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Profiles In Innovation

Transcript of BioCentury This Week TV Episode 175

 

GUESTS

 

Dr. Christopher P. Austin, Director, National Center for Advancing Translational Science, NIH

 

Dr. Steven A. Rosenberg, Chief of Surgery, National Cancer Institute, NIH

Hans Bishop, CEO and Co-founder, Juno Therapies

Dr. Stan Riddell, Scientific Co-founder, Juno Therapies

 

Products, Companies, Institutions and People Mentioned

 

Provenge sipuleucel-T, Dendreon Corporation

Yervoy ipilimumab, Bristol-Myers Squibb Co

Nature Magazine

Life Technologies Corporation

AesRX LLC

Defense Advanced Research Projects Administration (DARPA)

Anthony S. Fauci, MD, NIAID Director, NIH

Freda Lewis-Hall, Chief Medical Officer, Pfizer

Science Magazine

Fred Hutchinson Cancer Research Center

Memorial Sloan Kettering

Seattle Children's Hospital

Food & Drug Administration

St. Jude's Children's Hospital

City of Hope

State of Alaska

Alaska Permanent Fund

Arch Venture Partners

Venrock Associates

Jeff Bezos, CEO and Founder, Amazon.com, Inc.

Lion Biotechnologies

H. Lee Moffitt Cancer Center and Research Institute

University of Texas MD Anderson Cancer Center

University of Pennsylvania

Kite Pharma Inc.

Celgene Corp.

Novartis AG

Zelboraf vemurafenib, Roche, Daiichi Sankyo Co. Ltd

Isabelle Rivière, PhD, Director, Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center

 

Michel Sadelain, MD, PhD, Molecular Engineering and Chemistry Program, Memorial Sloan Kettering Cancer Center

 

Renier J. Brentjens, MD, PhD, Director Cellular Therapeutics, Memorial Sloan Kettering Cancer Center

 

HOST

Steve Usdin, Senior Editor

 

SEGMENT 1

 

STEVE USDIN: NIH says it can transform the way science is turned into medicine, but is it delivering? And today we begin our Profiles in Innovation with immunotherapy, teaching the body to beat cancer. I'm Steve Usdin. Welcome to BioCentury This Week.

 

NARRATOR: Connecting patients, scientists, innovators, and policymakers to the future of medicine. BioCentury This Week.

 

STEVE USDIN: In December 2011, NIH opened the doors to a new center, NCATS, the National Center for Advancing Translation Sciences. NCATS' mission is to re-engineer the way basic research is translated into medicine. Supporters say NCATS will solve problems academics and industry can't tackle on their own, but skeptics inside academia and industry and even at NIH say it diverts funds from NIH's core research mission and is taking on tasks that should be left to drug companies.

 

This week we'll try to separate the hope from the hype with the first NCATS director, Dr. Chris Austin. I'm pleased to be joined today by Dr. Chris Austin. Chris, what's translation? And why does NIH need a center to advance it?

 

DR. CHRIS AUSTIN: So translation is the process by which an observation in the laboratory or in the clinic is transformed into an intervention -- a drug, a diagnostic, a device -- which has been shown to improve human health. It's really that simple. The process of translation, however, has multiple steps to it. And so like translation in languages, it depends on where you're starting and where you want to end up.

 

So depending on who you talk to, they will define translation in different ways. And so if you're a geneticist, translation might mean figuring out what a gene does and what its role in therapy might be. If you're a cell biologist, it would be translating to an animal model.

 

STEVE USDIN: And if you're a patient?

 

DR. CHRIS AUSTIN: If you're a patient, translation means the process by which a drug is developed or an intervention is developed gets into people and is shown to be beneficial.

 

STEVE USDIN: So it seems to me that kind of gets to the chase. And really, one way to look at the problem that NCATS is trying to solve is -- it's like a line from that Jack Nicholson movie -- is this as good as it gets? We have about 25 new drugs approved every year. A handful of them are first in class.

 

DR. CHRIS AUSTIN: Right.

 

STEVE USDIN: And basically your premise is that's not as good as it gets. We can do better.

 

DR. CHRIS AUSTIN: Right. That's exactly right. And to just give you some numbers to put this problem in perspective, there about 7,000 diseases that affect the human family. There are treatments available currently for less than 1,000 of them. That's about 6,000 untreatable diseases. At the current rate of going from untreatable to treatable, which is about three to five a year, it will take over 1,000 years for every disease to be treatable. I would argue that is simply not an acceptable answer.

 

STEVE USDIN: So maybe to give some kind of concrete example going through the development process, one of the things that NCATS is looking at to start with is something that's called target validation.

 

DR. CHRIS AUSTIN: Right.

 

STEVE USDIN: What's the problem? What does that mean?

 

DR. CHRIS AUSTIN: So target validation is very simply the process of identifying a molecule, usually a process, which an external agent -- a drug, a biologic, an antibody -- is going to physically interact with and either make it more active or less active depending on what the basic science tells you is the problem in the disease. They're basically levers. And in the body, if levers are in equilibrium, there's health. If it gets out of kilter, if it's either underactive or overactive, then you need a drug that's either going to turn it on or turn it off. And the process of target validation is identifying what those levers are.

 

STEVE USDIN: And that's what drug companies exist to do. So why do we need NCATS to do it?

 

DR. CHRIS AUSTIN: Right. So it's a numbers problem, as much as anything else. So thanks to the Genome Project, among other things, there are many more targets than we can possibly deal with. So there's about 21,000 human genes. But thanks to the wonders of mother nature, those genes make about 500,000 individual proteins. And every single one of them could be a target.

 

Give you another number. There are about 6,000 rare diseases. And we now know, thanks to the Genome Project and other advances, the genetic basis of about 4,000 of them. That's up from 50 about 15 or 20 years ago. And so there are thousands and thousands of targets, putative targets, that could be investigated. And the problem is we don't have very good ways of figuring out -- sifting through those data to figure out what would be good targets and what wouldn't.

 

STEVE USDIN: And how are you going to do that, and are you doing that alone? Are you doing that in collaboration with others?

 

DR. CHRIS AUSTIN: And this gets to one of the core principles of NCATS, which is that translation is a team sport. Early on in the science process, it can be a fairly solitary exercise. That's how I got my start in fundamental genetics research, but translation requires multiple players with distinct expertise from multiple disciplines and multiple organizations. Every project NCATS does is a collaboration with somebody in the public sector or the private sector, so we are not doing this alone.

 

STEVE USDIN: And what are the kinds of outcomes or the kind of timelines when we can see some real results? Or how will you know, because you've got this massive amount of stuff, you say? And you're going to sift through it and try to identify good targets.

 

DR. CHRIS AUSTIN: Right. So I'll give you an example which just happened last month. So there's a target validation technology known as RNAi or RNA interference you've probably talked about on the show before, and that is a very robust technology for knocking down the activity of genes. And theoretically, it's been cleared for a long time. If you could knock down every gene one at a time, you could identify every gene involved in a cellular process.

 

STEVE USDIN: Let's talk about how that works in practice when we come right back. We'll do that, and first we're going to hear some of what Tony Fauci had to say about how NCATS is impacting NIH.

 

ANTHONY FAUCI: NCATS is making a difference to virtually any of the institutes, at NIH and elsewhere, that are doing translational research, because they are providing information, providing technologies that will make our conduct of translational research at a higher level.

 

NARRATOR: You're watching BioCentury This Week.

 

SEGMENT 2

 

STEVE USDIN: We're talking about translating science into medicines with Dr. Chris Austin, director of NIH's Center for Advancing Translational Sciences. Chris, let's pick up where we left on RNAi.

 

DR. CHRIS AUSTIN: Right. So the RNAi program that NCATS has illustrates a general principle by which NCATS does all of its programs. One, it's fundamentally collaborative. So every project is a collaboration with a disease expert somewhere in the world.

 

Secondly, they're focused -- we're focused on the general principles that underlie using RNAi as a target validation tool, and we started using genome-wide RNAi that is knocking out every gene one-by-one to find every gene involved in disease or a cellular process and thereby identify targets. This technology was not usable for that indication, for that use. And so our people developed new technologies to allow that to happen.

 

There was also no public database of these data, so researchers around the world had no access to these data. And so we developed new technologies that were both screening technologies and informatics technologies and analysis technologies. We developed the first public database for these data in collaboration with Life Technologies, and we've done a number of projects now on very important diseases to identify novel targets for intervention. And we just had a very important paper that was in Nature last month on Parkinson's disease, as an example.

 

STEVE USDIN: So I want to move on to another area to something that you're working on that's clearly something that the drug industry and others aren't working on, which is the idea of trying to get drugs and new therapies to people who need them.

 

DR. CHRIS AUSTIN: Right.

 

STEVE USDIN: Not simply to get them past the goal post or getting approved, but actually getting them disseminated. What are you doing there?

 

DR. CHRIS AUSTIN: Right. So this is a very important problem, and it's a very important thing that I want everyone to understand about what NCATS does. Remember, the mission of NCATS is to catalyze the development of new methods, technologies, tools, data, information that will allow new diagnostics, new treatments to improve health. And notice the end of that is improve health. So getting a drug approved can be very important, but we actually haven't actually improved health there.

 

And it's very clear that it currently takes us between 10 and 15 years -- and when I say us, that means the system that we have in this country -- to get those interventions shown to be useful in clinical trials and approved by the FDA to all the patients that need them. And this is a problem of reimbursement. It's a problem of heterogeneity in the population, genetically and environmentally, heterogeneity of disease. It's a problem of patient access to medicine.

 

STEVE USDIN: So I wonder again why is this something that NIH needs to do? A drug company has a fantastic incentive to get these drugs- - to get new drugs used as widely as possible as quickly as possible.

 

DR. CHRIS AUSTIN: Right.

 

STEVE USDIN: And they put fantastic resources into doing that. Some of it may be questionable, but they do it. Why does NIH need to be in there?

 

DR. CHRIS AUSTIN: It's because of what NCATS is focused on particularly are the general principles by which we can do each of these things better. So I'll give you an example. It's well known that most patients who were prescribed a medicine either never fill the prescription, or they only take it one month and then they stop. And, of course, the best drug in the world isn't going to do -- no good for your health if you don't take the medicine.

 

And so this is an issue of physician behavior, prescribing behavior. It's an issue of patient behavior. And this is an issue of implementation science, which is quite different from the fundamental pre-clinical work that NCATS does.

 

STEVE USDIN: And what are you actually doing there? That's a very challenging problem.

 

DR. CHRIS AUSTIN: So through our CTSA program, the Clinical Translational Science Award program, which is a wonderful network of 62 academic medical centers all over the country -- it's actually NIH's biggest single program -- we have really pushed the idea of patient engagement and community engagement from the very beginning of projects. One of the reasons that patients do not take the medicines that might be prescribed them is they don't feel that they're partners with their prescribers in understanding what these medicines can do for them. And so they're not invested, and they don't take them.

 

It's an interesting development that -- and you've probably talked about it on the show, that patient groups are becoming much, much more active in the development and utilization of medicines for their diseases. And we think this is a transformational development, and I've actually challenged NCATS to have our people and our grantees and our internal scientists to involve patients in every project we do from the very beginning.

 

STEVE USDIN: Thanks. We're going to talk about that more when we come back. First, Pfizer's chief medical officer, Freda Lewis-Hall, says NCATS has the power to transform drug development. Here's what she says.

 

DR. FREDA LEWIS-HALL: Most people have no idea, no idea whatsoever what it takes to discover, to develop, and to deploy a new medicine into the hands of the people that need them. And that's why NCATS is so critical. This is our opportunity to help shorten the process, reduce the costs, speed the availability of these new therapeutics to the people who need them.

 

SEGMENT 3

 

NARRATOR: Now back to BioCentury This Week.

 

STEVE USDIN: We're back with NCATS director Chris Austin. Chris, NCATS has got this fantastic mission to transform drug development.

 

DR. CHRIS AUSTIN: Right.

 

STEVE USDIN: Your budget, when you look at it, the things that were -- there were a lot of things that were the CTSA's. Other things were combined into NCATS.

 

DR. CHRIS AUSTIN: Right.

 

STEVE USDIN: But the actual new money that you've got is what? It's, what, less than $100 million a year? Way less, right?

 

DR. CHRIS AUSTIN: Right. Right.

 

STEVE USDIN: So how are you going to transform drug development with something that's less than one half of one percent of NIH's budget?

 

DR. CHRIS AUSTIN: Right. Well, the first thing is that we are very grateful, of course, for the budget that we have. And we have great support from the Congress in our mission. That said, we've talked about how large the problem is and how large the opportunity is. NCATS aims to do what it does, however, as a catalyst. And a catalyst is something which is actually present in very small amounts but makes things happen by collaborating with other organizations to produce something that wouldn't otherwise happen.

 

STEVE USDIN: If you dilute a catalyst enough, it's homeopathy.

 

DR. CHRIS AUSTIN: Right. And that's the problem. I would say --

 

STEVE USDIN: Another example, there's something called the Cures Acceleration Network. A lot of people are really excited about that.

 

DR. CHRIS AUSTIN: Right.

 

STEVE USDIN: When it was envisioned, it was going to be half a billion dollars a year to do transform -- to transform the way that cures were created.

 

DR. CHRIS AUSTIN: Right.

 

STEVE USDIN: To get things over the finish line really quickly.

 

DR. CHRIS AUSTIN: Right.

 

STEVE USDIN: You've got $10 million a year now for it. What are you going to do with it?

 

DR. CHRIS AUSTIN: Right. And this is a challenge. I won't minimize that, and it's frustrating for us who -- and for me personally, who deals with patients with untreatable diseases every single day that I am confident we could help if that situation were different. But I should say that we are using that money very well and the CAN money in this case for something called the Tissue Chip Program which, if successful, will transform how we identify the safety and utility -- efficacy-- of novel therapeutics.

 

STEVE USDIN: That's something we've talked about on this show. It's a collaboration with DARPA --

 

DR. CHRIS AUSTIN: Right.

 

STEVE USDIN: -- to create a kind of body on a chip to do toxicology. Can you give us some other examples of the way that you've tried to catalyze change?

 

DR. CHRIS AUSTIN: So we have a wonderful collaboration called New Therapeutic Uses with eight pharmaceutical companies. It's a great example of addressing a systematic problem in collaboration with the private sector, which is characteristic of everything we do. So the problem here is that because of a very high failure rate of drug development, for every drug that gets approved for human use by the FDA, there about 10 which have been in people and then fail, often for efficacy reasons or for business reasons.

 

And so we teamed up with these companies to say, well, gosh. A lot of work has gone into these drugs. How about we go out to the academic community and we say, look, what ideas do you have for other diseases that these drugs might be used for and have repurposed those, so-called, in actually nine different diseases now that are in patients right now in collaboration between NCATS and academic organizations and the pharmaceutical companies who made the drugs and have all the data on them.

 

STEVE USDIN: And when are we going to get a readout on that? When do you think we'll see whether any of those nine different diseases actually -- it's going to work in any of them?

 

DR. CHRIS AUSTIN: Right. So great question. Clinical trials in general take about a year before you get first indication, so I would say about a year. Some of them are actually getting animal studies done on them, so we'll know a little bit earlier than that. But I should say that this whole program was about $13 million, very small amount of money that could catalyze nine new drugs.

 

And sometimes the way I think about this is a football game. And you could imagine these drugs being on the two-yard line, and they just need one quick play to get them over the goal line and help a lot of patients. And that's the kind of thing that NCATS does.

 

STEVE USDIN: Now, Chris, one of the projects that NCATS has -- and actually, I think you used to run it -- is called TRND, which is trying to look at -- find new therapies for really rare diseases. Can you give us some examples of what you're working on there and again why it's something that the private sector, which has invested a lot in rare diseases, wouldn't do on its own?

 

DR. CHRIS AUSTIN: Right. So there are many rare diseases, hundreds or even thousands of them, that are not at the point -- they are so-called not de-risked enough that a company could make a business case to adopt them. And the purpose of TRND is to be an adapter between the fundamental --

 

STEVE USDIN: -- on there and again why it's something that the private sector, which has invested a lot in rare diseases, wouldn't do on its own.

 

DR. CHRIS AUSTIN: Right. So there are many rare diseases, hundreds or even thousands of them, that are not at the point -- they are so-called not de-risked enough that a company can make a business case to adopt them. And the purpose of TRND is to be an adapter between the fundamental sites and the target validation and the starting of a proto drug development up to a point where a company is willing to adopt them. So it's really an adapter or a chaperone for those projects.

 

And I'll give you an example. So sickle cell disease, very important public health disease, affects about 100,000 people in this country, was the first genetic disease, the cause of which was identified in 1949. We still have no treatment for that disease based on that genetic discovery.

 

STEVE USDIN: And so the lack of a market isn't the problem. There's 100,000 people who have it. That's a huge, huge unmet need.

 

DR. CHRIS AUSTIN: Huge unmet need.

 

STEVE USDIN: And it's a huge pharmaceutical market --

 

DR. CHRIS AUSTIN: Right. So you'd ask, well, why has this been a problem? Well, it's a problem because the compound that a company called AesRX came to us with -- it's a little biotech in Boston -­­­­­- came to us with was an unconventional molecule. It's an unconventional mechanism. There have been regulatory issues of getting drugs for sickle cell approved, and there are clinical trial issues in that particular disease which have bedeviled that disease from the beginning.

 

And so no company would adopt that project because of the risk, all of those risks, despite the very important public health implications. So we adopted that project, working very closely with the company, having a joint project team that decided where the funding that NCATS put into it would go. And the company put their own resources into it. And within a year, we went from starting that collaboration to being in people.

 

So this is what I want to emphasize, is that these things are possible. Rapid advances in translation are possible. They weren't possible when I was in training 40 years ago. They are possible now. It's a matter of will and having the science and operational systems to do it.

 

STEVE USDIN: Thanks very much. We've been talking about efforts to improve the translation of basic science in the medicines. Next we're going to profile one of the most exciting examples of translation in modern medicine, teaching the human body's immune system to overcome cancer.

 

SEGMENT 4

 

NARRATOR: Innovation in healthcare can improve the lives of millions of people or profoundly change the life of a single person. Profiles in Innovation tells these stories, about the innovators and those lives they transformed.

 

STEVE USDIN: 30 years ago, the idea that our immune systems could be taught to fight cancer was dismissed as science fiction. Today experimental immunotherapies are making some deadly cancers melt away, and biopharma companies are poised to bring immunotherapies into the medical mainstream, joining chemotherapy, radiation, and surgery. Dr. Steve Rosenberg, chief of surgery at the National Cancer Institute, brought immunotherapy's potential to the world's attention in 1985 when he used a young woman's own immune system to rid her body of metastatic melanoma. The success came after years of lab research and scores of clinical failures.

 

DR. STEVE ROSENBERG: And so we began experiments in the laboratory, in experimental animals, and then in people. And it wasn't until 1984, after treating 80 consecutive patients with either low doses of IL-2 or T cells that had minimal antitumor activity, that we treated the first patient, a 31-year-old woman who was in the Navy, who had widespread melanoma, had been through other treatments, alpha interferon, other experimental treatments. The tumor had spread throughout her body. We gave her very high doses of Interleukin-2, and she was the first patient to ever show a complete regression of widely metastatic cancer due to the administration of an agent that was strictly immunotherapy, strictly affected the body's own T cell reactivity against the cancer. And she showed a complete regression that's ongoing now, 29 years later. I just saw her about two weeks ago.

 

STEVE USDIN: Rosenberg's studies confirmed that an immune-boosting compound, IL-2, could essentially cure some cancer patients who would have been sure to die.

 

DR. STEVE ROSENBERG: By 1987, we were capable of reporting 157 patients that we had treated. And we were seeing response rates in about the 15% range-- that is, regressions-- with about a third of those being complete disappearance of all cancer.

 

STEVE USDIN: Success with IL-2 lead to immunotherapies called checkpoint inhibitors, like Yervoy, the first drug to extend the life of metastatic melanoma patients. Eight years after reporting success with IL-2, Rosenberg published data on a new approach, adoptive cell therapy.

 

DR. STEVE ROSENBERG: And there's this third area called adoptive cell therapy where we take the immune cells out of the body -- and this is something that we developed here. Take the lymphocytes out of the body that normally circulate and now educate them outside the body to attack a cancer, either by selecting the cells that naturally react or by genetically engineering the cells to recognize a cancer, and then re-infuse them back into the body. And that's called adoptive cell immunotherapy. And that can be effective against a variety of different cancers, like melanoma, like lymphomas, like sarcomas, and other cancers as well.

 

So what you're doing in adoptive therapy is you're developing basically a new drug for every patient. It's the most personalized therapy you can imagine. You take a patient's lymphocytes out of their veins. You modify them. You give them back and see cancer regressions.

 

STEVE USDIN: Rosenberg's work and research by other scientists over decades have transformed adoptive immunotherapy from a fantasy to an effective experimental treatment.

 

DR. STEVE ROSENBERG: Immunotherapy was very much on the fringes of science. There were no known antigens against human cancer in the 1970s. There were no known immunotherapies that worked, and so there was a belief that immunotherapy would never work. Now immunotherapy has entered the mainstream, not only of basic science research, but the mainstream of cancer treatment. And it's joined surgery, radiation therapy, and chemotherapy as a fourth effective way to treat some cancers.

 

STEVE USDIN: Other researchers are achieving remarkable results with adoptive cell therapies. Dr. Carl June made headlines in 2011 when he used the technique to drive an aggressive leukemia into remission. Nearly 30 years after Rosenberg's first success, immunotherapy is finally close to becoming routinely available to cancer patients. Industry is scaling up, and investors see immunotherapy as the next big thing.

 

Just last month, Amazon founder Jeff Bezos, the State of Alaska, and their VC partners committed $145 million to Juno Therapeutics, a startup that aims to accelerate immunotherapy advances from the Fred Hutchinson Cancer Research Center, the Seattle Children's Research Institute, and Memorial Sloan Kettering. Juno is led by CEO Hans Bishop, who helped develop Provenge, the first cancer immunotherapy approved in the US. Juno is building on adoptive immunotherapy from trials at three cancer centers.

 

HANS BISHOP: We've reported results on 16 patients with acute -- with ALL. Of those 16 patients that are evaluable, 14 have had what's called a complete response. And the second piece of data is from a trial being run at the Fred Hutch Cancer Center based on technology from Dr. Riddell, which is largely an NHL trial, although we are enrolling other types of patients, too. And in that study we've got evaluable data on six patients, and five of those patients have had a complete response. And at Seattle Children's, a pediatric study which has treated two children with ALL, and both of those children have had complete responses.

 

STEVE USDIN: Juno isn't alone. Major pharma companies are partnering with academic centers to develop immunotherapies for a host of cancers, and last month Science Magazine declared cancer immunotherapy the breakthrough of the year. But Rosenberg isn't declaring victory.

 

DR. STEVE ROSENBERG: Last year, 600,000 Americans died of cancer. So there's a lot that is still to be done. I'm the world's most impatient person. And so am I satisfied with where we are now? Absolutely not. Taking care of cancer patients with immunotherapy, with any treatment, is a -- it's a roller coaster.

 

You walk in one room, and you've had an experimental treatment. And you see a patient's tumor disappearing, and that's an ecstatic experience. You walk in the next room, and the patient has not responded. The family is suffering, and so there's a long way to go. It's hard to remain very satisfied when you're taking care of patients with advanced cancer, and all of the patients that we treat with these experimental therapies are advanced cancer patients who don't have other alternatives open to them.

 

STEVE USDIN: That's our January edition of Profiles in Innovation. You can hear more from Dr. Steve Rosenberg in our extended online interview at BioCenturyTV.com. Thanks to each of our guests, and thank you for watching. I'm Steve Usdin. I'll see you next week.

 

WEB EXTRA

 

STEVE USDIN: How was cancer immunotherapy viewed when you first started to work in the field?

 

STEVEN ROSENBERG: Immunotherapy was very much on the fringes of science. There were no known antigens against human cancer in the 1970s. There were known immunotherapies that worked. And so there was a belief that immunotherapy would never work.

 

And when it started to get developed, that immunotherapy was on the fringes of cancer research, because its effectiveness was minimal in the early days. But now, immunotherapy has entered the mainstream, not only of basic science research, but the mainstream of cancer treatment. And it's joined surgery, radiation therapy, and chemotherapy as a fourth effective way to treat some cancers.

 

STEVE USDIN: When did you get the idea that the human immune system can fight cancer?

 

STEVEN ROSENBERG: I had a remarkable experience when I was a resident at West Roxbury VA hospital in Boston, Massachusetts. I was a resident, and a very unusual patient came in to the hospital. He was a gentleman, a 68-year-old gentleman, complaining of belly pain. And I saw him as a junior resident in the emergency ward and opened his chart and saw this remarkable story that 12 years earlier, this same fellow had come in and had gastric cancer, a cancer in the stomach. He had been operated on. It has spread throughout his body. It was multiple deposits in the liver. There were biopsied to prove they were cancer.

 

The belly was closed. Nobody expected him to survive. But as I followed the notes, he kept coming back and back, and here he was, almost 12 years later, looking perfectly fit. I operated on him. And he had gall stones, and all the cancer was gone.

 

His body had somehow found a way to cause that cancer to disappear. And that was sort of the first inkling that I got that perhaps the body's own immune system could successfully attack the disease. And that led me on this trail of trying to figure out how the body reacts against cancer and how we might manipulate it to cause cancer regressions. That was 1968 when I first saw this gentleman.

 

STEVE USDIN: How long did it take to show that immunotherapy can effectively treat cancer?

 

STEVEN ROSENBERG: From the first time that I began utilizing this interleukin 2 approach in 1978, it wasn't until 1984, six years later, before the 81st patient that we treated -- the first 80 all died of their cancer, despite our treatments -- showed us a response, showed us interleukin 2 could work. And that then led to the advances in using IL-2, now approved for use around the world.

 

So these things are complicated, and they take time, and they require support, not only from the NIH, but from industry as well.

 

STEVE USDIN: How does interleukin-2, IL-2, work against cancer?

 

STEVEN ROSENBERG: If one thinks about the immune system, one has to think about two aspects of it. There's an antibody-mediated system, antibodies that circulate. But there's a cellular immune system, which involves T cells in the body, lymphocytes, white cells that circulate. In they are the critical cell in the body that protects the body against foreign invaders.

 

There was no way to manipulate these T cells outside the body or inside the body until the discovery of a compound called T cell growth factor interleukin-2 in 1976, which is a molecule that caused the growth of T cells. And shortly after that was described, I began a series of experiments to see if we couldn't raise T cells that had reactivity against a cancer, and also to see if interleukin-2 as a T cell growth factor administered to patients could actually lead to T cell growth inside the body.

 

And so we began experiments in the laboratory, in experimental animals, and then in people. And it wasn't until 1984, after treating 80 consecutive patients with either low doses of IL-2 or T cells that had minimal anti-tumor activity, that we treated the first patient, a 31-year-old woman, who was in the Navy, who had widespread melanoma, had been through other treatments -- alpha interferon, other experimental treatments. A tumor had spread throughout her body.

 

We gave her very high doses of interleukin-2. And she was the first patient to ever show a complete regression of widely metastatic cancer due to the administration of an agent that was strictly immunotherapy, strictly affected the body's own T cell reactivity against the cancer. And she showed a complete regression. That's ongoing now 29 years later.

 

I just saw her about two weeks ago.

 

STEVE USDIN: Her prognosis in the absence of IL-2 therapy?

 

STEVEN ROSENBERG: The median survival -- that is, half of all patients who develop metastatic melanoma in the absence of effective therapy -- have a survival of about six months. That is, half live less than six months, half lives greater than six months. And she was right on that curve. Her tumors were growing rapidly. New ones were appearing through her body almost on a daily basis. And I would have estimated her survival to be a few months.

 

STEVE USDIN: What was the tipping point when your colleagues decided immunotherapy was real?

 

STEVEN ROSENBERG: So we published the first results of an effective immunotherapy, which is interleukin-2, the first reproducable effective immunotherapy that we have available in the New England Journal of Medicine in 1985. It included that young woman as well as other patients who had shown regressions. And at that point, it looked like patients with metastatic melanoma and metastatic kidney cancer were particularly susceptible to this kind of treatment.

 

Well, we published those 25 patients in the New England Journal in 1985. By 1987, we were capable of reporting 157 patients that we had treated. And we were seeing response rates in about the 15% range -- that is, regressions with about a third of those being complete disappearance of all cancer. And in fact, as we and others began to use interleukin-2 based on these early findings, it became clear that there was some patients, again in the 7% to 8% range, that no matter how far the tumor had spread throughout the body, would undergo a complete regression if you gave them enough IL-2 to stimulate the body's immune system.

 

And it was that trial and then a multi-institutional trial in over 20 different institutions that were giving high doses IL-2 that finally led the Food and Drug Administration to approve interleukin-2 as the first effective immunotherapy for the treatment of patients with metastatic kidney cancer in 1992, and finally, for the treatment of metastatic melanoma in 1998. And that FDA approval then led to the worldwide use of interleukin-2 as an immunotherapy.

 

STEVE USDIN: How does adopted cell therapy, ACT, work?

 

STEVEN ROSENBERG: So there are three basic categories of immunotherapy. One category is a non-specific stimulation of the immune system. And you can do that by directly stimulating the immune system or getting rid of factors that inhibit the immune system. Those are two ways to build up an immune reaction.

 

So interleukin-2 is a non-specific activator of the immune system, with the hopes that is there was an immune response against a cancer, it would elevate it to the point where it could impact on the growth of that cancer. And interleukin-2 therefore depends on the body's naturally having an immune reaction that could be stimulated by IL-2.

 

Now, an alternate approach to doing that is to release inhibitors. And those are called checkpoints that keep the immune system from working. And they have recently been described, some checkpoint inhibitors -- anti-CTLA-4, anti-PD-1-- that do the same thing. But those treatments are limited to cancers that naturally give rise to immune reactions. And so IL-2, anti-CTLA-4, anti-PD-1, work almost exclusively in patients with melanoma and kidney cancer, and perhaps in patients that have smoking-induced lung cancers because they have so many mutations that they give rise to immune effects.

 

But if you wanted to treat the 90% of patients that had other solid tumors, like ovarian, pancreatic, sarcomas, esophageal cancers, you need to do something different. People have tried to develop vaccines that naturally stimulate the body if you give them an antigen. And those basically have been completely ineffective.

 

And there's this third area called adaptive cell therapy, where we take the immune cells out of the body -- this is something we developed here -- take the lymphocytes out of the body that normally circulate, and now educate them outside the body to attack a cancer, either by selecting the cells that naturally react or by genetically engineering the cells to recognize a cancer, and then re-infuse them back into the body. And that's called adoptive cell immunotherapy and that can be effective against a variety of different cancers, like melanoma, like lymphoma, like sarcomas, and other cancers as well.

 

STEVE USDIN: ACT is a complex procedure. Will it be widely adopted, or will it lead to simpler therapies?

 

STEVEN ROSENBERG: Adoptive immunotherapy has had a major impact about thinking about the immune system and cancer, because it shows that if you give the correct T cell that's capable of recognizing a cancer in large enough numbers, with enough supporting materials -- interleukin-2 -- that can keep those cells alive in the body, you can mediate regression of a variety of cancers. And so we first showed that in melanoma in 2006.

 

In 2010, we showed that you could do that using what are called chimeric antigen receptors in a patient's cells to treat lymphomas successfully. That's been followed up now by many other groups. The following year, we showed that you could develop genetically engineered cells that could attack sarcomas and cause them to disappear.

 

So what you're doing in adoptive therapy is, you're developing basically a new drug for every patient. It's the most personalized therapy you can imagine. You take a patient's lymphocytes out of their veins, you modify them, you give them back, and see cancer regression. So you're developing this new drug, a lot more complex than taking a vial off the shelf and using it for treatment.

 

Now, pharmaceutical companies don't like this kind of complex personalized treatment. They want drugs off a shelf. They don't mind if you spend $500 million developing the first vial of a drug, so long as you make the next vial for $10. Adoptive cell therapy is different, because for every patient, you're creating a new drug.

 

And that's been difficult to widely apply. And pharmaceutical companies have been slow to pick it up. But in the past year, there's been a plethora of information of enthusiasm from pharmaceutical companies to develop adaptive cell therapy. Novartis is developing it in the lymphomas. Celgene is developing it -- another big biopharmaceutical company.

 

Kite Biopharma, a company that is working with the NCI to try to develop this is another company that's involved with it. And so I think in the past year, the pharmaceutical industry has gotten very interested in adoptive immunotherapy, because it can solve problems in cancer patients that can't be solved any other way.

 

STEVE USDIN: What are the response rates for ACT?

 

STEVEN ROSENBERG: Let me provide a few examples of adoptive immunotherapy. So for example, if you take a patient with melanoma, you remove one of their melanoma deposits, you can isolate from inside that melanoma the immune lymphocytes that are reacting against the cancer, ineffectively, because the cancers are still growing. We developed methods for isolating those lymphocytes that are infiltrating into tumors.

 

Intuitively, what better place to find a cell doing battle against cancer than within the cancer itself? We developed a technique for taking those lymphocytes out of the cancer, identifying the ones that recognize the cancer, grew them to large numbers, and then re-infused them after preparing the patient's body to accept them. And with that approach, we see objective responses by oncologic criteria in between 60% to 70% of patients now.

 

And in our last trial, 40% of those patients had a complete regression of all of their metastatic melanoma. Now, that's a very vigorous treatment. With lesser aggressiveness, you can see complete regressions in 20% of patients. But you can cure patients with metastatic melanoma using this kind of cell therapy, which is very rare in cancer. We do not have ways to cure virtually any patient with a solid cancer that's spread throughout the body by any systemic treatment. There are a few rare exceptions.

 

Melanoma was the first solid tumor to be reproducibly cured with an immunotherapy.

 

STEVE USDIN: Why is immunotherapy ineffective for 60% to 80% of patients? Can you predict who will respond?

 

STEVEN ROSENBERG: To understand why some people don't respond is difficult, but we're in the midst of a very large number of those studies? Some people just build up very weak immune responses against their cancer, or they have cancers that don't express these foreign materials that the body can react against. And that then led us to an alternate approach of adoptive cell therapy, which is called gene therapy.

 

We genetically engineer the lymphocytes to give them properties that they normally do not have. And so this is a quite remarkable application of modern molecular biology. You can use retroviruses or lentiviruses that you construct in the laboratory that can introduce new genes into our cells that they never had before, and give them properties they never had in the course of evolution.

 

And so what we've developed techniques to insert genes into normal lymphocytes and give them what are called receptors that can actually recognize the cancer. So we can take the lymphocyte that doesn't recognize the cancer and now insert a gene into it that enables it to do that.

 

STEVE USDIN: Will immunotherapy be effective for more common epithelial cancers, like breast cancer, colon cancer, lung cancer?

 

STEVEN ROSENBERG: We know how to make, in a laboratory, either naturally or by genetic engineering, very powerful T cells that can recognize and destroy cancer. The major problem confronting modern cancer immunotherapy is the identification of unique targets on cancers that are not present on normal cells. Now, there are such targets that are available for very common cancers, like breast cancer, prostate, ovary, and so on. And they're called cancer testis antigens.

 

These are antigens that are expressed throughout fetal development, but are then down-regulated in the adult normal tissues, but are re-expressed on the cancer. And so there are antigens like what are called NY-ESO-1, which we attack on sarcomas, or Mage -- M-A-G-E -- a different kind of cancer testis antigen, that are expressed in about 20% to 30% of very common epithelial cancers but not expressed on normal tissues. And so we're developing ways to attack those.

 

And that's in fact how we attack sarcomas and are now trying to apply that to the treatment of breast cancer and colorectal cancer as well.

 

STEVE USDIN: Combinations are often used to overcome mutations? Will immunotherapies be combined with checkpoint inhibitors or targeted therapies?

 

STEVEN ROSENBERG: Well, mutations in cancer, of course, are what cause the cancer. But it's a two-edged sword, because they also provide us with that target that's present in that cancer that's not in normal cells. And in fact, that's why melanoma is so susceptible to immunotherapy. It has many more mutations than other cancers. And that's also true with smoking-induced lung cancers, because there are carcinogens in cigarette smoke, and ultraviolet light on the skin cause a lot of mutations in melanoma.

 

So targeting those mutations is a very effective way to do immunotherapy. Now, some of the targeted therapies, like the use of vemurafenib to target BRAF mutations in melanoma, do the same thing, but they do them with drugs. And we're now beginning to explore the combination of adoptive cell therapy with these targeted therapies. And in fact, here at the National Cancer Institute, we have an ongoing trial in which we're combining a targeted therapy against a BRAF mutation in melanoma, along with our adoptive cell therapies.

 

And I think we're going to see that a lot more. One could also combine adaptive cell therapy with the checkpoint inhibitors, like ipilumumab or anti-PD-1. And we'll be beginning those kinds of trials soon. So this is a time in which we're seeing an explosion of information about how to use the immune system to target those unique aspects of cancer that separate the cancer from normal cells.

 

STEVE USDIN: What will it take to move immunotherapy from clinical trials to mainstream medicine?

 

STEVEN ROSENBERG: Immunotherapy is being developed. It's an experimental treatment still. We do it here. It's being done at M.D. Anderson in Houston, the Moffitt Cancer Center in Tampa, there's a group in Israel that's doing it. And the results have been the same as the results that we've reported.

 

And so industry is getting very involved in this. We're working with two companies -- Lion Biotechnologies, Kite Biopharma. The Moffitt Cancer Center is working with a group. The Memorial Sloan Kettering is working with a company.

 

University of Pennsylvania is working with Novartis and other companies. So I think, now that it's been shown to be so effective for the treatment of a variety of diseases, we're going to see a lot of industrial commercialization of adoptive cell therapy.

 

STEVE USDIN: Are you satisfied with how far immunotherapy has progressed?

 

STEVEN ROSENBERG: Last year, 600,000 Americans died of cancer. So there's a lot that is still to be done. I'm the world's most impatient person. And so am I satisfied with where we are now? Absolutely not. Immunotherapy can still impact on only a small percentage of patients.

 

But it's expanding. The universe of patients that can be successfully treated by immunotherapy is increasing dramatically. So there's some satisfaction in seeing it finally work. But taking care of cancer patients with immunotherapy, with any treatment is a roller coaster. You walk in one room, and you've have an experimental treatment. And you see a patient's tumor disappearing, and that's an ecstatic experience.

 

You walk in the next room, and the patient has not responded, the family is suffering. And so there's a long way to go. It's hard to remain very satisfied when you're taking care of patients with advanced cancer. And all of the patients that we treat with these experimental therapies are advanced cancer patients who don't have other alternatives open to them.

 

STEVE USDIN: What's your view of therapeutic vaccines?

 

STEVEN ROSENBERG: We ourselves have spent several decades, part of our group, studying cancer vaccines to see if we can't make them work -- that is, if you could somehow immunize a patient and have them develop an immune reaction against the cancer that didn't exist before. There are probably 10,000 papers that have been written on cancer vaccines. No one has yet figured out how to make a cancer vaccine work.

 

And there's a lot of excitement in publications about it, because it's easy to do. You give a patient an injection of an antigen and they go home. But it just doesn't work. There's only one cancer vaccine that's ever been approved by the FDA. And that is a vaccine developed by Dendrion that targets prostate cancer.

 

But it's barely effective. In large randomized trials, it improves survival by about three to four months. Everybody progresses. Everybody goes on to die of their prostate cancer. But it was on the basis of that small improvement with this vaccine that the FDA gave approval. It's a very low bar now to get approval for drugs.

 

There's a drug that's been approved by the FDA for pancreatic cancer that prolonged survival by 12 days. And so with the exception of this prostate cancer vaccine, which is really ineffective, there are no vaccines that anyone has ever shown to be effective in this treatment of a systemic cancer. And so will it ever work? I hope so. Does it work now? No.

 

WEB EXTRA

 

STEVE USDIN: What's the promise of adoptive immunotherapy for cancer patients?

 

HANS BISHOP: Well, the promise is a whole new standard of care. If you look at the clinical results that we generated today, we're seeing really encouraging responses. And those responses are generated without the toxicities associated with chemotherapy or radiotherapy. So we think it has the potential to be a new standard of care in a range of cancers.

 

STEVE USDIN: What has to happen to go from exciting experimental treatments to commercial products that can be widely used?

 

HANS BISHOP: We have to do several different steps with clinical trials. So the trials that we're doing today are referred to as Phase I, Phase II trials. And we have to move forward with clinical trials, which are designed to support a regulatory approval by FDA. And with some of the cellular treatments we have, we think that's likely to be our next step. And with others, we're still in an earlier stage development. And so there's more steps to go through.

 

The other major area of focus is figuring out the best way of manufacturing these cells. And that's a very large endeavour, as this is a very different type of treatment to the normal medicines that patients get, which are biologicals or small molecules. So it's clinical development and process and manufacturing development are the two main areas of focus for us.

 

STEVE USDIN: It's not like making a drug. How will it work?

 

HANS BISHOP: So the unique thing about this treatment approach is, we start by making the product using a patient's own white blood cells. So the first step is to geT cells from each of the patients we're treating, whether that's from a blood draw or from a procedure called a leukapheresis. And from there, there are a number of steps taken to turn those cells into a medicine.

 

And when that process is complete, it takes 10 to 20 days, depending on the product we're making. The cells are then reinfused back into the patient. And that's the complete course of treatment.

 

STEVE USDIN: What will the FDA approve? The cells?

 

HANS BISHOP: It's the cells, yeah. What FDA will improve is the actual cells that we've turned into medicine. And it's that medicine that they'll approve. And they'll look at the benefit to risk, like they do with all medicines they're reviewing. They'll look at the clinical data, they'll look at the clinical benefit, and they'll look at the safety. And by the way, there is a whole separate set of questions FDA always look at to ensure that the medicine is being made in a reproducible way that complies to all the relevant manufacturing standards.

 

So that's an important part of getting a medicine approved. But the primary part is the safety and the efficacy.

 

STEVE USDIN: Where will the cells be manufactured?

 

HANS BISHOP: I think initially, it is highly likely that the approach to manufacturing will be centralized. And whether that's one facility or more facilities, it's too early to say. But over time, the potential of these therapies and the potential to make them in different ways is really quite remarkable. And there are a number of different possibilities when you look across a longer time horizon.

 

STEVE USDIN: How did you put together a collaboration with three competitive cancer centers?

 

HANS BISHOP: We started by speaking to the experts in the field. You're going to meet one in a moment -- Dr. Stan Riddell. We started by talking to a range of experts and learning from them, what were the things that they believed were necessary to be best in class at making these products? And once we had arrived at an understanding of the different skill sets and the different technologies we needed, then we set about putting them all together.

 

And that was one of the reasons that scientists at the Hutch and Memorial and Seattle Children's decided it was the right thing to do to bring everyone together and cooperate. And it was one of the reasons, actually, we went even broader than that, to places like St. Jude's Children's Hospital and City of Hope to get other technology licenses. So the founding idea from the get go was defining the skills and resources we needed to do this best.

 

STEVE USDIN: And that's how you've raise $145 million?

 

HANS BISHOP: The reason I think the state of Alaska or the Alaska Permanent Fund and Arch Ventures, and now, we've recently announced that Venrock and also Jeff Bezos' investment fund, the reason these people have decided to invest in the company I think is twofold. First, it's the technical data, and second, it's the skill set, both inside the company and with our scientific founders that we've been able to put together. I think it's a belief in what we have in our hand today.

 

And it's a belief in how we can even make that better over time with the skills we put together.

 

STEVE USDIN: What's the clinical data?

 

HANS BISHOP: It's a number of things. First, it's clinical results in ALL -- acute lymphoblastic leukemia -- that come from a trial being run at Memorial Sloan Kettering by Dr. Brentjens and Sadelain and Riviere. We've reported results on 16 patients with ALL. Of those 16 patients that are evaluable, 14 have had what's called a complete response.

 

The second piece of data is from a trail being run at the Fred Hutch Cancer Center, based on technology from Dr. Riddell, which is largely an NHL trial, although we are enrolling other types of patients, too. And in that study, we've got a evaluable data on six patients, and five of those patients have had a complete response.

 

At Seattle Children's, a pediatric study, which treated two children with ALL, and both of those children have had complete responses. So there are the data we have in our hand today.

 

STEVE USDIN: You've raised $145 million? How far will that take Juno?

 

HANS BISHOP: We're raising the types of money that you mentioned not just to run clinical trials. As I said earlier, we started with an ambition to be the leader in this field. And the conventional biotech way of just focusing on the clinical data you have in hand and the products you have in hand today we don't think is the right way of doing justice to the science. So we've raised a lot of money because we want to do more than just run clinical trials in those areas.

 

We have a broad portfolio of other clinical candidates, including both TCR-based cells and CAR T cells based cells that can treat a range of solid tumor malignancies. So we want to develop a broad pipeline of candidates beyond the three I just talked about. And we also want to continue to invest heavily in the basic science.

 

As good as these technologies are -- and they really are quite remarkable -- we believe with the skills that come with our scientific founders, we can make these products better and better. But that involves investing in the science, understanding the immunology of these cells, and understanding opportunities to make them better starting from now.

 

STEVE USDIN: Dr. Steven Rosenberg and others have said Provenge is a failure. Your response?

 

HANS BISHOP: I don't agree with that. When Provenge was approved, it showed a 4.2-month overall survival benefit. And the standard of care at the time was a chemotherapy, which was much more toxic and a much more involved therapy that took many months to complete. And the chemotherapy's overall survival benefit was only just over two months. So Provenge has clear advantages over chemotherapy.

 

But the landscape's moved on. There are other newer agents now, which have different and have better data than chemotherapy did.

 

WEB EXTRA

 

STEVE USDIN: What have you seen so far in clinical trials, and how are the results different from standard cancer therapies?

 

DR. STANLEY RIDDELL: Well, I think the really encouraging results with immunotherapy are that they're accomplished with a lot less side effects for the patient. With chemotherapy and radiation, you have not only the acute side effects of the treatment, but you also have long-term side effects.

 

The chemotherapy and radiation are not just selective for the tumor. They damage all tissues. And one of the things about immunotherapy is that it is more focused on eliminating the tumor cells and sparing the normal cells. So you don't run into the same range of acute or chronic side effects that you get with chemotherapy and radiation.

 

STEVE USDIN: Can immunotherapy avoid the side effects seen in other effective treatments?

 

DR. STANLEY RIDDELL: Yeah, it does come at a cost, for sure. I mean, I think if you look at particularly the main treatments for ALL or chemotherapy in children, which cures the majority of patients actually, it's been a wonderful advance. And then in adults, we have to use both chemotherapy and often patients have to go on and get an allogeneic stem cell transplant to get a high rate of cure.

 

The problem there is that there is a lot of side effects. Now, I just would point out that the trials with immunotherapy and ALL are largely treating patients that have already failed these conventional therapies. So this is a real advance, because it allows us actually to treat patients who have failed the best currently available therapy and get high rates of remission.

 

So this is I think, really important. The next step, of course, is to move the treatment earlier in the course of the disease so we can potentially not need to do these really toxic therapies. But that will require a much longer follow-up, and we have to be cautious about moving in that direction until we've really proven the activity of these cells.

 

STEVE USDIN: Adoptive immunotherapy has been effective for melanoma and some rare types of cancer. Do you have data for more common tumors?

 

DR. STANLEY RIDDELL: We do. There is some encouraging evidence with some of the antibody checkpoint blockers in some other tumors other than melanoma, particularly lung cancer and renal cell cancer. But we also think that these T cell therapies can work effectively for these cancers. And we are working on developing both receptors that would target what we call antigens or molecules on some of these other tumors, particularly lung and breast cancer and also pancreas cancer, which as you know is a very difficult cancer to treat conventionally.

 

So we have optimism that we can develop therapies for these more common tumors. But of course, that's still at a more of a pre-clinical stage. The clinical trials, we anticipate, will be starting in the next year or two. And I think we'll learn from those trials and see how effective it can be and learn how to build on it.

 

STEVE USDIN: What's likely to be approved first?

 

DR. STANLEY RIDDELL: Well, I think the first focus is going to be on these B-cell malignancies, acute lymphoblastic leukemia, non-Hodgkin's lymphoma, and chronic lymphocytic leukemia. I think clearly the data there is very encouraging. And I think those are ploys to move into larger scale trials and hopefully eventually approval. And I think we'll see that in the next couple of years.

 

I think the Phase I work that will go on to now extend this to more common tumors is likely to start in the next year or two, depending on the various research groups working on this. And I think we'll have to see how the activities are to decide which of those are going to be the most promising to take forward.

 

STEVE USDIN: Is it going to be necessary to better characterize and standardize cell therapies?

 

DR. STANLEY RIDDELL: It's a great question. And in some ways I think it's an important scientific area that we have to work on. One of the things that we've been doing in our trial in B-cell malignancies is standardizing the product in every patient. We spent several years trying to understand the particular types of T cells that are likely to be most effective therapeutically when they're engineered to target cancer cells.

 

And so we do a step up front where when we get the blood cells from the patient, we actually purify out these specific subsets of cells to engineer and to make them into tumor-specific killer cells. We think that that has advantages. We think it, certainly in our pre-clinical work and in our animal models, it increases the potency of the cell product. So you can give much smaller cell doses.

 

And we also think it has the potential to give a more long-lived response so that the T cells would last longer and therefore more likely to eliminate every last cancer cell in the patient. So that's an advantage potentially for the efficacy of the therapy. The other advantage, I think, is that it does standardize the product.

 

And I think that from the standpoint of future regulation, we are going to have to look at standardizing these therapies so that they are much more like a drug that comes out of a bottle, or it's a pill that this is standard in every dose that you take. And I think we can get there with cell therapies, although it's going to take some time.

 

STEVE USDIN: Why do some people respond to immunotherapy and others do not? Can you predict who will respond?

 

DR. STANLEY RIDDELL: It's a great question. There's so many of us have been working on immunotherapy our entire careers. And to see the rapid advances in the past 5 to 10 years, and they've come from many different groups around the country that have been working on trying to understand how the immune system interacts with cancer and how to make it effective, what's happened in the last five years is literally transformationable.

 

Science magazine this year called immunotherapy the breakthrough of the year. But it really is, I think, the breakthrough of the last five years or even the last decade, where we've seen progressive advances. So it's a time of great excitement and great optimism and I think great hope for patients, which is really important.

 

But there is an enormous amount of work to do. And there's lots of things we still don't understand. The response rates are not as high as we want them to be in all cancers. And as you point out, we have to still look at whether we can extend this to the more common types of cancer that really affect the population at large.

 

STEVE USDIN: You've spent your career in academic medicine. Why are you working with a biotech company?

 

DR. STANLEY RIDDELL: What we can do in academics, we're largely funded through the National Institutes of Health, which is an extraordinary thing that we have in this country that funds biomedical science. But what the NIH can do is it can fund the early innovations, the work that goes to understand how you might either understand a disease better or develop new therapies for it. But it doesn't allow you really to commercialize the therapy. There just isn't enough money in the system to do that.

 

And so at the point that you have something that really looks promising, where you can get these early phase clinical trials done and demonstrate activity, then to really extend that and develop it as a therapeutic does require something beyond research funding that you can get from the federal government. So it does need to go to industry at that point. So the reason that we've come together, the academic institutions around this, is because of the opportunity.

 

We've all been working on various aspects of immunotherapy for many years. And we're now, all of us are in the clinic. We're seeing very encouraging results. And it's this opportunity now to come together, to build the science and the translation of this to a commercial product for patients. So it really is essential at this point.

 

And it is why most things eventually, even a drug does get license from an academic center to a drug company to develop it. I think in the cell therapy field, it's more complex. And so the fact that we've been able to do this as a partnership with Juno I think is very exciting.

 

STEVE USDIN: Is adoptive immunotherapy likely to be combined with other therapies?

 

DR. STANLEY RIDDELL: That's an area of very intense research right now. And we do have some insights, but it's going to take a lot more work to understand. I mean ideally, what you would do is you would use the therapy on patients that you know have a high likelihood of responding so that you can offer the other patients alternatives, or that we understand why it doesn't work, and we learn how to make it more effective.

 

One of the things with these immunotherapies is they're often targeting a single molecule or a single pathway. And it may be necessary in some patients to target more than one molecule or more than one pathway. And these kinds of combinations, you're going to see them increasingly being tested in Phase I trials. And I think we have a lot of hope that we can increase the response rates even beyond what we're seeing now, which is still quite remarkable.

 

STEVE USDIN: Will we see combinations of two immunotherapies, or combinations of an immunotherapy and a targeted therapy, or both?

 

DR. STANLEY RIDDELL: Both. I think you're going to see all of those things. But I think it's likely to be driven by understanding the mechanisms. We have to understand why patients respond and why patients fail. And as we start to study that, and if we understand the reason that a person is not responding, it may be that we'll say, well, we have to target an additional pathway in that patient to get it to be more effective.

 

So I think you'll see all of these things tested. But ideally they're done with an insight, with a question, not just say, well we have A and B. We're going to put them together and see if they work better. But actually because there's a logic behind combining A and B. And I think that's where the pre-clinical models and the academic research can really provide direction for doing those kinds of trials.

 

STEVE USDIN: In the future, do you think there will be a separate academic and clinical field called immunotherapy?

 

DR. STANLEY RIDDELL: Yes I do. In fact, at our center right now we're actually having those discussions about how we coalesce this modality into essentially a group of physicians that have experience in using this modality to treat patients. So I think you may see this more and more is that cancer therapies are going to be modality driven, whether it's immunotherapy or a targeted therapy.

 

It may turn out that the same treatment will work for different kinds of cancers because, in some ways, cancer cells share similar abnormalities that drive their growth and survival. So yeah, I think you will see that. It actually has happened in the past.

 

I mean, surgery is a modality. Radiation is a modality. And so I think you're going to start to see immunotherapy be more in the line of that. You may actually have a department of immunotherapy.