Not long ago making an effective cancer vaccine seemed like a dead-end proposition, but that sentiment is changing. The latest evidence: Gritstone Oncology, which makes its debut today with a massive Series A financing.
Gritstone has raised a $102 million Series A round led by Versant Ventures and The Column Group. Others pitching in include Clarus Ventures, Frazier Healthcare Partners, Redmile Group, Casdin Capital, and a special purpose vehicle for private investors called “Transformational Healthcare Opportunity.” The company is run by former Clovis Oncology (NASDAQ: CLVS) chief medical officer Andrew Allen, who helped found the Colorado-based cancer drugmaker with CEO Pat Mahaffy.
“We were just doing less of the early stage stuff, which is what I really enjoy,” says Allen, who left Clovis in August. Clovis could begin selling its first drug next year, a lung cancer drug called rociletinib. Mahaffy, meanwhile, agreed to become chairman of Allen’s new venture when the time came.
That venture is San Francisco-based Gritstone, and it’s the second company, along with Cambridge, MA-based Neon Therapeutics, to announce itself this month to develop vaccines containing what are known as “neo-antigens”—genetic fingerprints left behind by tumors as they mutate.
Allen became intrigued by this concept last year, after reading a paper published in the New England Journal of Medicine by researchers at Memorial Sloan-Kettering Cancer Center, Timothy Chan and Naiyer Rizvi. (Rizvi has since moved on to Columbia University.) The paper concluded that a melanoma patient’s response to “checkpoint inhibitors”—a new type of cancer drug that unmasks tumors to the immune system—depended on the presence, and abundance, of neo-antigens. These neo-antigens are little protein sequences that, in these patients, the immune system could see. That’s important, because the body could then find and wipe out tumors with these proteins.
“This is, to me, a massive, massive advance,” Allen says. “[It’s a] completely rational, totally understandable, and potentially exploitable insight into how tumors can be cleared by the human immune system.”
First, a little background why this is potentially a big deal. Traditional vaccines essentially train our immune system to spot a foreign invader and attack if it arrives. Despite numerous attempts, this approach has not worked with cancer—albeit one prospective brain cancer vaccine from Celldex Therapeutics (NASDAQ: CLDX) in Phase 3 testing has the chance to be the first.
The failures have piled up, according to Allen, for a simple reason. “They just had the wrong antigen,” he says. “If you’ve got the wrong antigen, it doesn’t matter how good the vaccine technology is.”
Allen believes genetic sequencing technology and advances in immunology have led scientists to the right antigens. Breakthroughs in these fields have already begun to change the way cancer is treated. Methods of spurring the immune system to recognize and fight tumors have produced remarkable results against cancers of the skin and lung, namely so-called “checkpoint inhibitors” like nivolumab (Opdivo) and pembrolizumab (Keytruda).
But checkpoint inhibitors only work for a fraction of patients. In their NEJM paper, and later in an article published in Science in March, Chan and Rizvy aimed to show that the answer to the limited effectiveness was held by neo-antigens. The more neo-antigens—or, genetic fingerprints—they found on tumors, the better pembrolizumab fared in patients with lung cancer or melanoma.
The researchers hypothesized that training the immune system to better spot the important neo-antigens—the ones that drive a cancer cell’s growth—would help checkpoint inhibitors work in more patients.
That’s the thinking behind Gritstone. Allen aims to make vaccines that contain groups of these so-called neo-antigens. The hope is that these therapies would improve how effective checkpoint inhibitors can be. They’d also be somewhat individualized treatments—meaning they’d be made up of a group of, say, 10 neo-antigens that are deemed to be critical to the growth of a specific person’s tumor.
Gritstone will start with vaccines for non-small cell lung cancer, which accounts for about 85 to 90 percent of cases, according to the American Cancer Society. Lung cancer is the most common cause of cancer death, and while checkpoint drugs have shown promise here, Allen says they work only in about 20 percent of patients. That means it’ll be easier for Gritstone to show a benefit here than in, say, melanoma, where combinations of drugs like ipilimumab (Yervoy) and nivolumab are already leading to much better results.
Allen says the hope is that the first therapy—Gritstone calls them “tumor specific, neo-antigen based immunotherapies,” or TSNAs—would be ready for clinical testing by late 2016 or early 2017.
If this sounds familiar, that’s because Neon got a $55 million Series A from Third Rock Ventures and others a few weeks ago to embark on a similar task. One difference is that Gritstone is only looking at vaccine approaches, while Neon may try developing engineered T cells as a product, as well. Neon hasn’t said which cancers it’ll attack first.
Competition aside, there are a host of challenges here. For instance, Allen notes that the company’s biggest immediate goal will be to separate the signal from the noise. Which neo-antigens on a tumor cell really matter? Which ones will T cells recognize, and which are just randomly altered protein sequences? Gritstone will spend a lot of cash accumulating one lung cancer tumor sample after another, trying to uncover which ones Allen calls “magical.”
“There’s some work to be done,” he says. “But sample collection from lung cancer doctors is obviously something that we at Clovis did many times. This is our bread and butter.”
This also looks to be a complex process. Gritstone aims to biopsy a patient’s tumor, sequence it, find the relevant neo-antigens, and then make a vaccine loaded up with those key neo-antigens. Allen says the goal is to do all this work inside a month for an individual vaccine. The company will first look outside for help and likely partner with “two or three” makers of different vaccine technologies—from nucleic acid-based vaccines to peptides—to see which might work the best.
Even if Gritstone does all this work, though, there’s no guarantee patients will benefit. As of yet there is no direct evidence that creating a vaccine with neo-antigens helps cancer patients—just links that, as even Allen acknowledges, could be entirely “circumstantial.”
All of this is why the company is called Gritstone. Allen used to do a lot of rock climbing while growing up in London, sometimes scaling gritstone—a coarse type of sandstone that’s tough to ascend. Starting a new biotech company seemed like a similar challenge.
“Just before you tackle a hard climb, you sleep poorly, you’re both excited and nervous,” he says. “But then you kind of just knuckle down and tackle it.”
Aragon Pharmaceuticals and Seragon Pharmaceuticals founder Rich Heyman is on Gritstone’s board, along with Peter Svennilson (Column Group), Tom Woiwode (Versant), and Nick Simon (Clarus). In addition to Chan and Rizvi, its other scientific founders are Jean-Charles Soria of the Institut Gustave Roussy in Paris, Graham Lord of King’s College London, and Mark Cobbold of Massachusetts General Hospital.