the remissions are lasting, or whether these patients are living longer, high-quality lives. But the data from that trial, and a few other isolated patient stories, were compelling enough to convince Juno’s investors to bet $120 million upfront for a strikingly ambitious clinical development plan that calls for as many as 13 early-stage clinical trials testing the company’s technology against various forms of cancer in the year ahead.
Bob Nelsen, a venture capitalist who lost a lot of money on an earlier-generation immunotherapy company called Xcyte Therapies, said he was initially skeptical of building a big new company such as Juno. Challenges around manufacturing scale-up, facility costs, logistics, and intellectual property are incredibly daunting with any cell-based immunotherapy company. But Nelsen says he’s gotten over his initial doubts, and now says the $120 million investment is “just the tip of the iceberg.”
The clinical data, in which patients with no other options and weeks left to live achieved an 88 percent complete response rate, is “unprecedented,” Nelsen said. The data convinced him that the bigger risk would be not investing big enough, or not moving fast enough, to seize the opportunity before others. Of course, he was well aware of formidable competition in this field from Carl June’s group at the University of Pennsylvania and his collaborators at Novartis. June and colleagues have reported, in the New England Journal of Medicine, on some quite impressive results with “chimeric antigen receptor modified T-cells,” also known as CART therapy.
While several competing biotech/academic teams have moved in—Cambridge, MA-based Bluebird Bio (NASDAQ: [[ticker:BLUE]]) and Los Angeles-based Kite Pharma to name a couple—June’s work at Penn has attracted the most attention until now. It was exciting enough to entice Switzerland-based pharma giant Novartis to move ahead a year ago with its own plans to commercialize the new brand of immunotherapy. Nelsen looked over the competitive landscape, and decided to invest in Juno after carefully reviewing the clinical data gathered by the founders.
“Once I saw the data behind Juno, it was a matter of saying ‘OK, how are we going to make this work?’” Nelsen said. “There is no other choice. It’s compelling enough so that there’s no choice but to make it work.”
The financing of Juno comes during what many scientists consider to be the most exciting period ever in immunotherapy. Not long after Dendreon, Bristol-Myers Squibb won FDA approval for an antibody drug called ipilimumab (Yervoy) that releases a molecular brake called CTLA-4, allowing the body’s immune system to fight melanoma. That drug has extended the lives of melanoma patients when most other drugs have failed miserably. Bristol-Myers, Merck, and Roche/Genentech followed up on that achievement by reporting a series of promising results with antibody drugs against targets called PD-1 and PD-L1; those drugs work by removing a cloaking mechanism tumors use to escape the immune system. Researchers everywhere are fired up about the possibility of combining various types of these immunotherapies, which don’t work for everybody, but do appear to work against multiple tumor types and, in some cases, to provoke long-term remissions. The excitement has helped a few other cancer immunotherapy startups raise money, including Cambridge, MA-based Jounce Therapeutics, Seattle-based Immune Design, and Redwood City, CA-based Armo Therapeutics.
Pharma companies were eager to trumpet their preliminary immunotherapy results this year at the American Society of Clinical Oncology meeting, and they are following up those enticing reports by pouring huge resources into this field they once ignored, partly because of promising anecdotal results that couldn’t be repeated in well-controlled trials.
“It’s a very exciting time in immunotherapy. This (Juno) is very exciting,” said Sally Church of Icarus Consultants, who writes for the popular Pharma Strategy Blog, and who has reviewed CART immunotherapy data from June’s group at Penn, as well as the work from the Fred Hutch and Memorial Sloan-Kettering.
So, for the scientifically minded out there, what does Juno really do?
It has two technology platforms, Bishop said. First is the chimeric antigen receptor-modified T-cells (CART) approach. That platform involves taking out some of a patient’s white blood cells—about 150 milliliters of blood—and then enriching the cells to find the desired population of “killer” T cells that are either few in number, or are just not recognizing the hallmarks on cancer cells they should. The company, in its lab, then essentially performs gene therapy on these cells to deliver a specific substance the cells should recognize and attack, known as an antigen, found on the surface of cancer cells. Juno has two different kinds of adeno-associated viruses (AAVs) that it uses to deliver a new receptor that “reprograms” the T cells to make them aggressive cancer killers. One approach uses a lentiviral vector, and another uses a gamma retrovirus to perform the reprogramming, Bishop said.
The entire process, from blood withdrawal to re-infusion back into the patient, takes about 15 days, Bishop said. Juno believes that its approach can be effective not just for blood-borne cancers, but also for tougher-to-treat bulky solid tumors. Scientists don’t know yet whether it’s necessary or desirable to do repeat infusions, and also don’t know whether they can create long-lasting immune memory or surveillance to keep tumors down. That’s something the company will watch closely, Bishop said.
The second main technology at work in Juno is based on what it calls “high-affinity T-cell receptors.” That work starts by looking for T cells that naturally have high-affinity binding capability to specific markers on cancer cells. Once the natural high-affinity T cells have been identified, and clones have been selected and modified, Juno uses the same gene therapy system to transform the T cells so they all express the high-affinity receptor against cancer antigens, Bishop said.
One potential advantage with the second approach is that it should be able to home in on cancer-related proteins that reside inside cells, not just those that are present on the surface of tumor cells, Bishop said.
“It really involves remarkable technologies,” Bishop said. “The breakthrough here I think has come from multiple different advances in the biology, in genetic re-engineering and in manufacturing. Several things have come together to get us to the point we are.”
How did Juno get this far along, with more assets and clinical proof for its programs than many newly minted public companies? Both the Hutch and Memorial Sloan-Kettering have been able to invest over the years in their own industry-like in-house manufacturing capabilities, through a combination of federal grant and philanthropic support. Corey, the president of the Hutch, singled out a $10 million donation pledge that the family of Amazon founder Jeff Bezos made four years ago to the Hutch, which helped the center build up its capabilities beyond what it could otherwise do.
When the technologies started to mature around CART therapy and high-affinity T-cell therapy, Corey said he sought to bundle the technologies together in a big way. The scope
