` The Cure Within


The Cure Within

By Neil Canavan

Due date: Due 2018
ISBN: 978-1-621822-17-2
Aprox 250 pages


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The way we treat cancer is about to change forever. This revolution—and it is precisely that—was sparked not by the invention of a new drug, but by the evolution of an entirely new way of thinking about and managing cancer. Going forward, doctors will not use pharmaceuticals to attack tumors – not directly. Rather, the oncologist will treat the patient’s immune system with a drug, and then the patient will treat the tumor.

Based entirely on interviews with the investigators, this book is the story of the IO pioneers. It’s a story of failure, resurrection, and success. It’s a story about science, it’s a story about discovery, and intuition, and cunning. It’s a peek into the lives and thoughts of some of the most gifted medical scientists on the planet.

This is not a textbook. This is a life book. This technology will save/is saving lives, and the book will celebrate the living, breathing, thinking, charming, arrogant, funny, obstinate, drinking-too-much, not-drinking-enough, amazing human beings who are making IO happen.

  •     Introduction    
  •     Overview    
  •     Chapter One    
  •     About the Author    
  •     Contributors    

Introduction

Immunotherapy has the potential to literally end cancer as we know it.
    — Vice President Joe Biden

The way we treat cancer is about to forever change. This revolution—and it is precisely that—was sparked not by the invention of a new drug, but by the evolution of an entirely new way of thinking about, and managing cancer patients. Going forward, doctors will not use pharmaceuticals to attack tumors—not directly—rather, the oncologist will treat the patient's immune system with a drug, and then the patient will treat the tumor.

This new branch of medicine is called immuno-oncology (IO) and to date the impact from using this approach in treating cancer is without precedent.

What is IO?

In brief, immuno-oncology is based on the idea that, just like with any bacterial or viral infection, the human immune system is capable of recognizing, attacking and killing tumor cells. This realization is not exactly new; what is new is that the capabilities of the immune system can now be leveraged.

A bit of history: In the early 1900s a renowned surgeon from New York City named William Coley read about the case of a cancer patient who had come down with a near-fatal post-operative infection. The patient not only survived the infection, but within days of his recovery all his remaining inoperable tumors disappeared.

This information was particularly striking to Coley because he had recently operated on a patient with a very similar cancer—that patient came though surgery with flying colors, without infection, only to later die of the residual cancer that the surgery failed to eradicate.

After seeking out and finding numerous related cases where tumors spontaneously regressed after the patient experienced a bout of infection, Dr. Coley embraced these observations and used them as a guide to develop a cancer treatment, a bacterial preparation later dubbed, "Coley's Toxins."

Unfortunately, the Toxins were only marginally effective. No one had any idea how they actually worked—if they worked at all—and after the more dependably effective treatment of radiotherapy was introduced in the 1950's, Coley’s Toxins fell completely out of favor.

Fast forward to the early 1980's when a researcher, another surgeon named Steve Rosenberg, was heralded for treating cancer with a drug called IL-2, a drug that is natural to the human body and is a critical component of the immune system. Using massive amounts of this substance Dr. Rosenberg was able to cure a number of patients with a variety of tumor types, but the treatment was/is highly toxic and like Coley's Toxins, only effective in a limited number of patients. And again, the precise way the drug was working was unknown.

Then came "ipi".

Ipi, short for the drug, ipilimumab, was approved by the FDA in 2011, and it is the shot that set off the IO revolution. In the pivotal clinical trial that led to the approval of ipi, patients with advanced melanoma—patients with only months, if not weeks to live were surviving for years. In describing some of these patients, oncologists are now even using the word, "cured".

In 2014, two more IO drugs were approved, nivolumab, and pembrolizumab. One of the patients to receive the latter drug—a patient that otherwise would almost certainly have already died of metastatic melanoma without this treatment is former President Jimmy Carter. As of this writing, Carter is alive and well and tumor free.

This is not hyperbole. This is real.

Unlike previous attempts at IO, scientists know exactly what these two drugs are doing, and in general, that knowledge has been put to work in discovering other agents that enhance the patient's immune system.

And this is just the beginning. IO is here. Hundreds of patients have already had their lives extended using this new therapeutic approach. Very soon that number will be in the tens of thousands.

Overview

Ending all cancer would rank among humanity's greatest achievements, and immunotherapy is bringing that dream within reach.
    — Former NYC Mayor Michael Bloomberg

The IO revolution almost didn't happen. The foundational idea that the immune system could even see a cancer cell, let alone kill it, was to many an anathema. Prominent researchers—highly intelligent men and women, each and all—had given the idea a great deal of thought and concluded that the approach simply would never work. The underlying principals were flawed.

Coley's Toxins had failed. IL-2 was too toxic. Cancer vaccines that made perfect scientific sense on paper were relentlessly ineffective in the clinic. There were some who held very dark opinions for some very good reasons. By the mid-nineties the anti-IO bias was so pervasive that researchers who were actually making real progress in IO could not convince their peers that their data was real.

"Michel pulled me into conference room and showed me the data that was emerging and I almost fell off my chair. My first reaction was that it was probably not true."

- Jose Baselga, MD, PhD, Physician-in-Chief, Memorial Sloan Kettering Cancer Center

But the data kept coming, and among those men and women that were previously skeptical there were some converts. They remained unconvinced, but at least some were listening; they were willing to wait for the clinical trial results.

When the first of the IO drugs finally emerged from animal testing and made it to the clinic some patients (very few) began to respond. It wasn't great, but it was something.

However, the drug had some horrific potential side effects and as the trials progressed the lack of efficacy became clear. The pharmaceutical company that was developing the drug pulled the plug. And that was that.

Yet, at almost the exact same time another company's IO drug—a drug of very similar design to the one that failed was also in clinical trials. Preliminary results for that drug, called ipilimumab, or ipi, were also poor but ipi had three distinct advantages:

1) The person who discovered ipi was a highly persuasive, charismatic man who would not take no for an answer

2) The clinician to first use ipi in a clinical trial had the rare ability to listen closely to his patients, who, despite having test results that showed the drug was failing them, said they felt better…

3) The corporate champion within the pharmaceutical company who realized the drug actually was working, but that to prove it he would have to propose an entirely new way to statistically validate his belief—a monumental argument to be made, and he made it

In short, the IO revolution is the doings of some very special people, a determined bunch, if not actually fanatical. There were IO fanatics because they had to be. Because no one believed in them.

This book is their story.

Based entirely on interviews with the investigators, this is the story of the IO pioneers. It's a story of failure, resurrection, and success. It's a story about science, it's a story about discovery, and intuition, and cunning. It's a peek into the lives and thoughts of some of the most gifted medical scientists on the planet.

This is not a text book. This is a life book. This technology will save lives, and the book will celebrate the living, breathing, thinking, charming, arrogant, funny, obstinate, drinking too much, not drinking enough amazing human beings that are making IO happen.

Finally, this book is not all about IO. Along the way of the story's telling there will be issues raised, problems in the scientific community like gender bias, and race, and funding. Along the way there will be anecdotes, like tales from the Dark Night (advice on how not to shoot yourself when it's all going wrong), like a discussion of art history, or the Six Day War, or Stalin, or Les Paul guitars, or dolphins or chickens or Star Trek. It's all here.

So, yes, it's a book about people.

They just happen to be scientists.

Section/Chapter/Investigator

Section I: CTLA-4

Chapter one: James Allison, M.D. Anderson Cancer Center

Chapter two: Jedd Wolchok, Memorial Sloan Kettering Cancer Center

Chapter three: Axel Hoos, GlaxoSmithKline

Section II: PD-1

Chapter four: Tasuku Honjo, Kyoto University

Chapter five: Gordon Freeman, Dana Farber Cancer Center

Chapter six: Suzanne Topalian, Johns Hopkins University

Section III: CARs

Chapter seven: Zelig Eshhar, Weizmann Institute

Chapter eight: Patrick Hwu, M.D. Anderson Cancer Center

Chapter nine: Michel Sadelain, Memorial Sloan Kettering Cancer Center

Chapter ten: Carl June, University of Pennsylvania

Section IV: Immuno-editing

Chapter eleven: Robert Schreiber, Washington University in St Louis

Section V: Vaccines

Chapter twelve: Elizabeth Jaffee, Johns Hopkins University

Chapter thirteen: Drew Pardoll, Johns Hopkins University

Section VI: Oncolytics

Chapter fourteen: Robert Coffin, Replimune

Section VII: Bispecifics

Chapter fifteen: Patrick Baeuerle, MPM Capital (formerly of Micromet)

Section VIII: MDSCs

Chapter sixteen: Dimitri Gabrilovich, Wistar Institute

Chapter seventeen: Vincenzo Bronte, University of Verona

Section IX: IDO

Chapter eighteen: David Munn, Georgia Regents University

Section X: STING

Chapter nineteen: Tom Gajewski, University of Chicago

Section XI: Microbiome

Chapter twenty: Laurence Zitvogel, Gustave Roussy

Section XII: Dendritic cells

Chapter twenty-one: Ralph Steinman, in memoriam (Note: Dr. Steinman is the only investigator highlighted posthumously. The reasons for this are explained within the chapter.)

Epilogue: Hope or Hype?

This last chapter features comments from many of the highlighted investigators regarding the possibility of IO falling victim to unrealistic expectations.

Cartoon Gallery

Glossary

Chapter One

James P. Allison, Ph.D.

Professor, Chair of Immunology, MD Anderson Cancer Center

I proposed treating cancer by ignoring it.
    — J. Allison

James P. Allison was born in 1948, in Alice, Texas.

"Alice, Texas — it's a very small town," intones Allison, in his comfortably worn Texas drawl. "It's got tall boots and mesquite, and cactus, and a lot of cows. Maybe hard to find on a map if you don't know… It's near Palito Blanco and Freer, if that helps."

A nice place to grow up, but Alice is a strange place to take a shine to science. "I was lucky," Allison is quick to acknowledge, "My dad was a country doctor, so through him I got to see medicine and science, and I also had some pretty good school teachers that recognized something."

These early champions got Allison into special academic programs, and he would spend his summers from the eighth grade on in one science program or another at the University of Texas in Austin. The teachings, and the teachers, made their mark on the scientist-to-be.

"There were two teachers, actually," Allison recalls. "One was Ernestine Glossbrenner. She was my eighth grade algebra teacher and she was very supportive." The other teacher provided both positive and negative reinforcement. "Larry Orare — he was my physics and chemistry teacher, except he was complicated because he was a Church of Christ lay minister and he made absolutely sure that no evolution was taught in the school."

This set up an intractable conflict for Allison. "I'd learned about evolution on my own, and since they didn't teach it in biology class I refused to take high school biology." This decision did not sit well with the school board. "It caused quite a rile," says Allison. "But I told them teaching biology without evolution is like teaching physics without Newton; I don't see how you can do it. So, they came around." Allison was allowed to take biology by correspondence from UT Austin.

Defender of the Faith

Years later, he was called upon again to champion the cause of science education: "So, by this time I'd finished my PhD, done a post-doc, and had come back to live in Austin and I get this call." His old eighth grade math teacher, Ernestine Glossbrenner, was now in the Texas legislature and serving on the Education Committee, and she had a problem. "She says there's this crazy guy named Mike Martin who introduced a bill to require teaching of Creation Science in the schools, and you've got to come down and help."

Representative Glossbrenner remembered Allison's run-in with the school board, and hoped that he would be willing to stand once again in defense of science. He accepted. Allison would debate Martin in front of a committee of the Texas legislature.

"Martin started in with stuff like, ‘If you put a Ford in a field it just rusts, it don't turn into a Cadillac.' That was the level of discourse. So my attitude was, okay, Mr. Martin, you tell me how you can use your creation science to explain how bacteria become resistant to antibiotics. You use your creation science to tell me how a tumor cell escapes the body's immune system. Use your science to explain anything. Tell me, give me an example of what you can use your science to predict, because science isn't about an incomplete fossil record, it's about predicting things."

As the debate went on Martin tipped his hand to his real concern: There was a secular humanist conspiracy to suppress creationist thought.

Allison bristled, and drove his point home. "I said, no. I said, creation science lost out in the free marketplace of ideas because it's not useful."

He then turned the tables on Martin, pointing out how others have tried in the past to contort science for political or religious reasons. For instance, said Allison, for many years the Soviets emphasized Lamarck over Darwin because Lamarck advocated the inheritance of acquired characteristics, which is more consistent with the socialist/Marxist idea of the perfectibility of man.

"Martin got so flustered by what I said that in his rebuttal time all he could do was keep denying he was a communist. So, luckily, I won the debate, and they killed the bill. It was a lot of fun."

Scientist, Know Thyself

From the eighth grade on Allison knew he wanted to be a scientist. "My dad still wanted me to be a doctor, so when I started college I was pre-med," says Allison. But it didn't last very long. "It quickly dawned on me that the pressures of making decisions, day-to-day decisions that affect people's lives and, you know, you've got to be right — you can't be wrong…" A scientist, on the other hand, is expected to be wrong most of the time: That's intrinsic to the journey; most experiments fail. "As a scientist you only have to be right sometimes. I liked that a lot more."

The choice of what sort of scientist to be was not quite so direct, but Allison again let his nature guide him: He likes puzzles; he likes taking things apart. "I was actually trained as a biochemist not as an immunologist, but I just got interested in immunology." He was fortunate enough to encounter his third mentor. "As an undergrad I took a course taught by a very good, very charismatic professor named Bill Mandy."

T cells had recently been discovered, but Mandy himself didn't believe they were relevant. "He liked B cells; he was an antibody guy all the way through. (Antibodies come from B cells)." But the entire topic was compelling to Allison. "The idea that you could have these cells going around in your body, traveling through the lymph nodes, communicating with the other cells and tissues in your body and protecting you from most anything that comes along — even things that might not have existed before, and then somehow do that without killing you? I just thought that was a fascinating biological issue."

The Journey to Yervoy

After completing his training, Allison began his research in earnest as a faculty member for the University of Texas — MD Anderson Cancer Center, initially working out the protein structure of the T cell antigen receptor (TCR). "That's the switch, the ignition switch that turns on T cells," he explains. When a T cell encounters an antigen that matches up with its TCR it becomes activated. "I was interested in general in how you regulate T cells. How do you turn them on? How do you stop them?"

Ten years and countless experiments later, Allison discovered a second activating pathway, a co-stimulatory signal beyond the coupling between TCR and antigen that is essential for an effective immune response. He thought of it this way: If the TCR/antigen interaction is the ignition, then this second signal was the accelerator, revving the engine, driving the T cell onward to fully engage (and kill) its target.

"It was a big mystery as to what that signal, that molecule was, but it was known to be present on very specialized cells called dendritic cells." These are the cells that present the tumor antigen to the T cell — not the tumor. The co-stimulating moiety Allison discovered is now known as CD28 (Cluster of Differentiation 28).

"We messed around with that a little bit," says Allison, "but when we cloned CD28 we encountered another molecule that had already been discovered called CTLA-4 (cytotoxic T-lymphocyte–associated protein 4)." Little was known about this molecule at the time except for a few tantalizing clues: It was not expressed in resting T cells, but only in T cells that had been activated, and it appeared to bind the same ligands as CD28: the ligands known as B7-1 and B7-2 found on dendritic cells (Wolchok 2013). A competing laboratory demonstrated that the CTLA-4 receptor bound the ligand more tightly than CD28. Given this relationship, that group proposed that CTLA-4 was another co-stimulatory molecule.

"They were working in human cells. We were a little behind, but we cloned the mouse gene and made antibodies to the gene product." This work was being mirrored by Jeff Bluestone at the University of Chicago. "Both Jeff and I independently came to the conclusion that CTLA-4 was not another gas pedal, if you will, but was actually a negative regulator in opposition to CD28: A brake."

Further investigation indicated that the other group had misinterpreted a key observation: They had concluded that the antibody they were using was an agonist, based on an observed increase in T cell activity, "But really what it was is that they were blocking the negative signal." Thus, instead of stimulating new activity, the antibody was restoring existing activity by blocking an inhibitory effect.

A-ha!

"The ‘A-ha' moment, at least with respect to cancer, came after I started thinking about how tumors just can't give that second (activating) signal." Allison reasoned thusly: The immune system has a number of built-in mechanisms to prevent autoimmunity: the attack on healthy cells by the immune system. One such mechanism is cross-priming, the process whereby the cellular debris of a dying cancer cell — DNA and all — induces an inflammatory response that summons dendritic cells to clean up the debris.

Discrete bits of the cellular debris — the unique tumor antigens — are then processed by the dendritic cells and presented on their cell surface for recognition and targeting by the T cells. A T cell that recognizes the specific tumor antigen being presented will bind to the dendritic cell where the second signal is given, stimulating the full immune response (Guermonprez 2002).

"Once fully activated, the T cell will kill, and continue to kill without further instruction. That's how it works," says Allison. So, there are failsafe conditions that must be met before an immune response is initiated. That had been shown. But this knowledge begged the question of what sort of mechanisms are in place to get the immune response to stop, because an unbridled immune response can kill you."

Everybody had been concentrating on this process where you get the T-cell receptor signal, and then a co-stimulatory CD28 signal, and then this whole cascade of cell cycle progression, and expression of cytokines — all these positive things," says Allison. "But what wasn't realized — what even I didn't realize for a little while, was that this all starts a negative program as well by inducing the C24 (CTLA-4) gene, and that's what's going to eventually turn the system off." CTLA-4 serves as a ‘checkpoint' to limit the immune response, and this activity occurs at a critical juncture in cell–cell signaling.

Evidence supporting this ‘off switch' checkpoint hypothesis was provided by a rather simple experiment. "We knocked out the CD24 gene in a mouse, and found that without it, these mice die when they're about three weeks old — they just fill up with T cells because they can't stop an immune response" (Wolchok 2013).

Based on these observations, Allison thought, what if activated T cells actually can detect tumors, but that the tumor cells themselves were able to inhibit an otherwise robust immune response? The next logical step for Allison was to try to remove this inhibition. "I figured, let's just disable the ‘brakes' by making an antibody that prevents CTLA-4 from binding its ligands, and then we can just keep the immune system running as long as we want." It worked: An "A-ha" moment built of incremental progress, but an "A-ha" nonetheless.

Nearly Lost in Translation

At the time however, Allison was not working on the problem of eliminating tumors. "I always wanted to do something about cancer — I've lost a lot of family members to cancer, and I've had prostate cancer myself, but that wasn't why I was doing this experiment. I was doing these experiments to learn how the T cells work, and only after that did I ask the question, ‘What have we learned that we can use to treat disease?'"

Allison had learned that T cells could be activated fully, through precise mechanisms, to kill tumor cells until such time as they are instructed not to. Tumor cells, via CTLA-4 signaling, had the ability to instruct T cells to stop the attack. Therefore, clinical translation would be simple: It didn't matter what kind of cancer it was, it didn't matter what the antigen was, all one needed to do was release the ‘brake' by inhibiting the CTLA-4 checkpoint.

It was a provocative idea and it was not well received. "Ever since Nixon declared the ‘War on Cancer' and the DNA sequencers came along, everybody said, ‘we're going to sequence, we're going to learn everything about cancer cells and we're going to beat cancer by learning what causes it.'" This translated to the therapeutic revolution of so-called 'targeted therapy‘, and at the time that approach was considered to be the way to the Promised Land. "And I was saying you don't need to characterize every cancer cell, you don't need to know what causes cancer. The immune system doesn't know if it's a kidney cancer, lung cancer, prostate cancer; the immune system doesn't know if it's caused by RAS (a mutated protein) or mutant epidermal growth factor receptor or anything. It just knows it shouldn't be there."

The second radical notion suggested by Allison's approach was to not treat the tumor directly at all. "I proposed treating cancer by ignoring it," says Allison, proudly. "I said, instead, treat the immune system. That was the idea — just let the immune system rip." In other words, Remove the inhibitory factors and allow the immune system to finish its job (with the caveat that the immune system knows the cancer is there, an issue addressed in other chapters).

It was a simple idea, with data to back it up, but there was still a lot of convincing to do. Allison spent the better part of two years making the rounds of pharmaceutical and biotech firms, and the negative feedback was largely the same: This is not a small molecule (that being the preferred form for a new drug, as they are easier to manufacture and administer) and besides, it was a form of immunotherapy — an approach that had proven less than effective in previous types of cancer treatment. Counter arguments were presented. There was a lot of fruitless back and forth, and a near miss: "There was a preexisting patent that Bristol-Myers Squibb had filed," Allison recalls, "but they got the biology backwards; they said it was a positive molecule." Allison had the mechanism right, and developed a sound intellectual property position from that perspective, but it was still an uphill battle to get anyone to take notice. "Finally, this little company called Medarex expressed interest. They had a mouse that had some immunoglobulin genes replaced with human and so they could make totally human antibodies from the start, so I said, okay."

A Phase I trial was performed. Typically, a Phase I study only generates data regarding dosage and toxicity of the treatment, not the treatment's efficacy. "Well, there were three objective responders in that trial, and one of them, one of the patients on that trial I met during her tenth annual checkup at UCLA after being cured. She's now 14 years out..." smiled Allison broadly (Weber 2008).

A Rose by Any Other Name, and the Latest Gig Allison expressed some amusement at the naming conventions for new drugs. "When we first started working on it, it was called MDX (Medarex)-010," says Allison. Then, for reasons not specified, the FDA named it ipilimumab. "It was kind of a letdown. I mean, I was at Berkeley at the time. I suggested they at least put an ‘H' in front of it, but I guess they didn't think that ‘Hippy-limumab' had enough gravitas for a cancer drug."

Although he failed to influence the FDA regarding the naming of the new drug, Allison had better luck in naming his blues band: It's called, appropriately, ‘The Checkpoints'. "Everybody in the band is an immunotherapist," says Allison. "You know Patrick Hwu, head of melanoma at MD Anderson? He's the keyboard player, and Tom Gajewski from the University of Chicago is the lead guitar player and he really holds the band together." Other band members include Rachel Humphrey, MD (head of immuno-oncology at Eli Lilly), Dirk Spitzer, PhD (instructor in the Department of Surgery at Washington University School of Medicine in St. Louis), and Keith Bahjat, PhD, (director of the Earle A. Chiles Research Institute).

"We play every year at ASCO (American Society of Clinical Oncology), and we play at the Society for Immunotherapy of Cancer meeting too. The last three years we played at the House of Blues in Chicago and sold out the room."

Not too shabby for an inquisitive boy from a little town called Alice.

About the Author

Neil Canavan

Neil is a veteran journalist specializing in science and medicine, a career he embarked upon after earning a master's degree in molecular and cellular biodynamics from Rutgers University. With over 15 years of reporting experience, and some 200 feature articles to his credit Neil has written for such news outlets as WebMD, Medscape, Drug Discovery and Development Magazine, and The Scientist. Currently, Neil is a contributing editor to The Oncology Business Review where he has written many articles on the technology of, and clinical outcomes for cancer immunotherapy.

For the last two years Neil has held the position of Scientific Advisor at The Trout Group, a New York-based investor relations firm focused on healthcare biotechnology. The Trout Group has 30 clients in the oncology space, with many of those companies pursuing the development of cancer immunotherapies. With the aim of informing and educating the general public—and thereby all the stakeholders in the setting of clinical oncology—The Trout Group is sponsoring the writing of this book.

Top Contributors Include

Carl June
University of Pennsylvania

Dr. June's laboratory has been dedicated to the development of new forms of T cell based therapies for nearly two decades, having developed a cell culture system that was tested for the first-in-human evaluation of chimeric antigen receptors (CAR) using T cells modified with retroviruses. His team also conducted the first clinical evaluations of a CAR targeting the cancer antigen CD19 in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. To date, results seen with his CD-19 CAR in this difficult-to-treat patient population have been described as “unprecedented”. Dr. June is a scientific founder of Tmune Therapeutics.

James Allison
University of Texas MD Anderson Cancer Center

Dr. Allison's research focuses on the mechanisms that govern T cell responses and applying that basic understanding to overcome cancer's evasion of attack by the immune system. His fundamental discoveries include the T cell antigen receptor used by T cells to recognize and bind to antigens; the co-stimulatory molecule CD28 that must signal the T cell to launch an immune response to a bound antigen; and the immune system inhibitory checkpoint molecule CTLA-4, which inhibits activated T cells from attacking. Allison developed an antibody against CTLA-4 that became ipilimumab, the first drug ever shown to increase survival for patients with metastatic melanoma. Dr. Allison is one of the scientific founders of Jounce Therapeutics.

Jedd Wolchok
Memorial Sloan Kettering Cancer Center

Dr Wolchok's specific research interest is the pre-clinical and early clinical development of novel immunologic therapies as they relate to the treatment of advanced melanoma. He has been the lead investigator of pivotal clinical trials of new immunotherapy drugs, ipilimumab, and nivolumab. Most recently, Dr. Wolchok has initiated several clinical trials using plasmid DNA vaccines for patients with melanoma. He has been involved in the development of the DNA vaccine program at every level--from initial studies in mouse models, through all levels of regulatory review, and now as principal investigator of the clinical trials.

Michel Sadelain
Memorial Sloan Kettering Cancer Center

Dr. Sadelain has made major contributions to the generation and optimization of CAR T cells to treat cancer, as well as the development of stem cell therapies for blood disorders. Dr. Sadelain's work has focused on developing novel strategies to extend survival of CAR T cells in the body and enable T cells with increased potency to overcome the resistance imposed by tumor and other cells in the tumor microenvironment. His group advances provided a broad platform to enhance CAR T cell therapy, leading directly to the development of new CAR T cell therapies that are showing increasing efficacy in patients. Dr. Sadelain is one of the scientific founders of Juno Therapeutics.