Immunopatient: The New Frontier of Curing Cancer - Couverture rigide

Rooney, Peter

Couverture rigide

ISBN 10 : 1578267145 ISBN 13 : 9781578267149

Editeur : Hatherleigh Press, 2017

Synopsis

When an X-ray of a sore arm quickly leads to a diagnosis of Stage IV kidney cancer—one which would soon affect his bones, his lungs, lymph nodes, and brain—Peter Rooney’s life will never be the same. Faced with the prognosis of an incurable disease and armed only with the will to fight back, Immunopatient chronicles Peter’s desperate quest for hope and healing, and the experimental treatment that will give him a chance to strike back at his disease.

Detailing both the medical breakthroughs that provided Peter with cutting-edge treatment and his inspirational quest to conquer both his fear and his illness through mindfulness and positive visualization, Immunopatient is a gripping memoir, one that offers new hope to cancer patients everywhere to never give up looking for answers. Peter’s story, both humble and human, showcases the heights of medical science and the depths of human endurance, proving that anything is possible as long as you keep moving forward.

A propos du livre

À propos de l'auteur

Peter Rooney has more than a decade's experience working as an award-winning journalist for newspapers in Illinois and for the Associated Press in Berlin. Peter also worked alongside Gehrung Associates to help academic institutions tell their stories through the publication of research breakthroughs, unconventional wisdom from the social sciences, and other insights from academia. He was heading up communications at Amherst College when he was diagnosed with advanced stage kidney cancer, which had already progressed to his bones, lungs, lymph nodes and brain. He lives in Keene, NH, with his wife, Katharina.

Extrait. © Reproduit sur autorisation. Tous droits réservés.

Two days before Thanksgiving, Dr. James Mier called to tell me I had two new brain tumors.
            He delivered the bad news as gently as possible — the tumors were extremely small, they could easily be zapped with high-dose radiation, and if all went well, I’d be cancer-free once again. But still, two new brain tumors? I had made so much progress fighting cancer over the last four years, but once again, reality was intruding on my plans for healing.
            I did the best I could to take Dr. Mier at his word—he would know better than me, after all—but a question kept nagging at me. A question whose answer would have much further-reaching effects on my life and my treatment than I would have ever imagined.
            Does my immune system work in the brain the same way it works in the rest of my body?
            Dr. Mier said that, while he didn’t know the answer to that question, he was inclined to think it didn’t.
            “I’ve always been a little doubtful,” he explained. “If the immune system could get into the brain that easily, we’d all have MS by now. But you shouldn’t be discouraged. The good news is there’s no evidence of cancer in the rest of your body, which could very well mean there aren’t any cancer cells to travel to the brain and seed more tumors.”
            My reaction was, as you might expect, less than thrilled. “Cancer-free from the neck down is great and all,” I said, “but I was hoping the news would be even better.”
            “I wouldn’t be so quick to assume that the news won’t be as good as all that in the future,” Dr. Mier replied. “Remember, these small brain tumors are very receptive to radiation, and there may very well be an immune response. We just don’t know yet.”
            I paused to think for a moment before asking, “Do you think Gordon Freeman would know?”
            Dr. Mier paused as well before cautiously saying, “He might. If anybody would know, he would.”
 
 
I’d first heard the name “Gordon Freeman” about a year earlier, while basking in the afterglow of a clean scan report.
            “If you had to pick one person to thank for this,” Dr. Mier remarked while reviewing the test results with me, “it would have to be Gordon Freeman at the Farber.” Dr. Mier wore a tie and a plaid shirt beneath the traditional physician’s uniform of a white laboratory coat, his name stitched in blue cursive on the left breast pocket.
            “Who?” I asked.
            “Gordon Freeman. He’s your typical science geek. I get the sense that he doesn’t realize how important his work is going to be, but people are already talking about a Nobel Prize for this new therapy of his. And not just for developing the therapeutics, but for elucidating the pathway where the immune system just dials itself down.”
            “Is he a pure researcher, or does he see patients?” I asked.
            “He wouldn’t know what a patient is,” Dr. Mier replied as he signed off on the paperwork that gave the green light for the hospital pharmacy to create a dose of my experimental cancer treatment. “He’s a hardcore molecular biologist.”
            Dr. Mier’s eyes seemed to glow as he went on to describe exactly why pure research science is so crucial to the eventual development of drugs that may one day cure cancer. “You’re
working on something, by yourself, all the time with no idea whether it’ll be important or not,” he said. “Of course, a lot of hard work gets wasted or thrown into the waste basket because the basic idea is already incorrect. That’s the nature of experimentation. But if you’re fortunate enough to work on something that pans out in a major way, the value of that contribution is remarkable. And I think the Nobel committee may someday recognize that.”
            Dr. Mier’s words resonated with me that day, and when I returned home I sent Freeman a holiday card in which I thanked him for his research. After all, it had led to a treatment I considered almost miraculous.
            Almost a year later, with my original cancer still in remission, I sent Freeman an email, wondering whether he remembered the card and whether he might be willing to meet with me.
            I now knew that Freeman was one of four scientists with a background in immunology who collaborated and competed, preferring to zig together in their research pursuits where so
many others were zagging, and who were now being credited for their unique insights—insights which were yielding a wave of promising new cancer treatments.
            Freeman quickly agreed to meet with me. It turned out he both remembered and appreciated my card from the year before. We settled on a date and time to meet in person, shortly after which I received the news about my two new brain tumors. Suddenly, what I had originally envisioned as a more detached conversation between a cancer survivor and a leading immunologist had become more urgent.
 
 
The poet Emily Dickinson calls hope “the thing with feathers,” perhaps because the feeling itself can be so light and fleeting.
            I was becoming increasingly worried by the information I was finding online about my prospective treatment options. What I read suggested that the various types of white blood cells that constitute the body’s immune system don’t easily pass through the blood-brain barrier.
            I was quietly beginning to panic. Throughout my cancer treatments, one of the foundations of healing— for me, at least— was positive visualization. Picturing my body’s white blood cells actively hunting down and killing cancer cells had become a vital mental exercise for me, one that helped me follow the concrete, scientifically-established path to remission and restored health. But that sense of focus and momentum was in danger of becoming unpinned as I pictured an impermeable locked gate somewhere at the base of my skull, keeping out a teeming swarm of frustrated T cells.
            I was counting on Freeman to help me erase that scenario and replace it with a more hopeful image—ideally one that featured marauding T cells and melting cancer cells. Maybe he could offer some encouraging insights about how the immune system works in the brain and how it shrinks brain tumors like mine.
            I know; it was a lot to hope for.
            When I arrived, I found Freeman standing outside his office, smartly dressed in a navy blue cardigan sweater worn over a blue dress shirt and tucked into khaki pants. He offered me a slight smile and a handshake as he beckoned me into his office. Located on the fifth floor of the Dana-Farber Cancer Institute, his office was small yet cozy, with a tall window that offered a view of a cloud-shrouded dreary December day in Boston. A credenza stood nearby, crammed full with scientific journals.
            After I sat down, placing my overcoat on a nearby chair, I asked him if he would allow me to record our conversation.
“I’m not sure what I’m going to do with all of this,” I explained, “but I’m hoping to write a book about being a clinical trial patient. Getting things on tape means I don’t have to try to take down every word, and hopefully I’ll be more accurate when I try to write about the science.”
            Freeman hesitated for a moment before saying yes, he supposed that would be okay.
            Whew, I thought. Really glad he agreed to that one.
            As our conversation progressed, I soon found out that Freeman, much like other scientists at the top of their game, chose not to hide behind the esoteric vocabulary of his discipline. Throughout our talk, he demonstrated his skill at explaining the complex workings of the immune system in a way that interested “civilians” could understand. There certainly were moments when he’d say something that I only half-understood. But all it took was a hint of confusion on my part—a quizzical look, a furrowed brow—for Freeman to stop talking, consider for a moment, and come up with a better way to explain it.
            It was just such a bewildered expression that prompted Freeman to reach for his favorite metaphor to describe the complex and convoluted workings of the immune system. “We’re not talking about intelligent design here,” he said. “It’s more like ‘Rube Goldberg on a Drunken Bender.’”
            I couldn’t help laughing, startled at the vivid chaos such an image brings to mind.
            “The reason I say that,” Freeman continued, “is because the immune system is under continual assault by different infectious diseases. Each of them tries to invade, overcome, or get around the immune system in a different way. So, if you try to attack the measles virus using just one method, measles will always be quicker and more nimble. It’ll learn to evade a single attack. On the other hand, if you attack the measles virus from ten different directions, measles might be able to evade one or two of those attacks, but the other eight will get it.”
            Freeman’s insight into the immune system’s insane complexity is hard-earned. His curriculum vitae (or CV) shows not only the typical fare—things like job titles, peer reviewed papers authored, honors received, research grants awarded, and degrees earned—but also included a section for “patents awarded.” There were 48 in total at last count. His first came in 1992, and twenty-two patents were awarded between 2000 and 2006. This was when much of
the basic research that has led to the new wave of immunotherapy drugs, recently approved by the FDA, was conducted.
By the time I met with Freeman, I was fairly familiar with the science behind the experimental cancer treatment that I had been receiving for the last fourteen months. At the time, I was in a Phase 1 clinical trial at Beth Israel Deaconess Medical Center in Boston that combined two recently developed immune therapy treatments. One of them, called ipilimumab and marketed under the brand name Yervoy, had received FDA approval in 2011. The other drug was called nivolumab, brand name Opdivo, referred to by medical staff at Beth Israel as PD-1. (My shorthand for the two is ipi and nivo.) After signing a clinical trial consent form that listed over fifty-three pages of side effects noted in the trial thus far, I had been given both drugs for the first three months and nivo alone since then. Every two weeks, the drug dosage was calibrated to my body weight and given to me through an IV line, which dripped the drugs into my bloodstream over the course of an hour.
As Dr. Mier had explained it to me, the treatment kept my T cells, a type of white blood cell the body uses to fight off infection, from being turned off. This gives the cells more time to hunt down and kill the cancer cells in my body. It seemed to be a simple enough concept; I wondered why it had taken so long to discover the treatment.
The reason, as it turned out, was because scientists still have so much to discover about the molecular workings of the immune system. Freeman began studying the immune system as a doctoral student at Harvard in the 1970s, his studies eventually leading him to a Ph.D. in microbiology and molecular genetics in 1979. Two post-doctoral fellowships followed, both at the Dana-Farber Cancer Institute. He was matter-of-fact about what led him to immunology, saying that it was an “opportune” time to dive into the field, especially for someone with a personality like his, which he described as, “very curious, probably shy. Retiring, ethereal; I’m a discoverer, I’m not a tremendous political fighter. I don’t like conflict. I like peace and quiet.”    And it seems he made his choice wisely. The Farber, as he often calls it, has pretty much left him alone over the years, content to see him churning out papers, reeling in grants, and plugging away in his quest to better understand the immune system and the different types of white blood cells that comprise its fighting force, especially the T cells responsible for combatting diseases as varied as cancer and AIDS.
            In the course of becoming what he calls a “competent molecular biologist” during his post-doctoral years, he decided that the opportune thing to do was to “clone a gene,” and focused his efforts on duplicating a gene called B7. This molecule had been discovered by Arnie Freedman and Freeman while both were post-docs in Lee Nadler’s lab at the Dana-Farber, during which time they established that the B7 molecule strongly stimulated immune responses by activating T cells.
            “It was sending an important signal,” Freeman explained. “But the other thing that was surprising was that the B7 molecule had two receptors; the other receptor, which is called CTLA-4, actually turned off the immune response.”
            Even as Freeman was working to clone the B7 gene, the Human Genome Project was being launched in a massive bid to assemble a complete transcription of the tremendously complex genetic blueprint for building a human being.
            “Suddenly, instead of cloning one gene at a time, you had 25,000 to look at,” Freeman said. Their single B7 molecule had become an entire family of related B7 molecules. “We found
two more molecules called PD-L1 and PD-L2. Then, with Clive Wood at the Genetics Institute, we showed that a molecule called PD-1 was the receptor that bound to PD-L1 and PD-L2.
            “You could say one of the molecules is a key and the other is a lock—they fit into each other,” Freeman said. “So, if you want to make a drug which blocks something, what you need to do is block the key from going into the hole. If you made a blocker which binds to the part of the key that fits in your hand—the part that doesn’t interact with the lock at any point—it’s not going to prevent anything from happening. So our findings defined what the lock and key relationship was, and what its function was, which was how we showed that it inhibited immune responses.” Freeman paused for a moment to make sure I was still following him—I was, if only barely—and then continued. “This finding was a surprise, because most things are expected to increase the immune response. It was somewhat unexpected to find there were molecules that shut it down.”
            Freeman and his collaborators began pursuing a counterintuitive notion— that the mission to cure cancer and other chronic diseases could perhaps be achieved by understanding how white blood cells such as T cells and natural killer (NK) cells were turned off, rather than how they were stimulated.
            What fascinated me as I tried to visualize the experimental treatment coursing through my veins (and hopefully making its way into my brain, as well) was how Freeman and his colleagues had arrived at these particular genes to study.
            “Certainly, computer analysis was essential in our discovery,” Freeman said when I asked him about it. “We couldn’t look at and compare 25,000 things without the rapid processing capacity of a computer. But even that just gave us hints and suggestions. It didn’t prove anything. So we then had to make the molecules and make the antibodies and do the experiments in the test tubes and in mice to show just what the molecules do.”
            Curing cancer in mice using immune therapy is one thing; doing so in humans is quite another. “It’s been sort of promised for a long time, and different laboratories have cured cancer in a mouse,” Freeman said. “But none of them translated to a successful human therapy; the treatments either didn’t work in people or they were too dangerous. But now that’s changed.”
            What also changed was the willingness of Freeman and other immunologists to look at the puzzle of curing cancer in a new way, by focusing on what turns off the immune system, and then trying to devise ways to prevent that from happening.
            “The old idea was always ‘stimulate the immune response to make it stronger,’” Freeman explained. “Vaccination is a great example of this, and is wonderfully successful at preventing, say, smallpox, because your body has never seen smallpox before—you can make an antibody against it when you’re vaccinated. What we realize now is that cancer is a chronic disease. When you go into your doctor’s office because of how you’re feeling and get a diagnosis of cancer, it’s not something that just happened. It’s been a five, ten, or twenty year development. Throughout that period, your immune system has been looking at the cancer and trying to fight it off. When it succeeds, you don’t go to the doctor’s office; you never experienced any problems from it. But when the immune system fails, it’s because the cancer has learned to evade the immune system. That’s when it becomes a real problem.
“What we’ve since learned is that the immune system has multiple ways to turn off its immune response, one of which is the expression of the PD-L1 molecule. When expressed, PD-L1 basically acts as a shield or a cloak on the tumor and keeps the immune system from attacking it successfully.”
            For some time, I’d noticed Freeman occasionally glancing at a clear glass rectangular box mounted on a platform on his desk. Suspended inside the glass appeared to be two wispy strands.
            “Is that a model of the PD-1 molecule, by chance?” I asked.
            “It is indeed,” he said with an eager grin, reaching over to grab it. “You can see that the PDL-1 fits into this surface right here on the PD-1. That ‘lock and key’ interaction turns off the PD-1, which then shuts down the immune response, allowing the cancer to grow. The drugs are basically things that bind or cover over either the lock or the key. You can bind to the PD-1 side, or the PD-L1 side; both will work.”
            Freeman didn’t develop the drug itself. That task was taken on by Alan Korman and Nils Longren (among others), scientists at Medarex, a biotechnology company that was acquired by Bristol- Myers Squibb for $2.4 billion in 2009. Already, Korman and Longren had successfully converted the B7 molecule’s CTLA-4 mechanism discovered by Freeman and his team into an antibody, which eventually became the ipi (or Yervoy) currently residing-- and hopefully working--in my system.
            Since then, several immune therapy cancer treatments that modulate T-cells have entered clinical trials. Bristol-Myers Squibb’s Yervoy (ipilimumab) is based on the CTLA-4 mechanism and was approved by the FDA in 2011 for metastatic melanoma. Another Bristol-Myers Squibb product, Opdivo (nivolumab), which is based on blocking PD-1, was given FDA approval in December 2014 for the treatment of advanced melanoma and squamous non-small cell lung cancer, and has also been approved for use in Japan and Europe. Meanwhile, Merck & Co.’s Keytruda (pembrolizumab) surprised many pharmaceutical industry observers by being the first PD-1 drug approved by the FDA in the United States, receiving the green light in September 2014.
            While analysts predict that these drugs will be expensive, with treatment courses costing $100,000 or more, they are also likely to be pervasive, with experts like Freeman predicting that
immune therapies will supplant chemotherapy as a first line cancer treatment within five to ten years.
            Exactly how much money will come to Freeman and Dana- Farber as a result of nivolumab’s development remains to be seen, and will be determined by royalty rates negotiated by Dana-Farber on the patent claims that pertain to the development of nivolumab and other immune therapies that draw upon Freeman’s work.
            Financial benefits notwithstanding, Freeman says his true passion remains his work to better understand the immune system so that cancer and other chronic diseases like hepatitis and AIDS can be conquered (or at least tamed).
            Curious, I asked whether Freeman felt vindicated in his decades long quest to better understand the molecular machinations of the immune system and to use such understanding to fight disease. He smiled broadly and said, “Absolutely.”
            “Why is that?” I asked.
            “Five years ago, if I said I was doing immunotherapy in cancer, the response would have been, ‘It’s a nice idea, but it’s not in your doctor’s office.’ For a long time, immunotherapy was a nice idea, but not successful. Ipi and nivo have really brought some success. It feels good because it shows that the ideas you’ve championed for so long are working. You really can successfully treat cancer if you can block the cancer from inhibiting the immune response.”
            Since the initial research that led to the development of nivolumab and other PD-1-based treatments, Freeman and others have discovered that inhibition by PD-1 is a common occurrence
in the body’s immune system, and that certain chronic diseases such as tuberculosis, malaria, hepatitis C, and AIDS cause T cells to become laden with PD-1 molecules, each of them an off switch waiting to be flipped.
            “In all of these diseases, the immune system tries to fight the disease, doesn’t succeed, and then the immune system just goes quiet,” Freeman said. “It tunes down. It keeps attacking, but only moderately. It finds a balance.
            “Say you have hepatitis. Your body doesn’t want to attack it so strongly that it destroys the liver, because you can’t live without a liver. So, you attack and keep the virus low, but you don’t burn it out.
            “What we’ve also realized is that in all these chronic infections, the T cells that are attacking the disease have lots of PD-1 molecules on them. They’re always susceptible to being turned off by PD-L1. And cancer, we now recognize, is like a chronic disease. It’s not
like a T cell coming across a tumor is seeing it for the first time. It’s been there 100 times in the last ten years.”
 
 
This all sounded very encouraging, yet there was still the issue of the brain and whether there was any reason to believe my body’s T cells, their off switches shielded to extend their life spans, could find their way into my brain.
            “What kind of treatment are you on, by the way?” Freeman asked, taking a break from his explanation.
            I quickly described my treatment and the clinical trial’s parameters: I had been on the trial since July 2013, and I was among the half of about 130 patients in the trial who had received a lower dose of ipi, one milligram per kilogram of body weight, compared to three milligrams per kilogram for the other half. We were all receiving a nivo dose of three milligrams per kilogram.
            “I got the results of my last scans after you and I set up our meeting,” I told Freeman. “It was good news from the neck down, but there are two new small tumors in the brain. I’m
happy about everything, but obviously I’m worried about what’s going on upstairs. There’s also a little concern about some swelling they’re seeing on a spot I had treated about two years ago. Tomorrow I go in for a Cyberknife treatment to zap the two spots on the brain.”
            I shifted nervously in my seat. “I guess that leads me to my current dilemma, which I see as a roadblock on my path to healing. I’m very much interested in the science of my treatment, but I’ve also been reading about the connection between the mind and the body, the power of the placebo effect, things like that.”
            I paused to see whether he was rolling his eyes yet. He wasn’t, which was encouraging, so I continued. “Where I’ve hit a bit of a dead end is that so much of what I’m reading suggests that the immune system doesn’t really penetrate the blood-brain barrier. That’s a good thing, I guess, because the cells in the brain are so densely packed that you’d see a lot of swelling if there were a lot of white blood cells up there. So I’m wondering if you could tell me a little about the immune system and whether it works in the brain.”
            Left unsaid but hopefully understood was my real question: Is there any reason to hope my immune system can fight cancer in the brain?
            “Basically,” Freeman began, “the blood vessels of the brain have a tighter fit than blood vessels in, say, your legs. So they can keep drugs from getting in and out. But white blood cells can still get in and out. For instance, the brain cancer that scientists conduct the most research on is glioblastoma. If you start glioblastoma in a mouse brain and treat it with CTLA-4 and PD-1, the tumor gets attacked and eliminated. So immune cells can attack brain tumors. In fact, I think people are now starting to de-emphasize just how tight the blood brain barrier is against T cell attack.”
            “That’s great,” I said. “I’m looking for something to be hopeful about.”
            “You’re an example of a combination therapy,” he replied. “Nivo plus ipi. The good thing about that is it’s the most successful combination we’ve seen so far. But we’re also seeing that many things can work with PD-1 to make the response rate even higher, including other immunological drugs, certain chemotherapies, and even radiation.”
            This gave me some pause. During the course of fighting my cancer, I had come to the grim realization that all cancer treatments extract their toll. Radiation may kill cancer cells, but it can also encourage mutations that lead to cancer later on. Xgeva, a drug I took to help rebuild radiated bone in my left humerus and right femur, can also cause necrosis in jawbones. Chemotherapy, in the form of an infusion or pill, has very serious side effects as well, but so far I had not needed to endure them.
            “I’m getting radiation tomorrow,” I told him. “It’s called a Cyberknife, but it’s really a high dose of focused radiation on those two spots.”
            He nodded and offered some more perspective from the cutting edge of cancer research. “Five years ago, I would have said radiation just kills cells directly,” he said. “But it’s since become clear that radiation has a lot of effects on the immune system, as well. In a mouse, if you radiate a tumor in the arm, you can spark an immune activation which will attack a tumor in, say, the liver. Radiation and PD-1 can also synergize and work together to attack cancer cells all over the body.”
            “In the brain, as well?” I asked.
            He nodded. “Again, I think the immune system accesses the brain. The worry isn’t that it can’t access the brain; it’s more that if you get brain swelling, do you have to treat with steroids to dampen things down?”
            He quickly added a qualifier: “Remember, I’m not a physician, so don’t take any of this as medical fact.”
            “Don’t worry about that,” I replied. “But I still really appreciate the insight. And I really appreciate your work on all of this, and for sticking with it for so long.”
            I stood up to leave, but before heading out, I asked whether I could take some photos of him at his desk. He graciously agreed, and between shots he stressed how quickly the field of immunotherapy is evolving and how promising the new treatments seem to be, primarily because their application allows for multiple angles of treatment approach.
            “The weakness of classic chemotherapy is that it’s focused on one target,” he said. “It can work initially, but the tumor learns to evade the attack. Ten months later, the chemotherapy doesn’t work any longer. The difference with immunotherapy is that it lets the immune system attack the cancer eight or ten different ways. It’s harder for the tumor to learn to evade lots of different ways of attack.”
            He offered a mild-mannered smile. “I sort of think of it as attacking with a machine gun rather than a single shooter.”
            As I exited his office, a number of young Dana-Farber employees just outside Freeman’s door glanced up at me from their computer workstations. I briefly wondered how much of our conversation they had heard. Already I was feeling more optimistic about the future. I knew that my outward appearance betrayed no evidence of the cancer in my body, which was now confined to only a few small spots in my brain. And if science, my mind, and my body had anything to say about it, even those would be gone soon enough.

Détails de l'édition

• Éditeur: Hatherleigh Press
• Date d'édition: 2017
• Langue: anglais
• ISBN 10: 1578267145
• ISBN 13: 9781578267149
• Reliure: Relié
• Nombre de pages: 208
• Coordonnées du fabricant: non disponible
• Personne responsable: non disponible