Immune to Cancer: The CRI Blog




Charles Graeber Follows Glimmers of Light Leading to the Breakthrough Emergence of Cancer Immunotherapy

As an award-winning writer, Charles Graeber has examined the stories of the ruined city of Kamaishi, besieged tech entrepreneur Kim Dotcom, and the “insanely illegal” cross-country Cannonball Run. In his New York Times-bestselling book The Good Nurse, he followed serial killing nurse Charlie Cullen, who may have murdered as many as 400 people across nine hospitals. For his next book, he turned to an even more insidious killer: cancer.

The Breakthrough by Charles GraeberIn The Breakthrough: Immunotherapy and the Race to Cure Cancer, Graeber examines the long journey toward understanding how the immune system recognizes and fights cancer and the recent development of a new class of cancer treatments. The Wall Street Journal called it “Engaging… In Mr. Graeber’s hands, the evolution of immuno-oncology is both captivating and heartbreaking. We are immersed in the stories of the brave, desperate patients who try emerging therapies…We can’t fail to see ourselves, our friends and our families in these stories.” James Gulley, Head of the Immunotherapy Section and Director of the Medical Oncology Service at the National Cancer Institute’s Center for Cancer Research, recently declared The Breakthrough a “must read” for patients and scientists alike.

Brian Brewer, Cancer Research Institute (CRI) director of marketing and communications, sat down with the author to discuss his book and the pivotal role CRI has played in keeping alive the long-elusive dream of effective cancer immunotherapy. In this interview, they delve into the evolution and revolution in the field of immuno-oncology, fundamentals of science, and how the cancer patient experience is changing dramatically. Below is an edited transcript of their conversation.

Brian Brewer: What turned you to the subject of immunotherapy?

Charles Graeber: It was on a trip back from New Zealand, where I was following my story about Kim Dotcom. I was seated next to somebody who was familiar with my other stories. He was a biologist, and after hanging out and having a couple cocktails on the flight I said, “Well, you tell me, what’s the most interesting thing in biology? You have a view, I don’t.” And he told me essentially the story of CTLA-4; he told it to me in about two sentences.

Brian Brewer: The first FDA approved checkpoint inhibitor.

Charles Graeber: Right, and what he told me about really was the action, just the sheer notion that cancer interacts with the immune system. It takes advantage of built-in brakes, because there is nothing more dangerous in the human body than us, than our own defenses. That’s how powerful they are, and I thought that’s the most incredible thing I’ve ever heard. That sounds like the biggest scientific advance of my generation.

I looked into it further and tried to get my arms around it a little bit. I spoke to my book agent about it; I didn’t know if I could make a book out of it because it was hard and doesn’t sound like a story. It just sounds like a fact. She said, “Well, that can’t be true or I would have heard of it.” And then she spoke to her father, who was a retired oncologist, who said, “Oh yeah, that stuff. Well everyone knows that doesn’t work, so don’t bother going that direction.”

Brian Brewer: It was the commonly held opinion for many decades that immunotherapy would never amount to anything and anyone who pursued it was pursuing career suicide.

Charles Graeber: Right, at best deluded, at worst, quacks, which was what makes the continued existence of the Cancer Research Institute all the more remarkable. One of the chapters in my book is called “Glimmers in the Darkness” because there were these little flashes that this was real: that cancer could be recognized by the immune system; the immune system could kill cancer cells. Those little flashes were also a flame or spark that was kept alive here [at CRI].

The book almost did not exist because publishers didn’t want it. They said, “This doesn’t make sense, and also you’re really going to write a book about things called PD-1, CTLA-4, and what else? What story is that?” And I can’t really blame them, I guess.

Author Charles Graeber Headshot
Author Charles Graeber

I realized that there was a great view at the top of this mountain, but I needed first to climb the mountain to really see what that view was. That took a while, and then I needed to figure out a way to carve out a slowly winding path up that mountain that everyone could follow, and would want to follow, so that they could see this view, too. That was difficult. I honestly did think of quitting because I had run out of money. I was pulling my hair out trying to figure out what stories to tell and what stories not to tell.

It took a while to find the right characters. You had to have people that could carry this story forward that weren’t just diligently looking into microscopes, or just happened to be cured, but real stories. And luckily again, one of those big stories is the story of why the Cancer Research Institute exists, which is like “Gangs of New York” meets “The Knick.”

Something seemed to work: a bacterial infection created a cure—there is something happening here. And at the time you could do experiments that would be ethically impossible today, and try to reproduce it, whether or not you understand the science.

Brian Brewer: You’re referring to Dr. William B. Coley and his first experiments of injecting live, potentially fatal bacteria directly into the tumors of patients who couldn’t be operated on. In some cases, after a response to infection, which is fevers, chills, sweats, aches, some patients suddenly experienced total remissions. Their cancers just melted away, and it was almost miraculous.

Charles Graeber: Right, and it turns out that these “miracles” had been observed for centuries. They are described in Egyptian papyri. The letters of Chekov contain some mention. It reminds me of Arthur C. Clarke saying that any sufficiently advanced technology is indistinguishable from magic. And that’s what it was, and so we’ve been trying to figure out that magic for a long time.

But what was most incredible to me, and one of the reasons this story needed to be written, is that very few people even considered that that magic had happened, had even seen the trick. In digging into this story, I found that science and scientists can be as biased and blind as anyone else. They are people.

This is something I come across in every story. It doesn’t really matter what uniform they wear or what their job is, they are at the end of the day people. They would ignore data just to go with belief. Overcoming that has been the work of generations, and it’s amazingly recent that we’ve actually cracked the code on that and opened up a whole new field of inquiry.

Brian Brewer: William Coley practiced 100 years ago, and his daughter, Helen Coley Nauts, was completely dismissed by the cancer establishment of her day. When you think about it in terms of how long it’s taken to get to this point, it’s almost as if immunotherapy has materialized out of nowhere. In The Breakthrough, you walk us through the origins of this idea and the negative response that it received. But now that’s all changed.

Charles Graeber: So dramatically. That’s the other thing that makes this such a great story. This is not the story of slowly putting pebble on pebble until it reached a sufficient height. This is a comeback, and it’s a very sweet victory. Many generations have passed that never got to see this victory. William Coley and his daughter, for example, were mocked, vilified, and degraded. One of the researchers I spoke to said that people used to call themselves immunologists, even if they were cancer immunotherapists because they didn’t want to be pegged and mocked. Now immunologists are calling themselves cancer immunotherapists.

Brian Brewer: Everyone loves to jump on this bandwagon. In your book, you likened the advent of effective immunotherapy to a penicillin moment. Penicillin completely transformed medicine. Why do you think immunotherapy is like a penicillin moment for cancer?

Charles Graeber: Penicillin obviously saved hundreds of thousands, millions of lives right away. But it was the concept of penicillin, that something like that could work, that you could actually have a drug that could kill microbes, that would fight disease in this way. It encouraged an entire generation of scientists and researchers to begin looking in that direction. Once you begin to look you find more and more, and so now we’re much more sophisticated.

So it’s not really just these checkpoint inhibitors, but it’s the sheer fact that oh, the immune system has built in brakes and safeties that cancer has evolved to take advantage of. We can block cancer from taking advantage of them, or help the immune system to overcome those blocks and safeties and do a better job. And that was not a valid field of inquiry before.

The idea is to cure cancer, right? Cancer is us. It is alive. It is mutating. It escapes. It dances away. A drug doesn’t mutate. No single drug, no single knife, or poison, or anything else is ever going to be able to match something that’s creative and mutating and transformative.

We were never going to cure cancer going the direction we were going. And yet we have now enlisted the help of the immune system, in fact it turns out it was always the immune system. We were always bombing cancer, treating it like a monster that if we could weaken it enough the immune system could mop up the rest. And we didn’t know that was happening. I’ve been likening the immune system now to the butler in one of these locked room mysteries.

Brian Brewer: Escape-the-room sort of thing?

Charles Graeber: Well no, more of like an Agatha Christie-type thing, where the butler did it. It’s because you sort of forgot about the immune system was always there, and it turns out oh, it’s the immune system. It’s always been the immune system. In fact it’s the immune system for all these other diseases and who knows what else, but we’re now realizing we need to look there. The only time I’ve ever quoted Goethe in my life is in this book. He said, “We search where there is light.” We just turned on the lights and realized there is an entirely new area where it might actually work.

It’s a genuine reason for hope. It’s not one of those breakthroughs where maybe we’ve found a magic pill or magic bullet.

Brian Brewer: The magic bullet language led to disappointment in immunotherapy back in the day.

Charles Graeber: Right, and there were many, but it’s the first time that the field has been validated, not just one approach, not one miracle drug, not one Time Magazine cover with a test tube filled with very specific stuff, whatever it is, but an approach. And it’s the only approach that will work. Instead of having to invent new drugs and hope we’re really that smart, which we’ll continue to do, we can also enlist the help of 500 million years of engineering and problem solving that’s designed to do nothing but what we’re looking for it to do. So that’s exciting.

Brian Brewer: It’s a real testament to the power of science to do that. It has taken decades of basic research to understand the fundamentals of our own immune systems, and then overlay on that the fundamentals of cancer, and then further overlay how the two of those things work together, and then trying to come up with a solution to either interfere with or enhance either side of that equation.

You had the pleasure of interviewing Dr. James Allison, the director of our Scientific Advisory Council, who also happens to be the 2018 Nobel Prize Laureate in Physiology or Medicine along with Dr. Tasuku Honjo for their work on checkpoint blockade. A lot of this new renaissance started with Jim, who kind of blew it all open.

Charles Graeber: Yeah, he did, and his story is a rollicking great yarn because he tells a good story. He is such a character, one of the better stories in modern science because it really talks about the power of basic research, the point of pure research. The truth is we don’t know how stupid we are. You don’t know what you don’t know.

Brian Brewer: If only more people realized that.

Charles Graeber: Pure research ignores the question of whether we know everything already or not entirely and just pushes the ball forward. It expands the circle of light a little bit further, and Jim Allison was one of those guys who just wanted to understand how it worked. He especially was interested in T cells. When he started with T cells his own professor of immunology told him privately during office hours he didn’t think that they actually they existed. It’s just something they were making him teach because they maybe got discovered that year, it was 1968 or so.

What Jim said, is they just seem too weird because they were so different. They were not B cells. Why would evolution create two things that did the same thing but in totally different ways? Evolution is a conservative force, it’s as if you had two kidneys, and each one of them filtered in a completely different manner. That’s not the way evolution works. It just is inefficient.

I think this is one of the more inspiring stories for young scientists. I’m actually hearing from a lot of junior scientists and wannabe scientists saying, “I didn’t know that science was so interesting. I didn’t know you could be someone who has so many interests, just be purely curious, do basic work, and have it be important.” Not all the basic work ends up being important. It’s generations of people grinding away. That ends up being really one of the most important messages of the book. And this is an encouragement to funding. Funding any organization that supports the increase of knowledge for knowledge’s sake, and maybe there are practical outcomes to that too.

Brian Brewer: For the reader who is naive to the idea of cancer immunotherapy your book draws a nice story out that involves many of the main players and people who have contributed. As Jim Allison would acknowledge, it’s no one person, no one institution. This has taken thousands of minds focused on this question over decades, and we’re fortunate to have arrived here.

This is a moment of celebration. We have reached a new place. There has been a real breakthrough. Immunotherapy doesn’t work for everyone, and that draws back to the need to do more research so that it ultimately does work in all patients.

Charles Graeber: The story you want is a story that begins with the how are we going to cure cancer and ends with we’ve cured cancer. Hopefully one day that story can be written.

Brian Brewer: We can’t wait to close our doors: okay, mission accomplished.

Charles Graeber: This is a different story. It marks and memorializes an important turning-of-the-page scientifically, the legitimizing of a field. The big deal here isn’t just the fact that we can cure cancer in a subset of patients and are saving tens of thousands of lives at the very least over what we could have done very recently, only a few years ago.

The big deal is that we now know that it works, that this is the way to go, and that this is where the solution is going to be. We were never looking here before, at least not in a well-organized, well-funded, broad fashion. You had the funding of the Cancer Research Institute and a few other flame-holders keeping this thing going.

But with the firepower now being put behind it we could do in a year what took generations, and we also know that this is the right place to look. We now know that the solution is going to involve the immune system, harnessing it, unleashing it better, a better understanding of that relationship, so this is that story. And that’s the breakthrough.

Brian Brewer: That’s a very hopeful story also. Is there anything that you want audiences that are reading this book to walk away with?

Charles Graeber: In addition to, “Hey, science is cool,” and “Wow, I didn’t realize we had made a breakthrough against cancer that’s legitimate,” an understanding that cancer immunotherapy is fundamentally different than the cut, poison, and burn approaches. That’s important for a lay audience to understand, especially a lay audience that may be dealing with cancer.

Less than five percent of all patients ever end up in a clinical trial. A lot of people think of the clinical trial as being essentially the ‘Hail Mary’: I’m willing to be a guinea pig, they might not even give me real drugs, and–

Brian Brewer: Last resort.

Charles Graeber: Last resort, and if that was ever true, it’s certainly not true now. Cancer clinical trials are largely combinations of things that have been shown to be effective individually. It’s where all the good stuff is, and we are trying to test it as quickly as possible because it’s that important.

If you get into a clinical trial, the costs of these expensive drugs go away—talking about the cost of healthcare is a separate issue, an important one, but I’m more focused on the science here.

A lot of people are still told, especially in underserved areas of the country, that really there is nothing more for them. There is nothing more they can do. When you get cancer you go to your familiars and your support group. That might include the oncologist that was trained 40 years ago, and really doesn’t still have a sense of what’s happening right now or what’s possible, who might not even know how to get you involved with immunotherapy, might not know the latest statistics, who might only be able to bill for radiation therapy or chemo.

You cited a remarkable statistic to me the other day about lung cancer, and how for many patients that diagnosis is the last time they see a doctor. Because it was considered a death sentence, and the best you could do was go home and die with dignity. Take care of your affairs. That’s not true anymore, so one thing I’d like patients, and everybody really, to walk away from this with is a sense of empowerment: the right to ask questions, the right to seek out clinical trials. Cancer Research Institute is a fantastic resource for finding out more about that, including the ones that you’re funding here. The sense of empowerment that science is not impenetrable, and it’s not someone else’s job and they just have to do whatever.

I’m having a lot of doctors read this. They then told me they now know how to explain the immune system to patients, to their own students.

I wrote this book so everyone can read it, so you can understand what’s going on, make more informed choices, and understand cancer immunotherapy. It’s not really just what’s in this book. It’s not the handful of drugs we have now and the handful of treatments. It’s the over 3,000 that are in the pipeline already and the tsunami, as the researchers call it, of drugs and treatments yet to come. So this is a way of preparing for that future.

Brian Brewer: You capture that patient experience very well in the book. You tell the story of at least two patients, one in particular you follow from soup to nuts on the journey. It wasn’t necessarily easy, and he had to really push to get into a trial, find the right trial. I really appreciate you talking about how immunotherapy is transforming the patient experience.

Charles Graeber: That patient, Jeff Schwartz in chapter one, who had a kidney cancer diagnosis, stage four, was told by his oncologist that there is nothing more they could do for him. And he believed that there was really nothing left, because nothing was working, and was discouraged from clinical trials or looking elsewhere. And that’s one of the reasons he spoke to me, and he’s very vocal about this and very animated.

I’ve gotten letters from other patients who said, “I am Jeff Schwartz…. that happened to me, too, the exact same thing happened to me. It was a different cancer. I was discouraged in the same way but I decided to do this anyway because I just happened to meet somebody that said it was a good idea. And I’m cancer free today. I have no evidence of disease, and I was told to go to hospice. And I almost didn’t make it on to a clinical trial.”

I’m realizing through these letters that this story is being repeated over and over again in this country and around the world. They’re not alone. This is building a community and giving them and their experience a voice. That’s really satisfying for me.

The Breakthrough: Immunotherapy and the Race to Cure Cancer by Charles Graeber is available on Amazon (and AmazonSmile), Barnes & Noble, and many fine independent bookstores.

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