Out of jobs, a pair of early cell therapy executives went to Seoul, came back with a new company, $70M and a plan to leapfrog natural killer…

Tom Farrell didnt have much to do after Bellicum announced in January 2017 that they were bringing in a new CEO. He had led the CAR-T company for over a decade, since before Carl Junes New England Journal of Medicinepaper had made cell therapy the hottest thing in cancer research. Now he was facing an 18-month non-compete.

So he worked quickly when, not long after that clock expired in 2018, a banker who helped take Bellicum public told him about a South Korean company called Green Cross LabCell that had built a natural killer cell factory and was looking to develop therapies off it. Farrell hopped a plane to Seoul.

It was hugely impressive, Farrell told Endpoints News.There was nothing [else] I came across that was truly disruptive from a business model perspective.

A year and a half later, Farrell has his new company. Called Artiva, it launches with $78 million in Series A funding and an exclusive deal with Green Cross to push some of their natural killer cell technology into the clinic. Theyll start with a therapy that combines NKs with an approved antibody therapy like rituximab to improve the antibodys effectiveness. Behind that, theyre working on CAR-NK therapy and, longer term, gene-edited CAR-NK cells. RA Capital Management, venBio and 5AM Ventures led the round.

Artiva joins what, after many years, has recently become a booming field. In February, MD Anderson showed that a Takeda-licensed CAR-NK therapy cleared tumors completely in 7 of 11 non-Hodgkins lymphoma patients. Two months later, J&J gave Fate Therapeutics, one of the earliest biotechs in the field, an up-to $3.1 billion deal for their CAR-NK and CAR-T therapies. The Big Pharmas are joined by a slate of recent upstarts, including Celularity, Nkarta, NantKwest, and Cytovia.

Unlike the other newcomers, Artiva makes virtually no claim on having original science. In fact, Farrell said, biotechs emphasis on novel technologies is part of why cell therapy has advanced only incrementally since the approval of the first two CAR-T therapies. Industry hasnt focused enough on addressing the manufacturing issues that have made therapies so costly and difficult to scale, he said.

Lewis Lanier, an immunologist at the University of California, San Francisco and an early pioneer in NK cell research, said Artiva would still face the same questions other drug developers face will some patient reject the cells? Will the natural killer cells actually last a significant amount of time after infusion? but the collaboration could give them an edge.

The Korean Green Cross manufacturing facility is really first rate, thats where the advantage is, Lanier, who is not involved in Artiva, told Endpoints. The science is really routine, theyre not doing anything particularly innovative.

For years, NK cells have been viewed as one of the key potential ways of making off-the-shelf cell therapy. Part of the innate immune system, implanting these cells from donors doesnt lead to the same resistance that donor T cells can. One of the problems, though, is that NKs are finicky, as Lanier puts it, vastly more difficult to grow and manipulate in a lab. Only recently have a couple companies figured out ways to do it consistently. Fate, for instance, uses master lines of iPSC stem cells.

At the Green Cross facility Farrell toured two Novembers ago, the South Korean company had refined a process to derive NK cells from donated umbilical cord blood and cryo-preserve it. A week after his tour, Farrell flew to San Diego for the ASH conference, where he ran into Pete Flynn, another longtime biotech executive out of a job. Flynn had run early development for Fate in its early years before leaving to run R&D for the anti-obesity company Orexigen, which had just gone bankrupt.

Farrell explained what he saw in Seoul and the two debated different approaches to off-the-shelf therapy. They figured the manufacturing base could be a launching pad.

Even though were a Series A company, were looking to become the go-to NK cell, Flynn, now COO, told Endpoints. Basically all the pieces are in place already, whereas for some of those other companies, there might still be some work to do.

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Cernostics Announces Blinded, Independent Validation of TissueCypher(R) Performance for Predicting Risk of Progression to Esophageal Cancer in…

PITTSBURGH, June 25, 2020 /PRNewswire/ --Cernostics, a leader in the development of AI-driven image analysis technologies for precision medicine testing, today announced publication of new clinical results demonstrating further validation of how its TissueCypher(R) diagnostic test predicts future disease progression in patients with Barrett's Esophagus (BE). (Abstract available here. Full article available via journal subscription.) By identifying "at-risk" patients much earlier than traditional methods, TissueCypher provides actionable results that allow physicians to target early therapeutic interventions to prevent cancer.

TissueCypher is the first and only precision medicine test designed, developed, and commercialized to predict which patients with Barrett's Esophagus will progress to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC).

In this study, funded by the NIH/NCI, patients with BE who progressed to HGD or EAC after at least one year following endoscopy (n=58) were matched to patients with BE without disease progression after a median of seven years surveillance (n=210). Results demonstrated that patients classified as high-risk by TissueCypher were at 4.7-fold increased risk for HGD/EAC compared to those classified as low-risk (p<0.0001). Furthermore, this study demonstrated that patients with non-dysplastic BE who TissueCypher scored high-risk progressed to HGD or EAC at a rate of more than 5%/year, which is at least a 10-fold increase in reported progression rates for NDBE, based on large population studies.

In an editorial accompanying the published results, Prasad G. Iyer, MD, MSc, at Mayo Clinic in Rochester, Minnesota, describes TissueCypher as the potential "Holy Grail" for Barrett's Esophagus. "Identification of those at higher risk may allow either intensive endoscopic surveillance (to detect incident dysplasia/EAC) or proactive EET, whereas surveillance intervals could be lengthened in those at low risk. This risk prediction has been referred to as the 'Holy Grail' in BE."

"This is the third independent study showing that TissueCypher gives physicians crucial predictive power beyond expert diagnosis, especially in that difficult subset of patients whose true risk may go unnoticed if we rely solely on traditional methods," said lead author Jon M. Davison, MD, Associate Professor of Pathology at University of Pittsburgh in Pittsburgh, Pennsylvania.

TissueCypher's unique advantages stem from its patented, AI-based digital platform with multi-channel fluorescence imaging that provides physicians with a more in-depth, accurate, and comprehensive view of each patient's unique pathology.

"The TissueCypher image analysis platform simultaneously and objectively extracts protein expression information from multiple biomarkers, as well as provides a digital expression of tissue architecture and nuclear morphology," says Vani J.A. Konda, MD, Clinical Director, Center for Esophageal Diseases, at Baylor University Medical Center in Dallas, Texas, and a key opinion leader in the use of imaging and novel screening techniques to improve early detection and treatment. "The information physicians receive is meaningful, accurate, and immediately actionable." Dr. Konda has published extensively on the role of biomarkers for improving risk stratification in patients with Barrett's Esophagus, including an upcoming review paper in the July 2020 issue of Gastroenterology & Endoscopy News.

Cernostics' innovative technology is unique in today's market because tissue structure is preserved while immune, stromal, stem cell and tumor biomarkers are analyzed all of which is done by evaluation of standard esophageal pinch biopsies readily available from the endoscopy procedure. Biomarker intensity and spatial relationships within the tissue structure are also analyzed and reported, creating an in-depth picture of the patient's risk from which the physician can create successful patient management protocols.

TissueCypher has been tested and validated in five independent clinical studies at leading centers around the world, including Cleveland Clinic, University of Pennsylvania Medical Center, Geisinger Health, and Academic Medical Center in Amsterdam. Most recent peer-reviewed results are published currently in the June 2020 issue of the American Journal of Gastroenterology.

Using a pinch biopsy specimen routinely collected by the gastroenterologist during an endoscopy procedure, TissueCypher is easily incorporated into a physician's current practice. The test requires no additional tools or collection devices, as are needed with other currently available diagnostic options.

About Barrett's Esophagus

Barrett's Esophagus (BE) affects more than three million Americans, occurring when chronic exposure to stomach acid causes the esophageal cell lining to deteriorate and undergo changes that can create an environment for cancer. Without treatment, Barrett's can lead to EC, with a poor five-year survival of less than 20%. Today, Barrett's is commonly managed by surveillance, involving regular endoscopic procedures with biopsy, monitoring disease progression, and GERD-related drug therapy to control symptoms and prevent esophageal injury.

About Cernostics

Cernostics, a leader in tissue-based diagnostic testing, provides diagnostic tests with deeper tissue insights, better patient outcomes, and lower cost of care. Cernostics' mission is to quantify the tissue system complexity, providing physicians and patients with individualized, actionable information to improve outcomes and reduce the incidence and mortality of cancer. For a complete listing of Cernostics' published patents, visitwww.cernostics.com/IP.

Media Contact:

Lisa Bichsel

Cernostics

Tel: +1 719-640-5640

Email: lbichsel@cernostics.com

Related Images

tissuecypher-sample-image.jpg TissueCypher Sample Image TissueCypher detected multiple high-risk features in this biopsy from a patient with short segment, non-dysplastic Barrett's esophagus, as confirmed by the GI subspecialist. TissueCypher scored this case High Risk for progression to HGD/EAC within five years. The patient was diagnosed with HGD on surveillance endoscopy 2.5 years later.

Related Video

http://www.youtube.com/watch?v=trHl_hMPJiE

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Manipulating proteins to make ‘cold’ tumors responsive to immunotherapies – FierceBiotech

Some cancers create a hostile environment that allows them to evade immune attacks. That's why many cancer patients don't respond to immuno-oncology treatments like checkpoint inhibitors. Scientists are looking for ways to turn these so-called cold tumors into hot ones that are susceptible to immunotherapy.

Two separate research teams led by Yale University and the University of Cincinnati have discovered proteins that can be targeted to overcome resistance to cancer immunotherapy in animal models.

Researchers at Yale focused on cytokine therapies, which harness the bodys inflammatory molecules to guide immune cells to go after cancer cells. Theteam, led by Aaron Ring, M.D., Ph.D., hypothesized that tumors were employing immunological countermeasures to hamper a powerful cytokine called interleukin-18.That may explain whya recombinant IL-18 drug called SB-485232 from GlaxoSmithKline failed to induce a meaningful response in metastatic melanoma patients in a phase 2 study.

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In a new study published in Nature, Ring and colleagues discovered that a decoy receptor called interleukin-18 binding protein (IL-18BP) was highly expressed in the microenvironment of many cancers. The protein lured IL-18 away and prevented it from binding to its true receptor on immune cells to trigger an immune response.

To solve the problem, the researchers used a process called directed evolution to search nearly 300 million different forms of IL-18 for candidates that can bind to the true receptor rather than the decoy. A modified version dubbed DR-18 with a high binding tendency toward the IL-18 receptor emerged from the process.

In mice with a variety of cancers, DR-18 significantly reduced tumor growth compared with wild-type IL-18. It also completely cleared tumors in many of the animals. Further analysis showed that the treatment changed the tumor microenvironment, leading to increased tumor-infiltrating lymphocytes and a type of stem-like precursor T cellthat sustained a durable immune responses.

We just changed IL-18's frequency in order to eliminate the jamming signal, Ring explained in a statement.

Ring has turned the findings into a startup called Simcha Therapeutics, which just raised $25 million in series A funding. The company expects to advance its lead asset, a humanized IL-18 variant coded ST-067, into the clinic in 2021.

RELATED:Marrying CRISPR with immuno-oncology to defeat remote tumors

In a separate study published in the journal Cancer Research, scientists at University of Cincinnati showed a protein called FIP200 was responsible for limiting T-cell recruitment and activation in breast cancer, thereby making tumors unresponsive to immune checkpoint inhibitors.

Disrupting FIP200s function led to increased inflammatory cytokine expression, the team showed. When coupled with a PD-1 inhibitor and a CTLA-4 inhibitor, the strategy led to reduced tumor growth in mice when compared to monotherapy with checkpoint inhibitors.

"These findings indicate that targeting FIP200 could create a 'hot spot' for immunotherapy within these tumors," saidSyn Kok Yeo, Ph.D., a research instructor in the department of cancer biologyat the University of Cincinnati, in a statement. The next step, he said, would be to develop drugs that target the protein and test them in combination with immune-boosting drugs in breast cancer.

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Simcha Therapeutics Launches to Engineer Therapeutic Cytokines to Unlock the Full Potential of the Immune System – Business Wire

NEW HAVEN, Conn.--(BUSINESS WIRE)--Simcha Therapeutics, a biotechnology company developing first-in-class biologic drugs that modulate powerful cytokine pathways, launched today with $25 million in Series A financing and a mission to harness the precision and power of the immune system through the use of directed evolution.

Simchas lead program involves a customized variant of interleukin-18 (IL-18), a cytokine with potent antitumor effects, developed in the lab of Scientific Founder Aaron Ring, M.D., Ph.D., Assistant Professor of Immunobiology at the Yale School of Medicine. The biology and preclinical profile of this molecule, which Simcha expects to advance to the clinic in the first half of 2021, is described in detail in a scientific paper published today in the journal Nature.

Cytokine therapies heralded the immuno-oncology revolution more than 30 years ago with the discovery that interleukin-2 (IL-2) could promote rare, but dramatic, responses in melanoma and kidney cancer patients. However, they have not lived up to their promise as a class due to substantial toxicities and limited efficacy. Simcha was founded to overcome those obstacles by using directed evolution to engineer a new generation of cytokines with improved properties relative to those of their native variants. Simchas molecules are purpose-built to control immune cell activation, differentiation and proliferation and to reverse the immunosuppressive tumor microenvironment that is a barrier to effective eradication of the cancer.

Cytokines represent a compelling therapeutic class because they tap into pathways that are hard-wired into immune cells. The challenge is that nature didnt design them to be anti-cancer therapies; theyre signaling molecules, so their activity can be hard to specifically direct, Dr. Ring said. At Simcha, we set out to improve on natures design by engineering custom-built proteins that can precisely activate and expand populations of crucial immune responders, such as natural killer (NK) cells and T cells. Too many cancer patients do not respond to the immunotherapies available today. Were hopeful that our approach will provide new options and potential benefits to these patients.

Evading a Decoy Receptor

Simchas lead asset, ST-067, activates the IL-18 receptor, triggering potent inflammatory signaling in antitumor immune cells of both the adaptive and innate branches of the immune system.

Early efforts by leading pharmaceutical companies to develop IL-18 into a drug failed. Dr. Rings lab broke new ground by identifying the reason for that failure: The tumor microenvironment is teeming with a decoy called IL-18BP, which binds IL-18 and blocks it from activating its receptor. When infused as a drug, IL-18 is drawn to the decoy and fails to reach its true target. As described in the Nature paper, the decoy receptor is a major barrier to IL-18 immunotherapy.

To overcome that barrier, Dr. Rings lab used directed evolution to create a version of the cytokine that would evade the decoy and bind only to the true IL-18 receptor. This was a difficult task, since IL-18 normally binds its decoy 10,000 times tighter than it does to the IL-18 receptor. The designer version of IL-18 made in Rings lab has dramatic alterations in its receptor binding properties, biasing binding towards the IL-18 receptor and away from the decoy by more than one million-fold. This decoy-resistant property enables the custom-built cytokine to work effectively in the immunosuppressive tumor microenvironment.

Potent Single-agent Antitumor Effects

When Rings lab tested the decoy-resistant IL-18 and compared it to natural IL-18 in mice, they found that just as in human patients natural IL-18 had little to no antitumor activity. By contrast, the decoy-resistant IL-18 had potent single-agent activity that inhibited tumor growth and even produced complete tumor regression in many animals, including in tumor types that are refractory to checkpoint inhibitors.

Rings lab also examined the effect of decoy-resistant IL-18 on the tumor microenvironment. A key finding: The engineered IL-18 acted on a crucial population of stem-like T cells within tumors, increasing their numbers over tenfold and skewing their development toward a highly active effector phenotype, as opposed to an exhausted or dysfunctional state. In checkpoint-resistant tumors, the engineered IL-18 also acted on innate NK cells, increasing their numbers and maturation to promote antitumor activity.

The mechanism of action of decoy-resistant IL-18 is unique and distinct from immunotherapeutic agents that are being developed for other pathways. For this reason, we are hopeful it could be effective in tumors that have not otherwise responded to immune-based treatments, as well as enhance the activity of standard cancer immunotherapies, said Dr. Ring.

Founders Strong Record in IO Drug Discovery

Dr. Ring has a strong track record in immuno-oncology drug discovery. He co-invented the first described CD122-biased IL-2 variant, originally detailed in Nature in 2012, which is now advancing through preclinical studies at Medicenna Therapeutics. He also developed a high-affinity SIRP antagonist, featured in Science in 2013, that is now in clinical development at ALX Oncology as ALX-148. For these and other discoveries, Ring was named to Forbes 30 under 30 list of rising stars in health care in 2016 and has been honored with an NIH Directors Early Independence Award and recognition as a Pew-Stewart Scholar in Cancer Research.

Simcha plans to build out a full executive team as the company prepares to move ST-067 into the clinic next year.

The companys investors include WuXi AppTecs Corporate Venture Fund, Sequoia Capital China and Connecticut Innovations.

About Simcha Therapeutics

Simcha Therapeutics uses directed evolution to engineer novel cytokines designed to unlock the precision and power of the immune system. Simchas lead program, ST-067, is a designer IL-18 cytokine that has shown potent antitumor effects in animal models, both as a monotherapy and when combined with anti-PD-1 checkpoint inhibitors, as described in Nature in June 2020. A Phase 1 trial is expected to be launched in the first half of 2021. Simcha was founded by Aaron Ring, M.D., Ph.D., Assistant Professor of Immunobiology at the Yale School of Medicine. The company has received $25 million in funding to date and is based in New Haven, Conn.

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Simcha Therapeutics Launches to Engineer Therapeutic Cytokines to Unlock the Full Potential of the Immune System - Business Wire