All things new: Gritstone Oncology unveils its cancer vaccine roadmap at AACR

Gritstone Oncology splashed onto the scene in late-2015, with a $102 million Series A that hinted at some lofty goals for cancer immunotherapy.

Some 18-months later, the team is presenting the first of its data in a poster session at the American Association for Cancer Research (AACR) annual meeting, which kicked off in Washington, D.C., on Saturday.

It’s the company’s first big reveal. So what have they got?

Enough to shoot for an IND filing and human trials in the middle of next year, said Cofounder, President, and CEO Andrew Allen.

The poster outlines three concepts, each with supporting data. Combined, Allen said they close the loop on what the company is trying to achieve: A model for predicting tumor-specific neoantigens that can be used to trigger a robust T-cell immunotherapy response. The initial target is lung cancer.

What does that all mean?

Like Neon Therapeutics and The Parker Institute for Cancer Immunotherapy, Gritstone is targeting neoantigens. These are mutations that arise “de novo” in a given cancer — they’re not otherwise found in the human genome.

As an immunotherapy target, they offer two major benefits: They’re foreign to the immune system and they’re not found in healthy tissue.

By comparison, traditional lung cancer targets such as ALK or EGFR have been present in the body since early development. They may be overexpressed in cancer cells, but the immune system has over time learned to tolerate them as “self.” That’s not a good platform for triggering a T-cell attack. Conversely, if the immune system was activated against those receptors, some healthy tissue would be hit.

Neoantigens are next-level personalized medicine, with next-level logistical challenges.

Predicting cancer neoantigens

Given the recurrent failures in cancer vaccine development, Gritstone is taking a two-pronged approach that verifies that specific neoantigens are truly being expressed on cancer cells.

“For success here, you’ve got to do two things well,” Allen said. “You’ve got to predict neoantigens well because that’s a big part of the problem. And then you’ve got to deliver them in a way that is going to drive large numbers of highly active T-cells.”

The first half of the puzzle is being pieced together by a team of around twenty, working in a facility in Cambridge, Massachusetts. The resulting data also make up the first findings in Gritstone’s AACR poster. The company asked whether the predictive modeling can be out-sourced.

Lung cancer has a high mutational burden, Allen explained — there are on average around 300 genomic changes. Of those, only around 1 percent will be truly novel neoantigens. It’s a drop in the ocean that is easily missed when a generalized approach to tumor profiling is deployed. Third-party labs that look for standard receptor targets typically omit between 20-25 percent of the mutations, Allen said. In some patients, 50-60 percent of the mutations are lost. Scientists need better data to build a cancer vaccine that works.

Zooming in on lung cancer, the Cambridge crew have extensively characterized hundreds of real tumor samples using DNA and RNA sequencing, mass spectrometry and deep learning.

Deep learning fast-tracks the process and removes the limitations of current thinking, Allen explained. It’s pure mathematics: it doesn’t apply the researcher’s biases and hypothesis and it’s not limited by our imagination.

“You’re saying, let me look for associations in a completely unconstrained way,” he said.

Those associations are then iteratively tested, to be rejected or strengthened. It eventually leads to a model that can predict from the sequence alone, which of those mutations will create peptides or antigens that will be presented on the tumor cell surface.

Andrew Allen, cofounder, president and CEO of Gritstone Oncology

Andrew Allen, cofounder, president and CEO of Gritstone Oncology

“Our estimate, when we test ourselves on fresh data, is that we’re operating at something like ten-fold better than the public domain approach that many of our competitors are using,” Allen said.

Therein lies the second segment of findings in the AACR poster, which asked if Gritstone’s in-house approach is effective. It seems it is. In the future, its scientists can sequence fresh tumor biopsies to accurately predict what mutated peptides could be targeted.

Rallying the immune response

The second challenge with cancer vaccines is learning how to weaponize the neoantigens to ensure the immune response doesn’t fall flat.

“Our model doesn’t necessarily predict antigens, it predicts whether a peptide will be presented by an HLA class 1 molecule on the cell surface,” Allen noted. “To be an antigen, you also have to stimulate a T-cell response.”

A West Coast team of around 30 is working on this problem in Gritstone’s headquarters in Emeryville, California.

Lessons on how to make a successful cancer vaccine, Allen said, could not be found in the cancer vaccine field. Not a lot has worked. Instead, Gritstone looked to the field of infectious diseases. Certain viruses, such as Malaria, are able to bury themselves deep within cells, he said. That necessitates a robust CD8 T-cell response — the kind Gritstone is hoping to produce.

“What was striking to us was that so many people were using viruses as a vector for delivering the antigens, in order to get these really effective T-cell responses. And so that’s the path that we’ve pursued,” he explained. 

It led to the third component of the poster. The company took the isolated peptides and some HLA-matched T-cells and asked; can they prime a T-cell response to a given neoantigen in vitro. Can they show that it does register an immune response?

They could.

“So that’s really closing the loop and obviously suggesting that, were this to be a patient that we were predicting and making a vaccine,” Allen said. “We have identified an antigen that should in principle be able to make good T-cells in response to the vaccine that may have the potential to kill the tumor.”

The company can connect a DNA mutation to an altered protein and show that it is processed and presented as an altered peptide. Gritstone may be the first to connect those dots in lung cancer, he said.

An eventual vaccine would be given in combination with an immune modulator, such as a PD-1 inhibitor , setting the immune system up for an optimal anti-tumor response.

It’s all theory for now, but Gritstone’s integrated use of deep learning and bioinformatics is broadening the basic theories the human mind can generate.

Photo: Esben_H, Getty Images

New Bos Sci acquisition raises question: Will the Lotus (valve) ever blossom?

Boston Scientific has long expected to be the third wheel to Medtronic and Edwards Lifesciences in the U.S. transcatheter aortic valve replacement (TAVR) marketplace.

It has sung the praises of it Lotus TAVR valve but the product line stands pulled from Europe because of device malfunctions. and has suffered delays in its regulatory pathway in the U.S. And now, while senior management of the company argue that Lotus valve’s introduction in the U.S. is still on track for mid 2018, a transaction announced last week may allow the company to introduce a wholly different TAVR device to the marketplace.

On Thursday, Marlborough, Massachusetts-based Boston Scientific shelled out $435 million in cash to purchase structural heart company Symetis. The Swiss company makes the Accurate and  Accurate neo/TF valve systems for patients suffering from severe and symptomatic aortic valve stenosis and those who have a high-risk of undergoing open-heart surgery.

“The steps we are taking reflect our commitment to being a leader in TAVI and structural heart technologies now and over the long-term, as we broaden our portfolio and pipeline to address the needs of our global health care providers and their patients,” said Ian Meredith, M.D., executive vice president and global chief medical officer, Boston Scientific in a news release. “The ACURATE family of valve products is strongly complementary to our cornerstone Lotus valve platform, and this compelling combination of technologies will allow us to provide interventional cardiologists and cardiac surgeons with multiple TAVI offerings for varying patient pathologies and anatomy.” [TAVR is termed transcatheter aortic valve implantation (TAVI) inEurope]

Some analysts did not fully buy the line on Lotus being the cornerstone TAVR product

“… with Lotus being delayed multiple times, taken off the market in Europe, and with BSX yet to launch all five sizes, one has to wonder if this is a backup plan and if Lotus may not be as ready to go as the company hopes,” wrote Sean Lavin, an analyst with BTIG, in a research note on Thursday. “While BSX paid a hefty multiple and this deal may indicate Lotus isn’t quite ready at this point, we see having a backup option as a positive in this multibillion dollar growth market.”

Boston Scientific paid 12 times the 2016 revenue of Symetis, which was $38.2 million last year.

Another analyst — Danielle Antalffy of Leerink Partners —said that the purchase will provide “air cover” for the six-plus months that the Lotus valve is expected to be off of the market. Still, most analysts viewed the deal positively.

The transcatheter aortic valve space is dominated by Medtronic and Edwards Lifesciences in the U.S. though in Europe the two heavyweights have smaller rivals. It is also a place that has seen numerous legal fights over patent infringement.

Edwards Lifesciences prevailed over Medtronic in 2014 in its long battle and the saga ended with the Irish medtech company agreeing to pay royalty payments of at least $750 million to Edwards Lifesciences.

Meanwhile Boston Scientific and Edwards are in the midst of their own legal battle over TAVR. In Nov. 2015, the Massachusetts company slapped a  lawsuit against Edwards in Germany related to its European patents pertaining to outer seals of transcatheter heart valves. Edwards countersued, alleging patent infringement by the Lotus valve.

On March 3, a U.K court ruled that the Lotus valve did infringe on one of Edwards’ patents surrounding its TAVR valves but not the other. It also noted that the Sapien 3 valve from Edwards infringes two of Boston Scientific’s patents for outer seals of transcatheter heart valves. A German patent court issued a similar ruling days later. Edwards has promised to appeal.

In other words, the ” TAVI space is fluid and litigious,” wrote Lavin in the research note and he concluded that “With all the various IP issues, manufacturing issues, doctor preference, and different valves offering different benefits, the reasons for buying Symetis could be multifactorial.”

Photo: Ian Fung Koo / EyeEm, Getty Images

MedyMatch, Samsung NeuroLogica bring AI to stroke care

Artificial intelligence is continuing to make its mark in the healthcare field.

Tel Aviv, Israel-based MedyMatch Technology and Danvers, Massachusetts-based Samsung NeuroLogica have joined forces to use artificial intelligence to assist patients in prehospital environments.

MedyMatch is an artificial intelligence company. “Our business is based on machine learning,” MedyMatch CEO Gene Saragnese said in a phone interview with MedCity.

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Samsung NeuroLogica is the healthcare subsidiary of Samsung Electronics. “NeuroLogica has been in the CT business for many years,” Saragnese said.

The alliance, which brings together MedyMatch’s AI clinical decision support tools and Samsung NeuroLogica’s medical imaging hardware, was a smart move for the companies, according to Saragnese. “There’s a strong overlap between the two companies,” he said.

Initially, the companies plan to focus on assessing stroke patients. MedyMatch’s AI technologies will be integrated into mobile stroke units and other emergency vehicles that have a portable Samsung NeuroLogica CereTom CT scanner. Through this, the care team will more easily be able to assess whether the patient’s stroke is due to a hemorrhage or a blood clot.

Many of the nearly 800,000 Americans who experience a stroke each year have an ischemic stroke, which can be treated with a tissue plasminogen activator. The tPA must be administered to the patient within three hours of initial signs of stroke, but “it can take an hour after a stroke patient arrives in the emergency department to receive treatment because of the time needed to determine which kind of stroke the patient is having,” the companies point out in a release. By collaborating, MedyMatch and Samsung NeuroLogica are hoping to quicken the treatment process for stroke patients en route to the hospital.

“In stroke care, time is absolutely critical,” Saragnese said. “We want to improve the confidence physicians have in making these decisions.”

But MedyMatch’s goal goes farther than that. Saragnese told MedCity that MedyMatch strives to improve clinical outcomes and ultimately save money. “What we want to do is improve the quality of diagnosis and speed of treatment, and more people will recover from stroke,” he said. “There will also be fewer people in long-term care, and then there will be cost savings.”

MedyMatch launched in February 2016. Though it’s a startup, the company has already begun to make its mark in the healthcare field. Last June, it partnered with Capital Health in New Jersey. Capital Health vowed to help MedyMatch develop a clinical decision support tool for stroke care.

Photo: John Lund, Getty Images

Mass General is giving patients a new way to navigate its campus

Forget the paper maps. Massachusetts General Hospital in Boston has unveiled a new interactive map of its campus for patients, visitors and employees to use.

The map is powered by concept3D’s atlas3D technology. concept3D, a software and services company headquartered in Boulder, Colorado, has used its atlas3D platform to create similar maps for other healthcare organizations, including Roswell Park Cancer Institute, Oregon Health & Science University and the University of Texas Medical Branch.

Mass General’s campus map is built on top of Google Maps, and users can view it in either map mode or satellite mode. They can also use it to get walking directions from one spot on campus to another.

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The map comes complete with information on parking, transportation, dining facilities, pharmacies and buildings around the Mass General campus. It also includes a drop-down menu with details on banks, hotels, museums, post offices, restaurants and a sporting arena near the campus.

Additionally, users can use the map to send personalized links to others to help them find their way around, according to a press release.

Bob O’Melia, concept3D’s vice president of business development, told MedCity the map can assist in improving patients’ and caregivers’ time at the hospital. “We want to reduce that stress level and enhance the patient experience,” he said in a phone interview. “We want to provide a really good 3D digital map that they can explore.”

Mass General’s interactive map is currently patient- and caregiver-focused. But O’Melia mentioned organizations can choose to utilize concept3D’s technology to improve workflow from the employee side as well. For example, concept3D’s platform can be used to help an organization’s security department or human resources department.

concept3D is also in the early stages of working with organizations (though not Mass General) to amp up its technology. “We’re trying to become a little more clinical,” he said. “We’re talking about embedding our map links into appointment reminders.”

Healthcare isn’t the only realm in which concept3D is working. Its atlas3D technology is being used in everything from universities to retirement communities (like Shell Point Retirement Community in Fort Myers, Florida) to convention centers (like Tucson Convention Center in Arizona). “I think it all boils down to lowering frustration levels and enhancing satisfaction levels,” said O’Melia. “We also want to bring [organizations’] buildings to life. People can have an interactive online experience with the campus or buildings before they arrive. Then when they get there, they feel like they know it.”

Photo: Flickr user Tabsinthe https://www.flickr.com/photos/tabsinthe/

eGenesis bets on CRISPR to domesticate pig organs for safer xenotransplantation

Boston-based eGenesis recently received $38 million in Series A financing to develop a safer xenotransplant. Founded by research superstar and serial entrepreneur George Church and former Church lab scientist Luhan Yang, the company is using CRISPR gene editing to make pig organs suitable for human transplantation.

The need is great. Around 120,000 people are on an organ waiting list, but only 31,000 transplants were performed in 2015, according to organdonor.gov. As many as 22 people die each day waiting for a donor organ.

Luhan Yang Headshot

Luhan Yang, eGenesis cofounder

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“I think those numbers are smaller than reality,” says Yang, the company’s chief scientific officer, in a phone interview. “If we look at the number of patients who suffer from organ failure in this country, there are over three million.”

Xenotransplantation could solve the problem, but the practice has a long legacy of failure. As recently as the 1990s, a number of companies were working on it, but the dual problems of immune rejection and porcine endogenous retroviruses scuttled those projects.

“If you culture pig cells with human cells, the viral genome will jump from the pig to the human genome, similar to how HIV passed from non-human primates to humans,” said Yang.

But CRISPR could change that. In 2015, the Church lab published a landmark paper in Science detailing how they used CRISPR to disrupt 62 viral gene copies.

“From a science basis it was remarkably exciting when George and colleagues published how you can CRISPR 60-some genes at once, which was kind of the Olympic record at the time and probably still is,” said Eric Topol, who directs the Scripps Translational Science Institute in San Diego, in a phone interview. Topol has no affiliation with eGenesis.

While the paper produced fireworks, there’s still a long way to go for eGenesis. It’s unclear how many genetic modifications the team will have to make before porcine organs become tolerable in human patients. And though it’s theoretically possible to make organs more compatible than the human counterparts, that is not the company’s goal.

“Our measure of success in the near term is if we can create the organs so that a conventional immunosuppression regimen can be used after transplantation,” said Yang.

Funded by Biomatics Capital, ARCH Venture Partners and others, the recent financing will help eGenesis develop solid proof of principle. They hope to begin preclinical studies in the next three years.

Like gene therapy, xenotransplantation is experiencing a renaissance. United Therapeutics, in collaboration with Synthetic Genomics, is also developing pig organs for transplant. Bioprinting companies like Organovo may also be working their way towards transplantable organs.

While major technical hurdles remain, the rise of CRISPR makes them seem surmountable. And for eGenesis, having George Church on the team cannot hurt.

“Never underestimate George,” said Topol. “He is one of the most brilliant scientists I’ve ever known, and he has a strong sense that this is going to play.”

Photo: wildpixel, Getty Images