1. Rube Goldberg on a Drunken Bender, or How I Hope my Immune System Fights Cancer

 

Rube on bender

Dr. James Mier called me two days before Thanksgiving 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 felt 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 him at his word, but a question kept nagging at me — does my immune system work in the brain, like it has been in the rest of my body? 

Dr. Mier said he didn’t know the answer to that question but was inclined to think it didn’t.

“I’ve always been a little doubtful,” he said. “If the immune system got into the brain easily, we’d all have MS by now. But you shouldn’t be discouraged, because the good news is there’s no evidence of cancer in the rest of your body. That could very well mean there aren’t any cancer cells to travel to the brain and seed more tumors.”

“Cancer free from the neck down is great and all,” I said. “I was just hoping the news would be even better.”

“I wouldn’t assume that the news won’t be good,” Mier said. “Remember, these small brain tumors are very receptive to radiation, and there may very well be an immune response as well. We just don’t know yet.”

“Do you think Gordon Freeman would know?” I asked.

Mier paused. “He might. If anybody would know, he would.”

ABOUT A YEAR EARLIER, in the jubilant and thankful afterglow of a clean scan report, Mier had first mentioned his name.

“If you had to give credit to one person who is helping you so much, it would have to be Gordon Freeman at the Farber,” Mier had said. “He’s a typical science geek. I don’t have the sense that he realized how important this was going to be. But there are people talking about this winning the Nobel Prize, not just for developing the therapeutics, but for elucidating the pathway where the immune system just dials itself down.”

Standing at my bedside, Mier wore a tie and a plaid shirt beneath the traditional physician’s uniform of a white laboratory coat. His name was stitched in blue cursive on a left breast pocket, from which he produced a pen.

“Is he a pure researcher or does he see patients?” I asked.

Mier reviewed the results of my blood draw and signed off on paperwork that would give the green light for the hospital pharmacy to mix up a dose of my experimental cancer treatment.

“He wouldn’t know what a patient is,” Mier said. “He’s a hardcore molecular biologist.”

Mier’s eyes glowed as he described why pure research science is so vital a human enterprise, and so crucial to the eventual development of drugs that may one day cure cancer, in at least some patients, and perhaps someday in all.

“You are really working on something by yourself and you have no idea if it’s important or not,” he said. “A lot of these notions get jettisoned or Frisbee-ed into the waste basket because the idea is already incorrect. 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.”

Mier’s words resonated, that day, and later as well. When I returned home, I sent Freeman a holiday card in which I thanked him for his research, which, after all, had led to a treatment I considered almost miraculous. Almost a year later, as my cancer remained in remission, I sent him an email, wondering whether he by chance 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, zigging together in their research pursuits when so many others were zagging, and who now were being credited for insights that were yielding a wave of promising new cancer treatments.

(In addition to Freeman, the other scientists are Lieping Chen of Yale University School of Medicine, Tasuku Honjo of Kyoto University School of Medicine, and Freeman’s wife, Arlene Sharpe of Harvard Medical School. They are beginning to gain more recognition, as a group and as individuals. For example, the four received the 2014 William B. Coley Award for Distinguished Research in Tumor Immunology from the Cancer Research Institute, which for several decades has advocated using the body’s own immune system to fight cancer. The award was for each scientist’s research surrounding molecules that Honjo first discovered, molecules that have a curious function in the body’s ridiculously complex immune system: they tell it to stand down after fighting off an infection.)

Freeman quickly agreed to meet with me. He remembered and appreciated my card from the year before. The news about my two new brain tumors came shortly after we settled upon a date and time to meet. What I had originally envisioned as a more detached conversation between a cancer survivor and a leading immunologist became much more urgent, a lifeboat that might offer some reason for hope.

I was especially worried by information I was uncovering online that suggested that the various types of white blood cells that constituted the immune system didn’t easily pass through the blood-brain barrier.

In my mind at least, the foundations of a cancer fighting regimen I had developed that included meditation and visualization exercises were in danger of becoming unpinned, unless I could envision a path to healing in the brain, ideally one that was backed by science. After all, how could I imagine T cells attacking and killing cancer cells if those same T cells couldn’t even make it to my brain?

Maybe Freeman could help me find a path around this possible dead end. Maybe he had some encouraging insights about the immune system, and the extent to which it continues to function in the brain. Maybe he could even provide me some cancer-fighting images to focus upon during those restless early morning hours when sleep was hard to come by.

It was a lot to hope for.

 

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                                                  Gordon Freeman, in his office at Dana Farber

Freeman himself was standing outside his office when I arrived. Wearing a navy blue cardigan sweater over a blue dress shirt tucked into khaki colored pants, he offered a slight smile and a handshake as he beckoned me into his office. It was on the fifth floor of the Dana Farber Cancer Institute, small but cozy, with a tall window that offered a view of a cloud-shrouded dreary December day in Boston. A credenza was stacked with scientific journals. After I sat down, placed my overcoat on a nearby chair and closed the door, I asked to record our conversation.

“I’m not sure what I’m going to do with all of this, but I’m hoping to write a book about being a clinical trial patient,” I said. “If you’re OK with me taping I don’t have to try to take every word down. And hopefully I’ll be more accurate when I try to write about the science.”

Freeman hesitated for a moment before saying yes, he guessed it would be OK.

Whew. Really glad he agreed to that one.

I started my recording app, hoped it wouldn’t go buggy on me, and positioned my iPhone on his desk to better pick up his voice.

As it turned out, Freeman has something in common with other scientists at the top of their game. He doesn’t hide behind the esoteric vocabulary of his discipline, and can explain the complex workings of the immune system in a way that most interested “civilians” can understand. Sure, there will be moments during an explanation when he’ll say something that you only understand faintly, in a general sense, and you may show confusion on your face.

That’s when he’s likely to reach for a favorite metaphor that reveals his wry sense of humor.

“We’re not talking about intelligent design here,” he told me, when I asked to provide a visual description of how the body’s immune system looks and operates. “It’s more like ‘Rube Goldberg on a Drunken Bender.’”

I couldn’t help laughing, startled at the vivid and chaotic image that sprang to mind and looked something like this:

“The reason I say that,” Freeman said, “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 just one way, measles will be quicker and more nimble. It’ll learn to evade a single attack. On the other hand, if you attack the measles virus from 10 different directions, measles might be able to evade one or two of those attacks, but the other eight will get it.”

The Rube Goldberg analogy is familiar to some, but not all. Webster’s has considered Rube Goldberg to be an adjective since 1932 to refer to doing something simple in a very complicated way. The word is derived from a popular cartoon panel that appeared in newspapers during the 1920s and 1930s. Penned by Rube Goldberg, an engineer turned Pulitzer Prize winning cartoonist, the cartoons were schematic drawings dreamed up by one of his characters, Professor Lucifer Gorgonzola Butts, for machines that used not only belts, pulleys and levers, but also animals, auto bumpers, buckets, shoes, paddles, and sometimes canary cages. Goldberg depicted these contraptions with artistic flair in black pen and ink drawings that were accompanied by clever captions, including this one for “closing a window if it starts to rain while you’re away”:

Pet bull frog, A, homesick for water, hears rainstorm and jumps for joy, pulling string, B, which opens catch, C, and releases hot water bag, D, allowing it to slide under chair, E. Heat raises yeast, F, lifting disc, G, which causes hook, H ,to release spring, I. Toy automobile bumper, J, socks monkey, K, in the neck putting him down for the count on table, L. He staggers to his feet and slips on banana peel, M. He instinctively reaches for flying rings, N, to avoid further disaster and his weight pulls rope, O, closing window, P, stopping the rain from leaking through on the family downstairs and thinning their soup.

Freeman’s insight that the immune system is insanely complex is hard earned, and reflected in his curriculum vitae, or CV. Typical CVs in academia cite things like job titles, peer reviewed papers authored, presentations given, graduate students trained, honors received, research grants awarded and degrees earned. Freeman’s CV included all of this, along with a section I hadn’t encountered before, for patents awarded. There were 48 total in this section, his first in 1992 and his most recent in 2014, along with 22 from 2000 to 2006, when much of the basic research was conducted that has led to the new wave of immunotherapy drugs that have been recently approved by the FDA.

By the time I met with Freeman, I had read and been told much about the science behind the experimental cancer treatment that I had been receiving for the last 14 months. 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. Medical staff at Beth Israel also called it PD-1. My shorthand for the two was ipi and nivo. After signing a clinical trial consent form that listed over 53 pages of the side effects noted thus far in both drugs, I had been given both drugs for the first three months of the trial 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 through a plastic bolus bag, over the course of an hour.

As Mier had explained it to me, the treatment kept my T cells, a type of white blood cell, from being turned off, thus giving them 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 is because scientists still have so much to discover about the molecular workings of the immune system, which Freeman began studying as a doctoral student at Harvard in the 1970s. Freeman had arrived at Harvard as an undergraduate from Fort Worth, Texas, after thriving in a summer research program that the National Science Foundation had launched at the University of Texas Austin and other locations around the country.

“This was shortly after Sputnik was launched,” Freeman said, referring to the first artificial satellite, which was designed, built and launched by the Soviet Union in 1957. “There was a great deal of fear that Russian science was way ahead of us and we needed to catch up. So the government funded science education a great deal in the ’60s, which is when I was going to high school.”

Freeman said the experience working in the laboratory that summer showed him that he measured up to bright people from around the country. “You never know whether you’re a big fish in a little pond or whether you can play in the major leagues,” he said. “People there encouraged me to apply to good colleges, and I got into Harvard. So I went from Texas to Harvard and I’ve been here since.”

Freeman graduated from Harvard in 1973 with a major in biochemistry and molecular biology, and his graduate work studying viruses in animals led to a Ph.D. in microbiology and molecular genetics in 1979. Two post-doctoral fellowships followed, both at Dana Farber Cancer Institute. He’s 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 describes 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.”

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, which are 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-doc years, he decided that the “opportune thing to do was to clone a gene” and focused on cloning a gene called B7. This molecule had been discovered by Arnie Freedman and Freeman while post-docs in Lee Nadler’s lab at the Dana-Farber. They also established that the B7 molecule strongly stimulated immune responses by activating T-cells.

“It was sending an important signal,” Freeman said. “But then the other thing that was surprising was that the B7 molecule had 2 receptors and the other receptor, which is called CTLA4, turned off the immune response.”

While Freeman was cloning the B7 gene, the Human Genome Project was being launched, in a massive bid to assemble the complete, and 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. Soon their single B-7 became a family of related B-7 molecules. “We started looking and asking what was related to our B7 molecule. We found two 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.”

I was pecking away on my laptop in my loud but fast hunt-and peck style, trying to keep up with Freeman. While I was recording the conversation, technology had failed me too many times to trust the infallibility of the voice recorder app I was using. I was about to ask what a ligand was when Freeman shot me a glance that betrayed just the slightest hint of irritation in my awkward method for conducting my interview. The look told me, essentially,quit typing and just listen. And so I did, with a quick glance to my recorder to ensure that it was still recording. It was.

“These receptors are sort of like a lock and a key,” Freeman said. “You could call one of the molecules a key and the other is a lock, and they fit into each other. If you want to make a drug which blocks something, what you need to do is block the key going into the hole. If instead you make a blocker which binds to the part of the key that fits in your hand it’s not going to prevent anything from happening. So our finding defined what the lock and key relationship was, and what its function was, which was that we showed that it inhibited immune responses.

Freeman paused to make sure I was following him and then continued. “This finding was a surprise, because most things were expected to increase the immune response, to activate it,” he said. “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 cell types such as T-cells andNatural Killer cells were turned off rather than by how they were stimulated. What fascinated me as I tried to visualize the experimental treatment that now was 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. “We couldn’t look at and compare 25,000 things without being able to be able to do it with the rapid processing of the computer. But 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 what it does.”

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 in fact cured cancer in a mouse,” Freeman said. “But none of them translated to a successful human therapy; they either didn’t work in people or they were too dangerous. That’s changed.”

What also changed was a willingness by 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 real difference in the PD-1 therapy is that the old idea was always ‘stimulate the immune response to make it stronger,’” Freeman said. “Vaccination is a great example of this and is wonderfully successful at preventing smallpox. Because your body has never seen smallpox before you can make an antibody against it when you’re vaccinated. Whereas what we’ve realized 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, this is not something that just happened. It’s been a five, ten or 20 year development. Throughout that period your immune system has been trying to look at the cancer and fight it off. When it succeeds you never go to the doctor’s office, you never have any problems. But when the immune system fails the cancer learns to evade the immune system and becomes a real problem. What we’ve learned is that the immune system has multiple ways to turn off the immune response. One of them is the expression of the PD-L1 molecule. That basically acts as a shield or a cloak on the tumor site and keeps the immune system from attacking it successfully.”

For some time, I had noticed that Freeman would occasionally glance at a clear glass rectangular box mounted on a platform on his desk. 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 and he reached over to grab it. He pointed out how the PD-1 molecule fit snugly into the PD-L1 molecule, creating the lock and key effect that resulted in T-cells turning themselves off and thus in some cases allowing cancer cells to grow and multiply.

“You can see that the PDL-1 fits into this surface right here on the PD-1,” Freeman said. “That lock and key turns off the PD-1 which then shuts down an immune response. The drugs are basically things that bind or cover over 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, among others, Alan Korman and Nils Longren, two 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 CTLA mechanism into an antibody that eventually became ipi or Yervoy. Thus it was perhaps not surprising that the two scientists had been closely following the research about PD-1 that Freeman and his colleagues had been publishing.

“They’re basically reading our papers, and they had already made CTLA4, so they knew if you blocked inhibitory molecules that you could potentially have a therapeutic effect,” Freeman said. “They saw that PD 1 and PD-L1 inhibit the immune response and said, ‘Let’s make a blocker and see if it’s therapeutic.’”

Several immune therapy cancer treatments that modulate T- cells have entered clinical trials. Bristol-Myers Squibb’ Yervoy, or ipilimumab, is based on the CTLA4 mechanism and was approved by the FDA in 2011 for melanoma. Its Opdivo or nivolumab, which is based upon PD-1, was given FDA approval in late December 2014 for the treatment of advanced melanoma, and has been approved for use in Japan and Europe as well. Meanwhile, Merck’s Keytruda, or pembrolizumab, surprised many pharmaceutical industry observers by being the first PD-1 drug approved by the FDA in the United States, in September 2014. In March 2015, nivolumab was approved for squamous non-small cell lung cancer. The results of the clinical trial comparing nivolumab with chemotherapy in that type of lung cancer showed nivolumab was so much better that the trial was stopped early and the drug approved. Analysts are predicting that these drugs will be expensive, with treatment courses costing $100,000 or more. Provided questions about costs can be worked out they also will likely 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 specific patent claims that pertain to the development of nivolumab and other immune therapies that draw upon Freeman’s work.

“I would benefit if we and the company look at the patent and agree that it covers their drug,” he said, adding that such royalties help Dana Farber sustain its commitment to innovative cancer research while also providing a tangible incentive for researchers like himself. He stressed that the non-exclusive licensing agreements ensured that numerous companies had access to developing treatments based on the PD1 research of him and others.

“We didn’t license the patents exclusively, we licensed them non-exclusively,” he said. “We think that’s encouraged multiple companies to feel that they have the commercial freedom to develop products in the field.”

Financial benefits notwithstanding, Freeman said his true passion remained working to better understand the immune system so that cancer and other chronic diseases like hepatitis and AIDS could be conquered or at least tamed to extend life in patients.

“I’m not a physician,” he said. “I don’t see patients. What I do is discovery. Basically I make a discovery, I publish it, people see it, and in this case the pharmaceutical companies thought it was a good enough idea to develop into a drug therapy.”

I asked whether Freeman felt vindicated by 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,’” Freeman said. “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 the PD-1 molecules, each of them an off switch waiting to be pulled.

“In all of these diseases, it turns out that the immune system tries to fight the disease, doesn’t succeed and then the immune system goes quiet,” Freeman said. “It tunes down. It keeps attacking, but just moderately. It finds a balance. Say you have hepatitis. You don’t want to attack so strongly that you destroy 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 now is that in all these chronic infections the T cells that are attacking the disease have lots of PD-1 molecules on them, so they’re susceptible to being turned off by PD-L1. 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 10 years.”

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. In addition to radiation treatment to my brain and to bones in my left arm and right leg, I’d been getting plenty of radiation from the occasional brain MRI, along with quarterly CT scans. Xgeva, a drug I took to help rebuild radiated bone in my left humerus and right femur, could also cause necrosis in jawbones. Chemotherapy, in the form of an infusion or pill, had very serious side effects as well, but so far I had not needed to endure them. In reviewing the consent form for my Phase One clinical trial, I noticed that the side effects listed for ipimilumab were more serious that those listed for nivulomab. Freeman said scientists conducting experiments with knockout mice (so called because certain genes are “knocked out” of them when they are bred) were the first to discover the bad things that could happen if you blocked those genes.

“In terms of the two drugs — the CTLA 4 versus the PD-1 — you can get some idea of whether to treat forever with these drugs or not by making what is called a knockout mouse,” he said, explaining that one of his colleagues (and wife), Arlene Sharpe, successfully bred a mouse without the gene for CTLA4. “Arlene is one of the leaders in the PD-1 field,” he said. “When she knocked out CTLA4, three weeks after they were born they died of automimmune attacks. What that shows is that you wouldn’t want to block CTLA4 for a lifetime. It’s pretty clear you want to treat and stop.”

In separate experiments, Freeman said that Honjo in Japan and Sharpe bred knockout mice without the PD-1 genes. “The result was that it’s a normal mouse and that mouse has a long lifetime,” Freeman said. “When it’s an old mouse, let’s say a year or two old, that mouse may develop symptoms of nephritis (kidney inflammation). It’s not life threatening; it’s pretty mild.”

— — — — — — — — — — — — — — — — — — — — — — — –

“What kind of treatment are you on, by the way?” Freeman asked.

The question brought me back to my current situation, and a topic I was eager yet also nervous about discussing with Freeman: 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. I quickly explained my treatment and the clinical trial’s parameters, that 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 all were receiving a nivo dose of three milligrams per kilogram, and I had been on the trial since July 2013.

“So 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’s two new small tumors in the brain.

“So I’m happy about everything, but obviously I’m worried about what’s going on upstairs,” I said, pointing to my head. “Tomorrow I go in for a Cyberknife treatment to zap the two spots on the brain. They’re also a little concerned about some swelling they’re seeing on a spot I had treated about two years ago.”

I shifted nervously in my seat. “I guess that leads to this dilemma, which I see as a road block on my path to healing. I’m very much interested in science, including what I’ve been reading about the connection between the mind and the body, the power of the placebo effect, and things like that.”

I paused and looked at him to see whether he was rolling his eyes yet. He wasn’t, so I continued.

“What’s a bit of a dead end for me is that much of what I’m reading suggests that the immune system doesn’t really penetrate the blood brain barrier,” I said. “That’s a good thing, I guess, because the cells are so densely packed up there and you’d have 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 expressed was — is there any reason to hope the immune system can fight cancer in the brain?

I didn’t need to say it out loud; Freeman knew what I was getting at.

“You’re referring to the blood brain barrier,” he said. “Basically 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 the white blood cells can get in and out. For instance, the brain cancer that scientists conduct the most research on is glioblastoma. But if you start glioblastoma in a mouse brain and treat it with CTLA4 and PD-1, we’ve shown the tumor gets attacked and eliminated. So the immune cells can attack brain tumors. I think people are now de-emphasizing how tight the blood brain barrier is to 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 said. “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.”

“Radiation?” I said. “I’m getting radiation tomorrow. It’s called a Cyberknife but it’s really high dose, focused radiation on the 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. “It’s become clear that radiation has a lot of effects on the immune system also. In a mouse, if you radiate a tumor in the arm, you can get immune activation which will attack a tumor in say the liver. Radiation and PD1 can also synergize and work together to attack cancer cells all over the body.”

“Maybe in the brain as well?” I asked.

“Again, I think the immune system accesses the brain,” he said. “I think 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 said. “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.”

As I stood up, I asked whether I could take some photos of him at his desk, with the model of the PD1 and PDL-1 molecules on top of it. He graciously agreed, and between shots he stressed how quickly the field of immunotherapy is evolving and how promising new treatments appear to be, primarily because they can be used with each other to fight cancer cells from many angles.

“The weakness of classic chemotherapy is that it’s focused on one target,” he said. “You can blow that away but the tumor learns to evade an attack. With just one target, 10 months later the chemotherapy doesn’t work any longer. The difference with immunotherapy is that it’s letting 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. I sort of think of it as ‘you’re attacking with a machine gun rather than a single shooter.’”

He offered a mild-mannered smile, but there was gleam in his eyes that reminded me of his namesake in the popular shooter game Half Life, in which a silent theoretical physicist named Gordon Freeman blasts away at alien creatures and soldiers from the villainous Combine Corporation with all kinds of deadly weaponry, including a crowbar. Gordon likes to think of nivo as a little crowbar that keeps PD-1 and PD-L1 apart.

 

gordon freeman

                                                                      The Other Gordon Freeman

As I exited his office, I noticed a number of young Dana Farber employees just outside Freeman’s door glancing up at me from their computer workstations as I walked past them. I briefly wondered how much of our conversation they had heard. My outward appearance betrayed no evidence of the cancer in my body, by now confined only to a few small spots in my brain. And if science, along with my mind and body, had anything to say about it, those would be gone soon enough.

2 thoughts on “1. Rube Goldberg on a Drunken Bender, or How I Hope my Immune System Fights Cancer

  1. Fascinating article and conversation on evolution of immunotherapy with one of the founding fathers. It would be interesting to know or speculate as to how long does the effect of infusion of an immunotherapy drug last? If it appears to work and control lesions is the effect temporary till the activated immune system goes back to its old depleted state? If so how long ? Does anyone know?

    1. These are great questions; thank you for your feedback. As the fine print in many drug advertisements notes, “individual results may vary!” Dr. Freeman did show me a graph from a presentation he had prepared that showed a substantial number of participants in a nivo-ipi combo trial who had to leave the trial because of side effects nevertheless have had an enduring response. I continue to receive a nivo-only infusion every two weeks, and it is unclear how long BMS will continue the trial that I am on. Other questions that will need to be addressed: Can the same immunotherapies be used to rechallenge tumors effectively if they come back after treatment has stopped? What is the ideal recommended dosage — every two weeks? every three weeks (Keytruda, Merck’s similar product, is every three weeks.)? These drugs are priced very high, so these are very important questions to answer if immunotherapy is to be of benefit to a large number of cancer patients.

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