act passed by the U.S. Congress on March 27. The primary focus, at least publicly, has been on vaccine development. In May, it had reduced a possible 93 vaccine programs to 14 top candidates, and then weeded them out to about six: Johnson & Johnson; AstraZeneca-University of Oxford and Vaccitech; Moderna; Novavax; Merck and IAVI; Sanofi and GlaxoSmithKline. Operation Warp Speed invested billions of dollars in each program to assist in development, and also oversaw acquisition of doses of the vaccines for U.S. use and is also overseeing distribution of the vaccines.

The year has been marked by a historic amount of scientific work on understanding COVID-19 and developing therapies for it, including the development of vaccines using a mix of new, untried technology such as mRNA, and more traditional vaccine technology. Despite controversies (See #8), never before has the U.S. public and people around the world paid so much attention to science, vaccine technology, clinical trials, immunology and convalescent and therapeutic antibodies, just to name a few. Much of this was possible by open communication between researchers worldwide, the publication of the SARS-CoV-2 genome in late December 2019, and the work of hundreds of thousands of researchers working for biopharma, governments, academia and research organizations worldwide.

As an article in Nature noted, The speed of the coronaviruss spread has been matched only by the pace of scientific insights. Almost as soon as SARS-CoV-2 was discovered, research groups worldwide started probing its biology, while others developed diagnostic tests or investigated public-health measures to control it.

And multiple vaccines were developed in less than a year, broadly tested, authorized and began distribution. In the past, the fastest that had ever happened was four years.

President Trump and Controversy

Its difficult to sum up in a paragraph or two how complicated President Trump and his handling of the pandemic has been. Here are just a few examples:

Early in the pandemic, in February and March, Trump touted an older malaria drug, hydroxychloroquine, as a game changer, despite very little scientific data to back it up. This became a major political and cultural spark as Trump followers said anyone doubting the drug were lying and attacking Trump politically. On March 30, the FDA granted an EUA for the drug, then after more studies came out, the FDA withdrew the EUA on June 15. Trump continued to argue that the drug was effective for months afterwards, even when he eventually caught COVID-19.

Trump played a cat-and-mouse game with Anthony Fauci, the worlds leading expert on infectious diseases and pandemic, the director of NIAID. He often talked publicly about how Fauci was wrong and hinted during campaign rallies that he might fire Fauci, while simultaneously saying what a nice guy Fauci was.

On September 24, Trump signaled the White House may attempt to override the more stringent EUA guidance for a vaccine.

On December 11, Trump demanded the resignation of FDA Commissioner Stephen Hahn if the Pfizer-BioNTech vaccine wasnt granted EUA by the end of the day.

Donald Trump and his son, Donald Trump Jr., accused Pfizer of deliberately waiting until after the U.S. presidential election to release the vaccine trial results in order to make him look bad.

Although not directly related to COVID-19, a number of firms launched new and large venture capital funds for life sciences. Several indicated it was partly in response to the growing attention to biotech and life sciences during the pandemic. For example, On April 2, Cambridge, Massachusetts-based venture capital firm Flagship Pioneering announced it had closed on a $1.1 billion for its seventh origination fund to support biotech startups. Flagship began raising the funds in January. On the same day, ARCH Venture Partners announced two new venture capital funds to invest in early-stage biotech companies with a combined total of $1.46 billion. They are ARCH Venture Fund X and ARCH Venture Fund X Overage.

On April 6, Deerfield Management announced the closing of the Deerfield Healthcare Innovations Fund II with $840 million. The fund will focus on investing in science startups related to new therapies and technology related to improve the way healthcare is delivered to patients.

On December 8, Forbion, a European life science venture capital firm, announced its fifth fund, Forbion V. It has 460 million, or $545 million (U.S.), to invest in life science companies. Investors in the fund include a variety of existing and new limited partners, both groups made up of specialized institutional and corporate investors. They include Pantheon, Wilshire Associates, the Ewing Marion Kauffman Foundation and Argentum.

Forbions offices are in The Netherlands, Germany, and Singapore. It is focused on the life sciences, particularly in the biopharma space. It currently manages more than 1.7 billion.

There is little doubt that CRISPR gene editing is and will continue to revolutionize biology and medicine. The Nobel Committee confirmed their belief in that by awarding the Nobel Prize in Chemistry to Emmanuelle Charpentier and Jennifer A. Doudna for their discovery and development of CRISPR.

Of it, Gran K. Hansson, secretary-general of the Royal Swedish Academy of Sciences, said the award was about rewriting the code of life.

The winners were announced at the Royal Swedish Academy of Sciences in Stockholm. The prize comes with a cash award of 10 million Swedish krona, which comes to $1.12 million (U.S.), shared by the laureates, and a gold medal for each winner. The formal ceremonies will be held online in December because of the pandemic.

Charpentier, who is French, is based at the Max Planck Unit for the Science of Pathogens in Berlin, and Doudna is at the University of California, Berkeley.

CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats. With that and the Cas9 enzyme, the system allows researchers to specifically cut the genome at a desired location, which allows existing genes to be removed or new genes to be inserted.

Broadly, CRISPR-Cas9 as a technology was discovered by Doudna and Charpentier, who was then at the University of Vienna, then the Umea Centre for Microbial Research in Sweden, then the Helmoltz Centre for Infection Research in Braunschweig, Germany. The two began a collaboration in 2011 and published their landmark paper in Science in 2012.

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Top 10 Stories from 2020: COVID, COVID and More COVID - BioSpace

In August 2020, the FDA approved the first diagnostic test that combines next-generation sequencing and liquid biopsy. The test is intended to help guide treatment decisions for patients with specific types of mutations of the epidermal growth factor receptor (EGFR) gene in metastatic nonsmall cell lung cancer (NSCLC), which is particularly deadly. The FDA called it a new era for mutation testing. The approval was granted to Guardant360CDx to provide information on multiple solid tumor biomarkers and to help identify EGFR mutations in patients who will benefit from treatment with osimertinib (Tagrisso), which is approved for a form of metastatic NSCLC.

Read the full article here.

4. Dr Andre Goy Discusses What Weve Learned About CAR T Therapies and Cytokine Responses

In a video interview, Andre Goy, MD,chairman, director, and chief of the Division of Lymphoma at John Theurer Cancer Center in Hackensack, NJ,discussed what has been learned from existing chimeric antigen receptor T (CAR T)-cell therapies in managing cytokine responses.

Watch the interview here.

3. OneOncology, Foundation Medicine Create Partnership to Deliver Targeted Care

Also in August 2020, OneOncology, a network of nearly 170 community oncology care sites, and cancer genomic profiling firm Foundation Medicine announced a partnership to give patients and physicians access to genomic profiling tools as well as expanded research opportunities. In addition, OneOncology will help Foundation Medicine to create new assays for community oncology practices.

Read the full article here.

2. Broad Testing for Multiple Genes Benefits Patients With Cancer, Relatives

A study published in JAMA Oncology described how universalmultigene panel testingwas linked with increased detection of actionable, heritable variants beyond what one would expect to find using targeted genetic testing based on current cancer guidelines. The multicenter cohort study found that 1 in 8 patients had a pathogenic germline variant, half of which would not have been found if using guidelines alone. In addition, for the nearly 30% of patients with a high-penetrance variant, the findings led to a change in treatment.

Read the full article here.

1. How DNA Medicines Could Transform Treatment of Glioblastoma Multiforme

In an article appearing in the August 2020 edition of Evidence-Based Oncology, Jeffrey Skolnick, MD, the vice president of clinical development at biotech firm Inovio, discusses the companys proprietary technology that uses a computer algorithm to build DNA medicines that can target almost any antigen that can be presented to the human immune system through the major histocompatibility class I system. DNA medicines are built in the form of circular strands of synthetic DNA called plasmids, which can neither propagate nor integrate into the human genome. He also discusses their use in a potential application for glioblastoma, which is incurable.

Read the full article here.

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The Top 5 Most-Read Precision Oncology Articles of 2020 - AJMC.com Managed Markets Network

FILE PHOTO: A Union Jack design face mask is seen for sale in the window of a shop amid the outbreak of the coronavirus disease (COVID-19) in Manchester, Britain, December 26, 2020. REUTERS/Phil Noble

(Reuters) - The following is a roundup of some of the latest scientific studies on the novel coronavirus and efforts to find treatments and vaccines for COVID-19, the illness caused by the virus.

UK coronavirus variant associated with higher viral loads

The highly infectious COVID-19 coronavirus variant that has been circulating in Britain is linked to higher loads of the virus in the blood, according to a research report published on medRxiv on Sunday ahead of peer review. Around 35% of patients infected by the variant form had very high levels of the virus in their samples, compared to 10% of patients without the variant, study leader Michael Kidd of Public Health England and Birmingham University told Reuters. Higher viral loads have been linked with worse COVID-19 outcomes. The tests were conducted at the Birmingham Turnkey Lab. Kidd said additional study was needed to confirm or refute the findings. If confirmed, he hopes scientists will investigate how this particular variant manages to make more copies of itself in infected patients. (bit.ly/3nUEJrr)

Neanderthal gene protects against COVID-19

A specific form of a protein passed down from Neanderthals protects against severe COVID-19, and medications that boost levels of this protein could potentially help treat the disease, according to a study reported on medRxiv on Thursday ahead of peer review. The protein, called OAS1, is involved in the body's response to viruses. People with higher levels of the Neanderthal-related form of OAS1 are less susceptible to COVID-19, and if they do become infected, they are at lower risk for hospitalization, intubation and death, the researchers found. "This protective form of OAS1 is present in sub-Saharan Africans but was lost when the ancestors of modern-day Europeans migrated out of Africa. It was then re-introduced into the European population through mating with Neanderthals" who lived more than 40,000 years ago, said coauthor Brent Richards from the Jewish General Hospital and McGill University in Montreal. An earlier study linked a cluster of genes inherited from Neanderthals to higher risks of hospitalization from COVID-19. "These findings further implicate Neanderthal ancestry in COVID-19 severity," Richards said. (bit.ly/2KxrQVP)

Early antibody production key to COVID-19 recovery

The speed of patients' antibody production - rather than the volume of antibodies they produce to fight the new coronavirus - determines whether they will survive COVID-19, new data suggest. Researchers who studied more than 200 COVID-19 patients, including 179 who were hospitalized, found those who produced so-called neutralizing antibodies within 14 days of developing symptoms eventually recovered, while those who did not produce neutralizing antibodies until more than 14 days had elapsed developed higher viral loads and more severe disease. "It is unclear why antibodies generated after this time point are unable to promote viral clearance and recovery in COVID-19 patients," the researchers said in a report posted on medRxiv ahead of peer review. Study leader Akiko Iwasaki of the Yale University School of Medicine tweeted on Saturday, "It's possible that virus somehow becomes resistant by hiding in inaccessible tissues." The new findings, she added, suggest therapy with so-called monoclonal antibody drugs - such as those from Regeneron given to U.S. President Donald Trump -- is likely to work only if used soon after infection. (bit.ly/3pv6qaB)

Open tmsnrt.rs/3a5EyDh in an external browser for a Reuters graphic on vaccines and treatments in development.

Reporting by Nancy Lapid; Editing by Tiffany Wu

Originally posted here:
UK variant linked to high viral loads, Neanderthal gene offers protection - Reuters

A recruitment drive to enroll participants for Johnson & Johnsons coronavirus virus vaccine trial kicked off Tuesday at Jersey Shore University Medical Center as the New Jersey-based company seeks to give the public another vaccination option.

Hackensack Meridian Health, New Jerseys largest health network, is enrolling volunteers in the double-blind trial, which will study the effectiveness of a two-dose regimen of J&Js experimental COVID-19 vaccine in up to 30,000 adults over age 18. Half of the participants will receive a placebo and the other half will receive the vaccine.

Meanwhile, Pfizer and Moderna are continuing to distribute approved vaccines to essential workers in New Jersey.

Its really important we have various vaccine options... Were trying to vaccinate the entire world population and so one company, two companies, three companies wont be able to produce enough vaccine to do that. The more companies that we have, the better it is for the world, said Dr. Ihor Sawczuk, president of Hackensack Meridian Healths Northern Market and the chief research officer of the network.

Over the past few weeks, thousands signed up to take part in the Phase 3 J&J trial and will have to undergo a pre-screening process. Two of those volunteers who passed the screening were given shots on Tuesday at the Monmouth County hospital.

J&J is also running a separate trial, which began in September, for a one-dose regimen involving 45,000 people. This new study will look at whether administering two doses of the vaccine has potential benefits for the duration of protection compared to one shot, Sawczuk said.

The shots are administered on day 1 and day 57 of participation, with the total study period being more than two years.

The J&J vaccine is an adenovirus-based shot, Sawczuk said. A segment of a gene that represents the spike protein of COVID-19 is inserted into an adenovirus, he said. That segment, when injected into our cells, produces messenger RNA which then becomes a protein our bodies recognize as foreign and develop antibodies against.

Its not COVID. Its an inactive form, but it stimulates our immune systems to develop antibodies against the spike protein so when they actually see the real one, well be able to protect ourselves, Sawczuk said.

Having another vaccine on the market approved by the FDA could be advantageous to different populations.

It is possible the J&J vaccine could be approved as a single-dose vaccine, as opposed to the two-dose Pfizer and Moderna vaccines. That could be important for a subset of the homeless population who arent easily able to get a follow-up shot, said Dr. David Kountz, Co-Chief Academic Officer and Hackensack Meridian Health and Associate Dean, Diversity and Equity, Hackensack Meridian School of Medicine.

The Pfizer vaccine also requires refrigeration at about -94 F in specialized freezers, resources often only available at large medical centers in more urban areas. Medical facilities in rural areas and less developed countries would benefit from a vaccine that is proven just as effective, but doesnt require those expensive freezers, said Dr. Ed Liu, chief of infectious diseases at Jersey Shore University Medical Center and principal investigator for the trial.

If other vaccines are just as effective or similarly effective and safe and dont require those refrigerations, that will be a benefit, said Liu.

The trial team is putting a focus on recruiting people of color, those with co-morbidities and individuals over the age of 60 to prove the vaccine is safe and effective for different groups, Kountz said.

People of color, and Black Americans in particular, are often underrepresented and hesitant to join scientific trials due to the history of racism in America in the medical field. Kountz pointed to the infamous Tuskegee Syphilis Experiment, in which 600 Black men involved in a study on syphilis were told they were getting free medical care but instead never given treatment for their disease.

He said staff have been doing outreach with community groups and religious leaders in order to enroll minority populations. Over the past few months, he and other team members have gone to numerous local churches to talk about the program in an effort to recruit people.

Enrollment for the Moderna Phase 3 trial at Hackensack University Medical Center earlier this year was 31.37% Hispanic or Latino, 26.8% white, 13.73% Asian and 8.5% Black or African American, according to data from Hackensack Meridian.

Liu says there are plans to put out more radio and TV spots about the trial and how to enroll.

Its critical. As a health network, weve done well... reaching out to diverse populations in New Jersey for the Moderna trial, but we can do better, Kountz said. And as a nation we can do better.

For more information about the trial, those interested can contact (551) 996-5977 or visit https://www.hackensackmeridianhealth.org/covid19/.

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Avalon Zoppo may be reached at azoppo2@njadvancemedia.com. Follow her on Twitter @AvalonZoppo.

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Drive to get people to participate in Johnson & Johnson coronavirus vaccine trial kicks off at N.J. hospital - NJ.com

Tremendous progress has been made to understand the strategies that can be used to overcome ESR1 mutations in estrogen receptor (ER)positive breast cancer, said Debu Tripathy, MD, who added that potent selective ER modulators (SERMs) may be the key to combat these mutations.

Selective [ER] modulators can probably, to some extent, be effective [against] ESR1-mutant cells, said Tripathy. The effect to which they can reverse resistance probably depends on many aspects of the agent. These need to be formally studied not just in the lab, but in clinical trials. We are starting to get some hints of that [work], but its just the beginning.

ESR1 mutations generally arise following treatment with an aromatase inhibitor (AI), explained Tripathy, so acquiring genomic information after a patient progresses is critical to inform treatment selection.

The novel SERM lasofoxifene is currently being investigated in combination with the CDK4/6 inhibitor abemaciclib (Verzenio) in the phase 2 ELAINEII trial (NCT04432454) in patients with advanced or metastatic ER-positive, HER2-negative breast cancer whose tumors harbor an ESR1 mutation. Moreover, in May 2019, the FDA granted a fast track designation to lasofoxifene for the treatment of female patients with ER-positive, HER2-negative metastatic, ESR1-mutant breast cancer.

In an interview with OncLive, Tripathy, professor of medicine and chair of the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, discussed the role of CDK4/6 inhibitors in ER-positive, HER2-negative breast cancer, the emergence of SERMs, and the growing understanding of ESR1 mutations in this space.

Tripathy: When patients progress on a CDK4/6 inhibitor, I will generally discontinue the use of CDK4/6 inhibitors. No clear data [show] that patients who become resistant [to a CDK4/6 inhibitor] may be sensitive to other [CDK4/6] inhibitors; however, some anecdotal datafrom individual hospital series suggest there could be some non-overlapping sensitivity.

However, we have many other options, which is why I will generally move on to another form of therapy. We need to formally study the impact of 1 CDK4/6 inhibitor after progression on another because we may find that some of these agents perform better in that setting.

I tend to get genomics at the very beginning when patients are newly diagnosed, although I may not use that information in the first-line setting. However, it is good to have [the genomic information], especially for truncal mutations. [Truncal mutations] tend to be prevalent in most of the cells, such asPIK3CAmutations.ESR1mutations tend to be subclonal and may not be present [up front] but may arise later after the patient has been on an [AI].

If I havent gotten [genomic information] at the beginning, I will certainly get it at the time of progression on first-line therapy.

ESR1 mutations tend to arise in the presence of pretreatment, particularly with estrogen-deprivation therapy, which pharmacologically, would be AIs. The Cancer Genome Atlas published that ESR1 mutation rates were very low, at perhaps 1% or so at diagnosis and based on the patients primary tumor. However, [ESR1mutations] really [arise] after exposure to AIs.

That makes sense because AIs work by depriving estrogen from the environment. To be activated, ERs need to bind to estrogen. So, [AIs] select for any mutations that may occur where a mutation [is present] in the ER that allows it to be activated without the presence of estrogen; that is what most activating ESR1mutations do. Specifically, upon exposure to AIs, is when we start to see these mutations arise.

The PADA-1 trial showed that ESR1 mutations can be acquired and they can be subclonal, meaning that you can see a very low fraction of all the tumor DNA that has that mutation. However, you cant underestimate that power of a small fraction of activated ESR1-mutant cells. We do see that pattern of resistance. [Additionally, the trial showed] that patients can have multiple clones.

How do you combat ESR1 mutations? One way is to totally take them out of the equation and to target them for downregulation or proteasomal degradation, which is what selective ER downregulators like fulvestrant [Faslodex] do. However, they dont do it completely; these drugs dont completely circumvent resistance. Another way is to use [SERMs] that may not necessarily inactivate the ER, but instead, modulate the ER in the way it behaves, the conformation of it, and how it binds to co-activators, co-receptors, and co-repressors. [Doing this], ultimately, mediates the expression of genes that guide what estrogen does, which is generally a growth signal.

Lasofoxifene does have the ability to downregulate the transactivating nature of the ER, including ESR1mutations. In the lab, we can study how well an ER is able to activate the genes it targets. ERs are known to target numerous genes of interest that lead to cell growth. We can measure to what extent a drug will interact with ESR1 so that it negatively regulates it. In other words, the genes that are normally transcribed by estrogen are not transcribed. More importantly, growth is arrested. That hasnt been demonstratedin vitroandin vivousing ESR1-mutant models.

Those data are compelling. They show that we can get growth inhibition in ESR1mutations and that it can be potentially aided with CDK4/6 inhibitors. Although I dont have the exact data at hand, I have seen examples of this and other data that show [tumor growth] can be reversed in cell-line models.

What we see in those cell-line modelseven in animal models, which are more accurate but may not be the whole storymay not turn out to be the case in the tumor microenvironment and all of the other factors involved. Therefoe, although this is very supportive and raises enthusiasm for getting these types of drugs into clinical trials, we need to wait to see what happens when patients are taking these drugs.

The ELAINE trial is comparing fulvestrant with lasofoxifene in patients with ESR1 mutations. Its a direct test of the hypothesis that [lasofoxifene] may be more favorable than [fulvestrant], which we now consider a reasonable drug to use when we see ESR1 mutations or in the second line in general.

ELAINEII is designed to move [lasofoxifene] further, combining it with a CDK4/6 inhibitor. It will allow patients who have seen prior CDK4/6 inhibitors [to enroll].There is some anecdotal evidence that responses have been seen with abemaciclib after progression on other CDK4/6 inhibitors.

The approval of abemaciclib was based on a trial that showed responses in refractory hormone receptorpositive disease as a single agent, but those patients had not been previously exposed to CDK4/6 inhibitors. We believe that the combination of these 2 different strategies could bring about more responses and longer time to progression.

One of the issues is pairing CDK4/6 inhibitors with different endocrine therapies; we havent formally compared that. We do know from the FALCON trial that, when using endocrine therapies alone, fulvestrant is slightly better than AI therapy, particularly in patients who havent been treated before or have non-visceral disease. Then, the MONALEESA-3 study was a trial that took advantage of the FALCON findings and compared treatment with fulvestrant alone versus fulvestrant plus ribociclib [Kisqali] regardless of first- or second-line therapy. That study showed a significant improvement in outcomes with a hazard ratio of around 0.5, which has been seen before.

The PARSIFAL trial, on the other hand, was a direct comparison with palbociclib. Patients received an AI or fulvestrant. The trial did not show a difference in progression-free survival.We are left without knowing what population fulvestrant might be best for, but certainly fulvestrant is a reasonable option in the first- or second-line setting. We have less data regarding what to do in the second line for patients who received fulvestrant up front, but the PARSIFAL and MONALEESA-3 studies showed that [ribociclib and palbociclib] are both reasonable agents to use and could be building blocks for [combinations] with other targeted agents.

The sub-classification of the breast cancer subtypes is very important in general. In breast cancer, not all patients with luminal A or luminal B [disease] are the same. There may be certain aspects about the different pathways involved in growth and other cellular functions, such as invasion and apoptosis that may vary depending on different gene profiling. Gene profiling is basically a way to categorize cancers, but if we can categorize them in functionally relevant ways, then we are really making advances.

This takes studying large numbers of patients, ideally in the context of a clinical trial where they are being treated similarly or we are comparing 1 treatment with another. Then, we can dissect the different molecular profiles that may predict a benefit. More importantly, we can use that information about the molecular profiles to identify mechanisms of resistance that could inform newer strategies.

Not all mutations are the same. There may be certainESR1mutations that are generated in certain situations and under certain treatments that we need to understand better. What is really fascinating is trying to understand the functional consequences of ESR1 mutations, not only in terms of proliferation, but in terms of many other phenotypes that we are interested in targeting, such as metabolic activity, DNA repair, or other hallmarks of cancer. Whether it is invasion, the ability to resist apoptosis, or immunogenicity is critical. Studies in the basic aspects of what ERS1 mutations do [are important]. [Also, evaluation of] the nitty gritty molecular structure and how the ER interacts with co-activators, co-repressors, and other aspects of the transcriptional machinery that make the ER work [is needed] to understand what ESR1 does.

Of course, we are aware of many other mutational isoforms, such asRASmutations and growth factor mutations, like exon 20. We need to understand the inner workings of what these mutations cause. When you think about it, cancer is selection of the fittest. Cancer cells do have a higher mutational rate. Many of the mutations that arise out of accident lead to cell death. However, it is those that lead to cell advantage that perpetuate. By understanding the most common driver mutations that arise over time, we can start to develop therapies against each one. Although, there will always be rare mutations that are going to be more difficult to understand and target.

Read more:
Lasofoxifene Emerges as Understanding of ESR1 Mutations Expands in ER+/HER2- Breast Cancer - OncLive