Illinois-based AbbVie and La Jolla, California-based The Scripps Research Institute entered into a broad research collaboration in oncology, immunology, neurology and fibrosis.

Based on our strong switchable CAR-T alliance launched in 2018, we feel the expanded relationship with AbbVie represents a robust path forward for some of our programs, complementing a diverse ecosystem of innovation weve created over the past several years at Scripps to advance life-changing therapies, said Peter Schultz, chief executive officer of Scripps Research and Calibr, its drug discovery division.

Under the terms of the 2018 agreement, AbbVie paid Calibr an upfront license fee and picked up exclusive access to Calibrs switchable CAR-T platform for up to four years. The plan was to develop T-cell therapies against solid tumor targets chosen by AbbVie. AbbVie had the option to develop more cell therapies toward its targets and license existing Calibr cell therapy programs in hematological and solid cancers, including Calibrs lead programs.

In the new collaboration, in addition to the initial programs, Scripps will offer AbbVie a certain number of preclinical programs each year to be included in the partnership. They will work together in parallel to advance CD3 bispecifics against cancer targets picked by AbbVie

Under the terms of the deal, Scripps will run preclinical R&D, and in some cases, Phase I clinical trials. AbbVie will have an exclusive option to continue development and possible commercialization activities.

Once AbbVie chooses to exercise its option on any given program, it will pay Scripps additional payments that include option exercise fees, success-based development and commercial milestone payments, and tiered royalties. At hitting a milestone, AbbVie will make an undisclosed upfront payment as well as near-term milestone payments.

The best way to develop transformational medicines is through collaborations that bring together the brightest minds, said Mohit Trikha, vice president and head of oncology early development at AbbVie. This partnership with Scripps Research will collaboratively advance next generation programs, build stronger relationships with proven and emerging scientific leaders, and most importantly help us advance novel medicines for patients.

Trikha added, We are eager to partner with Scripps on these assets as they enter the clinic over the next few years as Scripps has one of the strongest track records of any academic institution when it comes to advancing novel medicines for patients.

Although neither organization released financial terms, they did say the partnership requires antitrust review. Under the law, reports The San Diego Union-Tribune, antitrust review has to be conducted for deals exceeding $84.4 million.

The Tribune notes, A deal of that size will bolster the La Jolla biomedical science institutes troubled finances for several years, and perhaps much longer. And if approved cancer therapies result, the payout could be gigantic.

The early work will be on an immuno-oncology treatment for lymphoma, which Calibr plans to launch in the clinic in 2020.

What were developing is a fully controllable, universal switchable CAR-T cell platform that allows a physician fine control over the activation and specificity of the CAR-T cells, Travis Young, director of protein sciences at Calibr told The Tribune.

At the moment, there are two CAR-T products approved, Novartis Kymriah and Gilead Sciences Yescarta. Both are quite effective in certain patient populations, but the process is expensive and time-consuming, requiring immune cells be collected from the patient, engineered to focus on the patients specific cancer, then be infused back into the patient. A number of companies are working on off-the-shelf CAR-T, that would not require the specific engineering catered to each patient.

CAR-T and other immunotherapy approaches also have high risks of immune reactions, although Novartis and Gilead have both developed protocols for minimizing or dealing with them. Scripps argues that their type of CAR-T improves over these, particularly in terms of safety, convenience and versatility.

These antibody-based switches bridge the CAR-T cells to the target cell. And so, by forming that bridge, they develop an immunological synapse, which redirects the CARs very specifically towards the target cells, said Young.

They also claim they can control the intensity of the response by varying the number of antibodies infused, would should minimize the adverse immune reactions.

The Tribune notes that in recent years Scripps has reported annual deficits that have hit as high as $20 million. The company currently has a drug in early clinical trials for osteoarthritis and is prepping another for prostate cancer, which it is hoping to partner with a company for commercialization.

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AbbVie and Scripps Research Enter Research Partnership in Cancer, Immunology, Neurology and Fibrosis - BioSpace

Chase Burton, Mee Y Bartee, Eric Bartee

Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA

Correspondence: Eric BarteeDepartment of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Ave, Charleston, SC, USAEmail bartee@musc.edu

Introduction: Cancer has become one of the most critical health issues of modern times. To overcome the ineffectiveness of current treatment options, research is being done to explore new therapeutic modalities. One such novel treatment is oncolytic virotherapy (OV) which uses tumor tropic viruses to specifically target and kill malignant cells. While OV has shown significant promise in recent clinical trials, the therapeutic use of viruses poses a number of unique challenges. In particular, obtaining effective viral spread throughout the tumor microenvironment remains problematic. Previous work has suggested this can be overcome by forcing oncolytic viruses to induce syncytia formation.Methods: In the current work, we generated a series of recombinant myxoma viruses expressing exogenous fusion proteins from other viral genomes and examined their therapeutic potential in vitro and in vivo.Results: Similar to previous studies, we observed that the expression of these fusion proteins during myxoma infection induced the formation of multinucleated syncytia which increased viral spread and lytic potential compared to non-fusogenic controls. Contrary to expectations, however, the treatment of established tumors with these viruses resulted in decreased therapeutic efficacy which corresponded with reduced viral persistence.Discussion: These findings indicate that enhanced viral spread caused by syncytia formation can actually reduce the efficacy of OV and supports a number of previous works suggesting that the in vitro properties of viruses frequently fail to predict their in vivo efficacy.

Keywords: myxoma virus, syncytia, fusogenic, oncolytic virotherapy, lung cancer

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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Impact of Induced Syncytia Formation on the Oncolytic Potential of Myx | OV - Dove Medical Press

New research by scientists at Harvard Medical School has found that nerves in the guts of mice do not merely sense the presence ofSalmonellabut actively protect against infection by this dangerous bacterium by deploying two lines of defense.

The study,published Dec. 5 inCell, casts in a new light the classic view of the nervous system as a mere watchdog that spots danger and alerts the body to its presence. The results show that by directly interfering withSalmonellas ability to infect the intestines, the nervous system is both a detector of danger and a defender against it.

Our results show the nervous system is not just a simple sensor-and-alert system, said neuro-immunologistIsaac Chiu, the studys lead investigator and assistant professor of immunology in the Blavatnik Institute at Harvard Medical School. We have found that nerve cells in the gut go above and beyond. They regulate gut immunity, maintain gut homeostasis and provide active protection against infection.

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Specifically, the experiments reveal that pain-sensing neurons embedded in the small intestine and beneath cells called Peyers patches are activated by the presence ofSalmonella, a foodborne bacterium responsible for a quarter of all bacterial diarrheal disease worldwide.

Once activated, the nerves use two defensive tactics to prevent the bug from infecting the intestine and spreading throughout the rest of the body. First, they regulate the cellular gates that allow microorganisms and various substances to go in and out of the small intestine. Second, they boost the number of protective gut microbes called SFB (segmented filamentous bacteria), which are part of the microbiome in the small intestine.

Bacteria get on our nerves

Under normal conditions, Peyers patchesclusters of lymphatic and immune tissue found exclusively on the wall of the small intestinescan the environment, sample substances and determine what can go into the intestine. To perform this function, Peyers patches are studded with microfold cells, or M cells, which are cellular channels that open and close to regulate influx of substances and microorganisms into the intestine. M cells are the major entry points thatSalmonellaand other dangerous bacteria exploit to invade the small intestine. To do so, theSalmonellabacterium injects into the gut transcription factors that stimulate intestinal cells to become M cells. Next, Salmonella latches onto sugars sitting atop the M cellsthe cellular gatesand uses its tentacles to prop the gates open. The bacterium then wiggles its way into the intestine.

To understand the role of pain-sensing gut neurons in infection protection, researchers compared how mice with and without them responded toSalmonella. One group of mice had intact gut neurons, another group had these neurons genetically disabled or deleted, and yet another cohort had them chemically disabled.

Experiments showed that in the presence ofSalmonella, gut neurons fire back by releasing a neurochemical called CGRP, which slows down M cell differentiation, thereby reducing the number of entry points that Salmonella can use. Additionally, the experiments show, gut neurons launch another form of defense. By releasing CGRP, they boost the presence of SFB microbesmicroorganisms that, among performing other beneficial functions, also guard againstSalmonellainvasion. Precisely how they do so remains unclear, but Chiu and colleagues say one plausible mechanism may be that SFB uses its tiny little hooks to attach itself to the intestinal wall and form a repellent coating that shields against the disease-causing bacteria.

Both defense mechanisms functioned reliably in mice with intact gut neurons. Not so, however, in animals that lacked these gut neurons. Indeed, intestinal biopsies from mice with inactivated neurons showed their Peyers patches more densely infiltrated by Salmonella at a greater rate than animals with intact neurons. The neuron-deficient animals also had fewer protective SFB microbes in their guts. Not surprisingly, these mice got sick fromSalmonellaat a greater rate and had more widespread disease than mice with intact nerve fibers.

It is becoming increasingly clear that the nervous system interacts directly with infectious organisms in various ways to affect immunity, Chiu said. Bacteria literally do get on our nerves.

The findings are in line with past research by Chius group showing a powerful three-way interplay between infection and the nervous and the immune systems. But in contrast to the new findings, the previous work showed that the nervous system can, at times, be exploited by infectious organisms to their advantage. For example, Chius previousresearchfound that nerves in the lungs can alter immune response in serious lung infections with the bacteriumStaphylococcus aureus, commonly known as staph. In anotherstudy, Chius team discovered that the bacterium that can cause flesh-eating disease hijacks nerves as a way to dampen immune defenses and weaken the bodys defenses.

A diverse repertoire

The new findings add to a growing body of knowledge showing that the nervous system has a repertoire far broader than signaling to and from the brain.

Our findings illustrate an important cross talk between the nervous system and the immune system, said study first author Nicole Lai, research fellow in immunology in the Chiu lab. It is clearly a bidirectional highway with both systems sending messages and influencing each other to regulate protective responses during infection.

Indeed, the gut contains so many nerves that it has often been called the second brain. As an alert system designed to warn the body of looming threats, the nervous system acts ultrafast. Thus, the new findings, the researchers said, suggest that evolution has taken advantage of this feature for added protection.

If you think about it, the nervous systems involvement in immunity is an evolutionarily smart way to protect the gut from infection by repurposing an existing feature, Chiu said.

The researchers say their findings could also help explain previous observations showing that the use of opioidswhich silence pain-sensing nerve fibersand other nerve-modulating drugs can make people more prone to infections.

If you dial down nerve signaling in an effort to reduce pain, you may be inadvertently also dampening their protective abilities, Chiu said. Our observations support that idea.

The interaction between gut neurons and gatekeeping M cells represents an area ripe for future research, the team said, because M cellsthe molecular gates of the small intestineare also exploited by other organisms that cause serious human disease, including the bacteriaE. coli, ShigellaandYersinia, as well as prions, self-propagating clumps of misfolded protein that can cause rare but universally fatal neurodegenerative conditions.

The results also point to a possible therapeutic pathway that involves modulating nerve signaling either for boosting gut immunity or intestinal inflammation.

The idea would be that if we could somehow stimulate these protective gut neurons or mimic their activity with a drug, we could activate the immune response and increase the bodys ability to fend off infection, Chiu said.

Other researchers included Melissa Musser, Felipe Pinho-Ribeiro, Pankaj Baral, Amanda Jacobson, Pingchuan Ma, David Potts, Zuojia Chen, Donggi Paik, Salima Soualhi, Yiqing Yan, Aditya Misra, Kaitlin Goldstein, Valentina Lagomarsino, Anja Nordstrom, Kisha Sivanathan, Antonia Wallrapp, Vijay Kuchroo, Roni Nowarski, Michael Starnbach, Hailian Shi, Neeraj Surana, Dingding An, Chuan Wu, Jun Huh, and Meenakshi Rao.

This work was supported by National Institutes of Health grants DP2AT009499 and K08 AI108690, National Institute of Allergy and Infectious Diseases grant R01AI130019, NIH grant R01 DK110559, the Chan-Zuckerberg Initiative, Harvard Digestive Disease Center, National Institute of Diabetes and Digestive and Kidney Diseases (grant K08 DK110532), National Multiple Sclerosis Society (Career Transition award TA3059-A-2), and Whitehead Scholar award and Translating Duke Health Scholar award.

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LAWRENCE The University of Kansas has lost a longtime faculty member to a battle with cancer. Stephen Benedict, professor of microbiology, died Dec. 2 in Lawrence. He was 72.

Professor Benedict was a dedicated researcher and an inspirational and award-winning teacher to his many hundreds of students during his long career at KU, said Chancellor Douglas A. Girod. On behalf of the entire university, I offer my sincere condolences to his family, his friends and all who knew him throughout his time at KU.

Benedict came to KU in 1990 as an assistant professor of pharmacology & toxicology and later moved to the Department of Molecular Biosciences. Benedict was named full professor in 2008, a position he held until his death.

He touched the lives of many hundreds of KU undergraduates, said Susan Egan, professor and chair of the Department of Molecular Biosciences. Among Benedicts career honors were numerous awards recognizing his influence on students. Those honors included the Kemper Teaching Award, the Robert Weaver Graduate Mentoring Award, the J. Michael Young Academic Advisor Award, the Chancellors Club Teaching Professorship and the Mortar Board Outstanding Educator Award.

Moreover, Benedict was voted Favorite Biology Professor from among nearly 50 biology faculty members five times over the past 15 years, Egan said.

Benedicts research interests centered on immune-related disorders specifically related to T-cells. He published nearly 90 academic papers, received six U.S. patents and made numerous service contributions to the field, from serving on grant review panels for the National Institutes of Health to serving as associate editor of the Journal of Immunology.

Steves loss will be felt widely among the KU community and far beyond, Egan said. He will be remembered for the deep caring he showed for his students, his positivity and his tremendous sense of humor.

A celebration of life service is planned for Jan. 18, 2020, in Lawrence.

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CHICAGO, Dec. 9, 2019 /PRNewswire/ -- Advaite Inc., a Chicago, IL based oncology-focused biotech company developing novel therapeutics and diagnostics to help patients suffering from debilitating diseases, has announced that it has entered into an exclusive license option agreement with the George Washington University with respect to the intellectual property of a novel AMES Negative HDAC6 inhibitor. Histone Deacetylases modulate a multitude of cellular processes and are part of the regulation of cellular pathways involved in anti-tumor immunologic responses. Selective inhibition of HDAC6 slows tumor growth in various cancer models. Under terms of this agreement, Advaite has the option to exclusively license intellectual property covering methods of use and pharmaceutical compositions.

"We look forward to future success by advancing the development of this novel HDAC6 inhibitor to treat a multitude of cancers, to ease suffering and extend life. This epigenetic regulator can have a potentially enormous therapeutic effect on patients who continue to suffer from debilitating cancer, as there is a great need for therapies that deliver an effective response, and specifically ones which are not limited by their toxicity profile. George Washington University's expertise with HDACs provide a perfect relationship for Advaite to advance truly viable, state of the art, impactful technology," said Karthik Musunuri, CEO & Co-Founder of Advaite.

"The quest for newer and more effective ways of treating cancer has now led to an extensive focus on the involvement of the immune system and its capacity to recognize and engage tumor cells. Recent findings from several research groups have demonstrated that ultra-selective HDAC6 inhibitors have the unique capacity of remodeling of the cellular composition of tumors, favoring the recognition and killing of cancer cells by the immune system. Our novel HDAC6 inhibitor has shown to have reduced toxic effects, thus clearly differentiating from previous HDAC inhibitors used in the clinic," said Alejandro Villagra, Ph.D., Member of the Immunology and Microbial Oncology Research Program at the GW Cancer Center and Assistant Professor of Biochemistry and Molecular Medicine at the GW School of Medicine and Health Sciences.

About Advaite

Advaite Inc. is a biotech company focused on developing novel therapeutics and diagnostics to help patients suffering from a variety of debilitating diseases, primarily within the oncology space. Advaite strives to maintain a patient centric approach in developing healthcare innovations. For more information, please visit http://www.advaite.com.

Forward Looking Statement

This press release includes statements that are "forward-looking statements," within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. While Advaite has based any forward looking statements contained herein on its current expectations, the information on which such expectations were based may change. These forward-looking statements rely on a number of assumptions concerning future events and are subject to a number of risks, uncertainties, and other factors, many of which are outside ofAdvaite's control.

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Every year, about 300,000 people worldwide receive a new heart valve. Whenever possible, doctors use valves made of tissue from cows or pigs, because the synthetic alternatives can cause blood clots.

But there is a hitch. Although animal tissue valves can last up to 30 years in people over 60 years old, they can be destroyed in just five years in a younger person, probably because of their more aggressive immune system.

Enter the genetically engineered bull.

Scientists used CRISPR gene editing technology to create two bovine mutations that should lessen peoples immune responses to the animal tissue.

The mutations knock out two sugars which coat the bulls cells but are not found in humans: -Gal and Neu5Gc.

The objective is to have animals that express tissues that are less foreign to the human body, said Dr Emanuele Cozzi, coordinator of a project called TRANSLINK, which has been trying to improve the long-term success of heart valve replacements.

In theory this means peoples immune systems will be less likely to attack the animal tissue, added Dr Cozzi, who is director of the Transplant Immunology Unit at Padua University Hospital in Italy.

Clone

As part the project, an Italian company, Avantea, created bovine cells with the two mutations and used them to clone a bull with a technique similar to the one that produced Dolly the sheep.

We are the first to make cattle (with these) mutations, said Professor Cesare Galli, co-founder of Avantea.

The cloning step is required to make the founder animals. Then they can breed normally, said Prof. Galli.

Avantea had created the same mutations in pig cells using a technology called Transcription activator-like effector nucleases (TALEN) to edit the DNA, before CRISPR was available.

With CRISPR it is much easier to prepare the reagents that are needed to implement the system, said Prof. Galli.

That makes CRISPR cheaper because the reagents can be prepared in-house. However, in theory at least, it is less accurate, he added. Being less precise in recognising the sequence to cut, there is the risk of undesired cuts - this is a risk that has yet to be quantified.

'The animals we generated could have a potential application for food consumption, at least for people who do not tolerate red meat.'

Professor Cesare Galli, co-founder, Avantea, Italy

Quality of life

About 100,000 people a year are given synthetic heart valves because they are too young to receive the animal tissue version.

But these valves can lead to dangerous blood clots forming, so patients have to live on anticoagulants that impose severe limitations on a young persons life, saysDr Cozzi.

People have to avoid competitive sports and jobs with a high risk of injury, like construction or some police work.

If an accident occurs while on duty (they) may bleed to death, said Dr Cozzi.

Although preliminary data suggests that peoples immune systems attack valve transplants in response to the animal tissue used, scientists need more solid evidence of this before they can recommend using the genetically engineered animal tissue, says Dr Cozzi.

Other factors including someones blood pressure cannot yet be ruled out as affecting the valves lifespan, he says.

To understand more, TRANSLINK is carrying out a study of 1,600 cardiac patients the largest of its kind to compare their immune responses to animal or synthetic valve transplants or other types of surgery. The results are expected next year.

If the study shows convincingly that immunology is behind the premature failure of animal-derived heart valves, it should not be too difficult to find potential investors who could bring the genetically engineered tissue valves to market, says Dr Cozzi.

My hope would be that, based on the data of our study, we may change the outlook of young patients (and offer them) a better quality of life.

The mutations in both pigs and cows may pave the way for people to receive transplants of whole animal organs, Dr Cozzi says.

Red meat allergies

The cloned animals may also benefit people allergic to red meat a reaction which sometimes develops after they have been bitten by a tick.

Scientists think the main culprit is the -Gal sugar found in all animals other than primates.

Anything from a steak to collagen used in cosmetics can trigger a reaction, which can range from a skin rash to anaphylactic shock.

The animals we generated could have a potential application for food consumption, at least for people who do not tolerate red meat, said Prof. Galli.

Some scientists in the US are also looking at possible links between the Neu5Gc sugar and cancer. The World Health Organization has classified red meat as probably carcinogenic to humans,although there is limited evidence.

Millions of years ago, humans developed a mutation that stopped the production of Neu5Gc and produced a slightly different sugar called Neu5Ac instead. The mutation made people resistant to malaria, and quickly spread across the population.

Pigs, sheep, cows and most other mammals with the exception of deer and some dogs - produce the Gc form which is highly antigenic in humans, says Prof. Galli, meaning it prompts a strong immune response.

Chicken and fish do not, which is one reason they are considered to be healthier to eat.

The cloned cows could be a useful source of milk for baby food, as it would be closer to human milk because it does not carry the antigen, says Prof. Galli.

Avantea also plans to use CRISPR to create horses with the same mutations as the cows and pigs. Horse serum is used to make antidotes to snake bites, but it can trigger adverse reactions in some people. Knocking out -Gal and Neu5Gc may prevent that, he says.

The potential for the cloned pigs, cows and horses to improve peoples health is huge. But for the time being, much of it is still theory, the scientists say.

We have the tools now, but there is work to be done to prove whether there is an advantage or not, said Prof. Galli.

The research in this article was funded by the EU. If you liked this article, please consider sharing it on social media.

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Genetically engineered animals offer fresh hope to heart valve patients - Horizon magazine