“I think I am still interested,” I say. “Let’s say yes?” But now that I have the option of really doing this, I question whether I ought to. I’m cautiously optimistic about the ipi, but know next to nothing about the other drug or its effectiveness and potential consequences. And my consent to doing the trial means not starting immediately on the previously planned single ipi treatment—a nerve-racking delay in getting medicine into me while I’m still playing beat the clock with my fast-acting cancer cells. I remember Steve’s encouraging words, but I cannot forget that in most of the movies and television shows I’ve ever seen, trials are scary. Trials are what you do when you’ve given up on real medicine. One step above copper bracelets and cannabis oil. What if they give me this weird new drug and it doesn’t work, or it makes me even sicker but I’ve signed off on being a test subject so I’m stuck with it? What if my cancer gets a lot worse while I’m waiting to start the trial? What if I don’t even get the drugs? That happens, right? Isn’t the whole point of trials that some people get the real drugs and some people get empty useless pills that do nothing?
I say something quite like this, in one big torrent of skepticism and paranoia, when I come back to Memorial for yet another meeting.
Dr. Wolchok is a good doctor because he doesn’t look at me like I’m being irrational. He looks at me like he can help. “First of all,” he says, “most trials don’t involve placebos. That’s usually only in later phases. Second, even in those kinds of trials we continue to treat patients. It’s not like they’re getting nothing; they get the standard of care. Finally, if the trial is not working for someone, or the patient doesn’t want to continue for any reason, we can stop at any time and switch to conventional treatment.”
I am feeling reassured. A little excited. Hopeful, even. These people don’t see me as just an experiment. They want to treat me, as a patient.
Only about 3 percent of eligible adults with cancer participate in clinical trials, and 40 percent of trials never attain their minimum enrollment. Who wants some medical Russian roulette when there are FDA-approved options out there? I am scared too. But for me, the choice is clear. The melanin-producing cells in my body are incredibly resilient. They were designed to be mobile and adaptable—that’s why they let me freckle in the summer sun. That’s why melanoma tends to fend off chemo and radiation like King Kong swatting biplanes. I don’t have time to wait for the new mystery drug to make it safely to the general market, and I don’t have a whole lot of other options. And there’s something else—the most important and reassuring thing of all. My doctors think this combination has a realistic shot at working on me. As Dr. Wolchok tells me, “This isn’t a last course of action. It’s a first one.”
But before I get started, I have to prove myself truly worthy. Being asked if you’d like to be in a clinical trial is like being accepted into Harvard—you still have to be able to pay for it. The difference here is I don’t have to write a check; I just have to submit to a battery of pretrial tests. I need to hit the sweet spot of being sufficiently diseased for the doctors to have something to work with and measure, and healthy enough to withstand whatever it is they’re about to unleash on my system. I will later learn, when I read the trial results, that part of my qualifications include having “adequate organ function” and “a life expectancy of at least four months,” so I’ve got that going for me, which is nice. It’s funny the things that become your standards of victory when you’ve got Stage 4 cancer. When I read a medical report that describes my pelvic organs as “unremarkable,” I recall, there was probably a time I would have considered that a tad unflattering. When I see that one of the doctors on the immunology team has described me, after a routine consult, as a “well-developed, well-nourished female in no apparent distress,” I think it sounds a little like he’s describing a cow or a goat he’s thinking of purchasing. But I’m eminently glad of it nonetheless.
“All right, then,” I say. “Let’s do this.”
“Let’s do this,” Dr. Wolchok affirms. “We’ll get you started on the next part of the process next week.”
That night, I sleep more soundly than I have since that random nurse told me I was Stage 4. I am bug free, and if I pass all the screening tests, I could be getting two superexpensive cancer drugs free, courtesy of medical research. Because it’s a trial, Bristol-Myers Squibb would be footing the bill. My regular doctor visits and tests would still be the responsibility of my insurance and me. But all aspects of the treatment itself would be on them. This is better than Groupon. The next morning, I sip some water and down a few spoonfuls of yogurt, and nothing violent happens in my body. Maybe I’ll live after all.
INTERLUDE
How to Make a Drug
Though it’s gained an unprecedented degree of cachet recently, it hasn’t been so long since immunotherapy was a supertough sell. It was hard just to explain. A lot of people assume that treating cancer means chemo and/or radiation. I’ve certainly fended off the questions myself, from well-meaning, small talk–making friends and relations. How was your chemo? When do you start chemo? It’s chemo, right? Immunotherapy is not chemo. Yes, there’s an infusion involved, but not everything dispensed in an IV bag with a “High Alert” warning is chemo. And not getting chemo doesn’t mean you didn’t have real or serious cancer.
It’s not just laypeople who cannot always get out of chemo as default mode, either. When I later ask Dr. James Allison about his experience as a researcher, he says, “The subtlety of immunotherapy is in the whole paradigm shift. You’re not treating the tumor; you’re treating the immune system. That’s one of the reasons I moved to Sloan Kettering; they understood that.”
And a good place to start looking at immunotherapy happens to be with melanoma. As Jedd Wolchok explains, “Melanoma gave us a window into the fact that the immune system might have a role in controlling cancer, because everything is not uniform in melanoma. It can break off, but it can spontaneously regress. If you cast aside divine intervention, the best explanation for spontaneous regression is an immune response to the tumor. That, for a long time, was one of the pillars of support for why immunologists studied melanoma. The other was that the other treatments that were showing efficacy—chemotherapy, radiation—for other kinds of cancer were not so effective in melanoma. It was a strong call for thinking of something creative.”
CTLA-4 was first identified by researchers in France back in 1987. But it was Dr. Allison and his team, working in Berkeley, who first figured out that CTLA-4 operates on the T cell as an inhibitor, and theorized that controlling it could hold a crucial key to giving the immune system a fighting chance. It was the beginning of what would become ipilimumab.
“Everything at the time was concentrated on turning T cells on,” Allison will tell me later, understatedly reminiscing. “I kind of dabbled around. We finally figured out we could, in a very programmed way, turn the brakes off. It’s kind of like a gas pedal. It’s not really that complicated—just suspend the brakes in a way you can control. The immune system will know what to do. It’s just about unleashing it from the constraints.” Allison’s and his colleagues’ findings in mice experiments, published in Science in 1996, promisingly declared that “it is clear that CTLA-4 blockade enhances antitumor responses.” Translation: This stuff works. And as Allison told Jerome Groopman in the The New Yorker in 2012, “I just wanted to be the advocate who is keeping it in everybody’s face.”
Nils Lonberg recalls it similarly. Lonberg is currently a senior vice president of biologics discovery at Bristol-Myers Squibb, but he’s been delving into the mysteries of the immune system his entire career. On a swampy late summer afternoon in 2014, he and I are sitting in a room at BMS’s New York headquarters, where he tells a story that for him begins back in grad school.
“I’ll go back to 1989,” he says. “I was at Sloan Kettering. Jedd Wolchok was doing a summer internship in Alan Houghton’s lab, the lab that Wolchok now runs. I was downstairs working on genetically engine
ering mice. I was talking to people who were working with a mouse monoclonal antibody. The problem they were having was that our human bodies recognize them as foreign proteins. So I asked whether it would be useful to have a mouse that could make human monoclonal antibodies—if I could genetically engineer a mouse that would have human immunoglobulin genes, rather than mouse immunoglobulin genes. And,” he says modestly, “there was enthusiasm there.”
Though Lonberg speaks of this process with all the easy confidence that I generally employ when I’m offering to make a tray of cupcakes for a bake sale, it’s actually kind of a big deal to get animals to make human antibodies. It took Lonberg and his several associates years to get there. It was also an eminently hands-on process. Researchers had to isolate a specific part of the immune system code inside human DNA, inject it into mouse embryos, and then blow those embryos into mother mouse oviducts via a tube—a feat Lonberg repeated on tens of thousands of mice. “It is personal,” he tells me. “You get in there, and someone actually has to do that.” Lonberg and his team’s results on the mouse that could make human antibodies, published in 1994, were groundbreaking.
“There are now,” he says, “six approved antibodies that came from that mouse. There’s a psoriasis drug. Another is an arthritis drug.” And there’s Yervoy.
The next step was getting the antibodies into patients. “Alan Korman talked to Jim Allison shortly before Jim’s paper came out in 1996,” he says. Korman is now the vice president of discovery research at Bristol-Myers Squibb, and was at the time, like Lonberg, at the pharmaceutical company Medarex. “He became immediately enthralled. Jim had had frustration getting other people interested in this, but Alan was very interested. Alan had made a mouse monoclonal antibody, and he wanted to manufacture it to take it into the clinic. I gave him some advice about manufacturing, but I said, ‘You don’t really want to put a mouse antibody into patients. You want to put a human antibody into patients. Let’s make a human antibody.’ ”
Lonberg recalls an early meeting with James Allison. “He was really skeptical of all the promises he’d been made by the biotech industry, and his primary concern was that he was obsessed with getting this into patients as soon as possible. The first patient was treated with ipi in June of 2000. All the time to negotiate a three-way agreement between [Allison’s lab in] Berkeley and [pharmaceutical companies] Nextar and Medarex, all the time to work on the drug, to manufacture it for the clinic, the regulatory filing, the toxicity studies—all that was compressed into less than two and a half years. We were so urgent.” Nevertheless, in the more typical pace it generally takes for drugs to clear all their hurdles in the United States—though that’s now beginning to change—it would take more than a decade of trials before the treatment that became ipilimumab would be approved by the FDA.
When I talk to people like Lonberg or Allison or Wolchok, I see real humans doing things like blowing embryos into mice in the name of the rather amazing cause of developing new treatments for cancer. That’s why I really have to restrain myself when people go all conspiracy theory on me. I have to bite my tongue when a neighbor who overhears me talking with Jeff about my drug trial in the elevator one afternoon pipes up to say, “I don’t believe in drugs. Any of ’em. The cancer doesn’t kill people. It’s the drugs.” Or when on the playground one blustery afternoon, a fellow mom pityingly sighs at me as our daughters play and says, “It’s terrible you’re going through this. These doctors. They don’t want to find a cure.”
“I’m sorry, what?” I ask.
“The doctors,” she continues, “the drug companies, they’re all working together to keep people sick. They make more money treating cancer than they could to cure it. If they cure it, they’re out of business. All this money goes to research, so why isn’t there a cure?” Tip: This is the opposite of what you should ever say to someone with cancer.
“Gee,” I reply, “I’ve got to say it’s a very convincing hoax. My doctors have spent their whole adult lives allegedly investigating treatments and the researchers working on drug trials have done the same. It’s pretty impressive to think they’re really just sitting around letting everybody die. Totally had me fooled.”
“Well, no,” she says hastily, “that’s not what I meant.”
“You haven’t been there,” I tell her, “and you don’t know what you’re talking about.”
I would never claim that any industry that is profit driven doesn’t very much look out for its own interests. A popular drug—a drug there’s proven demand for—makes people money. That’s why, whenever there’s a big breakthrough in medicine announced in a prominent section of the news, there’s always a smaller but still significant story farther down about how the pharmaceutical company’s development will affect investors. And yes, I get that it’s undeniably weird that a large corporation’s financial success is often riding on the investment in the chance that people like me won’t die, but there it is.
In 2009, Bristol-Myers Squibb purchased Medarex Inc., the small pharmaceutical company that it had been co-developing ipi with, for $2.4 billion. That’s not a choice anybody makes emotionally. That’s a choice heavily influenced by, as an analyst at Credit Suisse noted to Forbes at the time, the promise of “future royalty streams.” As researcher friend Steve says, “The way it works in real life is that we’re capitalists. I have a fiduciary responsibility to the stockholders to not do anything stupid and risk their investments.”
That means hard realities, but it doesn’t mean everyone involved in drug development is a ghoul. Shortly after Yervoy was approved in March 2011, one of the doctors at Memorial told me that a neighbor who works on Wall Street had confronted him in his apartment elevator one morning on the way to work. “You know,” the neighbor had said, “the Street hates your drug.”
“I didn’t say anything,” he had told me, “because what would be the point? But I thought, first of all, it’s not my drug. Second of all, I don’t work for the Street. I work for my patients.”
There is a lot about the drug industry, about the insurance industry, and about the relationship that many of us as patients subsequently are forced to have with our wellness and illness that is radically screwed up. That is not the same as an elaborate plot. As Jedd Wolchok says, “All the things that you may think you know and understand about clinical trials, about pharma, about the health care system, about cancer—you can’t know it until you’re 360 degrees surrounded by it. You’re definitely not going to know it by reading someone ranting and raving on the Internet.”
CHAPTER 16
The Trial
October 8, 2011
By the time we drive down to Philly on Saturday, I am feeling almost not awful. As the car glides over the George Washington Bridge, Jeff drives as I fiddle with the car radio until I land upon Captain and Tennille. He and I reflexively belt out “Love Will Keep Us Together” with such disquieting gusto the kids can only sit slack-jawed in the back at our display. “I will! I will! I will!” we sing-shout. I am thinking of nothing else in the whole wide world, and it’s fantastic.
Deb’s just started on her course of Abraxane, but when she emerges from the house, sliver thin and bandanna wearing, I don’t feel the same scared butterflies I did in May. I just feel proud of how hard the two of us worked to get here, right now.
Tonight, our families laser tag. Debbie and Mike and Jeff and I suit up together, and before long we’re obliterating our children with extreme prejudice. I pull the trigger so often and so fast that I’m more often than not shooting blanks, rushing back to recharge and relishing the thrill of faux annihilation. Of being, for a change, the killer.
Debbie, ever the beanpole, has lost even more weight since May. As we putter around the next morning before breakfast, I notice how her jeans sit low on her hip bones, and how, peeking out between the top of her belt and the bottom of her shirt, I can see a dark vertical scar.
“So that’s it,” I say, glancing at her abdomen, and she tugs down her sh
irt hurriedly, embarrassed. But then she seems to remember how superfluous modesty has become, and she pulls up her shirt, revealing her belly with all the finesse of a girl on spring break, going wild. She pats it proudly.
There is a long, straight line from her chest to her pubic bone, flanked by two deep parallel scars on either side. It looks like an upside-down cross.
My eyes follow the trail of marks down the front of her body, and then back up to meet her eyes.
“Plus, I’m losing my hair again,” she says.
“Yeah, where’s Ellen?” I ask. She’s not on her old spot on the bookcase.
“Oh, I don’t know what to do about her,” Debbie says. “All my students have seen me with short hair already. I don’t know if I can walk in with a pageboy. I guess I have to go back to Lovely You and get something in a pixie.”
“It’s all impressive,” I say, lifting my shirt too. “Better than mine.” I point to the little gashes on my left side, under my armpit, and under my breast. “And this,” I say with a flourish as I swivel around to my right side, “is my tumor.”
“That thing?” she asks incredulously. “It looks like a little bruise.”
“Right?” I say. “It’s hard to believe that it’s actively trying to kill me.”
A Series of Catastrophes and Miracles Page 17
