Chasing My Cure

by David Fajgenbaum

  But concrete biological rules become exponentially more complex when you consider that this hypothetical cell we’re talking about is just one of billions of cells with myriad functions that must work together in a given organ and one of 37 trillion cells in the body. In fact, the signal for one cell (let’s call it cell A) to use its genetic instruction map to make a particular protein often comes from another cell (let’s call it cell B) that has secreted a protein, which has bound to cell A’s receptor for that specific protein. The binding of the protein to cell A’s receptor for that protein initiates a specific cascade of events within the cell that eventually reach the nucleus and signal for new proteins to be made. The cascade of events within the cell is kind of like a communication line or a game of dominoes. So, cells make and secrete proteins, which bind to receptors on other cells, initiating complex communication lines that instruct the receiving cells to make specific proteins. And on and on. Simultaneously throughout the body.

  That’s all settled science, but much of what we know about specific proteins and communication lines at the molecular level goes back barely two or three decades. That means that a huge source of knowledge is hardly older than your typical medical school graduate. There are still plenty of kinks to work out. Our limited ability to illuminate the exact nature of these pathways is perhaps matched by our limited ability to name them and their components elegantly. They’re overly technical and require rote memorization of their origins of discovery, what drugs inhibit them, and so on. However, my adventures in pursuit of a cure for Castleman disease would reveal one example bursting with all of that information packed right into the name.

  Back to the activated T cells and VEGF. Should we try the VEGF blocker? But what about the activated T cells? How did they fit together? Or was their relationship happenstance? It is known that activated T cells don’t usually make VEGF. Did the activated T cells and the VEGF point back to a single source between them, or a way that they were in contact? I hated the idea of taking yet another new drug and risking attacking only one half of the iMCD equation with a VEGF blocker.

  I considered the possibility of pairing the VEGF blocker with yet another chemotherapy carpet bomb, directed at my T cells, but I knew I’d be stacking up some truly horrific side effects. Maybe I could have withstood that kind of assault back before this all started, but I’d been weakened considerably by my many relapses. The chemo and VEGF blocker dual assault had to be reserved as my last resort.

  Could there be some other factor, communication line, or cell type at play in both the T cell activation and increased VEGF? Something we hadn’t yet seen, because we hadn’t been looking for it?

  I shook off my excitement and my fear and applied the last bit of focus I still had. I was in Philadelphia, Caitlin was with me, my family was behind me, my friends were supporting me…but it was up to me. It was overtime. Again. The fifth overtime. The ball was in my hands.

  Then a cascade of memories of blood vessel growth, research articles, and medical school lectures came together. After years of study, diligence, desperate searching, and devastatingly false “aha!” moments.

  Eureka!

  Even though activated T cells don’t make VEGF, the two are connected. I didn’t have to discover it. It was already known that the same cellular line of communication needs to turn on for VEGF to be produced and for T cell activation to occur. It’s called mammalian target of rapamycin, or mTOR for short.

  Mammalian target of rapamycin is critical for immune cells that are ramping up for war to become activated, stay activated, and proliferate, and it is separately critical for cells to secrete VEGF. For both T cell activation and VEGF production, mTOR is the intermediary between the initiation signal the cell receives on its receptors and T cells going into activation mode and other cells making VEGF. You can think of it as a long, key stretch in a very miniature game of dominoes going on inside your cells. When the mTOR pathway gets activated, T cells will very soon be able to shift into fight mode, and many different cell types will be able to start making VEGF. Activation of mTOR is basically a green light for the immune system to mobilize. The war is on. For good or for ill.

  It may seem like a simple connection that should have been landed on much sooner. But there are hundreds of other activators and downstream effects of the mTOR pathway. And hundreds of other pathways that overlap with the mTOR pathway. So you can think of that game of dominoes as actually being hundreds of games occurring simultaneously and intersecting in multiple dimensions using many of the same pieces. The T cell–VEGF-mTOR connection was not by any means clear-cut or certain to be the problem for me.

  But it was something. I wondered: Could mTOR be overactive in me? Could that communication line be stuck in the on position, causing a civil war to be waged throughout my body despite there being no enemy in sight? More important, could targeting it and turning it off deactivate the T cells and shut off VEGF production? Could it stop this deadly and relentless disease? Researchers had already developed an mTOR inhibitor called sirolimus, which was approved by the FDA for patients who received kidney transplants.*1 By blocking that communication line, sirolimus weakened cells of the immune system so that they wouldn’t attack and reject the newly transplanted organ. Of course, that meant patients on sirolimus were susceptible to infections due to a weakened immune system, but sirolimus had a much better side effect profile than the other two drugs I was considering. It had never been used to treat anyone with iMCD.

  Sirolimus is also known as rapamycin in homage to its discovery on the island of Rapa Nui. You might know Rapa Nui as Easter Island or “that Pacific island with the giant stone figures.” Rapamycin is a metabolite naturally produced by a bacterium found in the soil of that island. A pharmaceutical company called Ayerst had been collecting soil samples from islands all over the Pacific in hopes of identifying antifungal agents when they came across this compound on Rapa Nui, more than one thousand miles from its nearest neighbor. Its distance from other islands, the sheer number of islands that were visited, and the many others that were not mean that it could have easily been passed over. Then, there was an incredible convergence of science. Researchers had been trying to understand the function of a recently discovered complex of proteins inside cells that would later be named mammalian target of rapamycin. The name was given after it was determined that rapamycin targeted and inhibited this protein complex. Finally, a name in biology that indicates what drug inhibits it and its origin of discovery!

  But it still wasn’t clear what mTOR actually did. Then, the ability to inhibit this protein complex with rapamycin in laboratory experiments provided insights into how it worked and how the drug worked too. Mammalian target of rapamycin was a central hub for integrating diverse cellular signals and initiating various activities like cellular proliferation; the drug inhibited mTOR and thus stopped these activities. The symbiosis was beautiful. This rapid advancement of understanding revealed that sirolimus was a potent immunosuppressant and led to myriad clinical studies of its use. More recently, it has become clear that sirolimus actually extends lives of healthy mice, dogs, and other animals. The earlier in life that it’s given, the longer these animals survive. This drug wasn’t sounding too bad after all. The story of sirolimus was a triumph of ingenuity as well as investment. Those trips to remote Pacific islands, the stormy seas, the dirt samples, the giant stone figures keeping watch—that kind of perseverance and imagination is possible only in a project with big ambitions and long schedules. I was thrilled by the story and the promise it held for me.

  Now I had a candidate immunosuppressant, which inhibited three new targets (mTOR, VEGF, and activated T cells) simultaneously, and I began to think about treating myself with it to see if it could stop my immune system from spiraling out of control and thus prevent relapses. But yet again, this treatment approach didn’t make any sense under the previous way of thinking about iMCD. Traditionalists woul
d certainly have wondered why I wanted to suppress immune activity. This was a lymph node disorder, they’d say. It was excessive IL-6. I just needed to block IL-6 and ablate the lymph node with more chemo.

  Ah, but the traditionalists had ignored those blood moles too.

  Before anything else, I knew I needed to test the levels of mTOR activation in my tissue. I pulled out the stored lymph node tissue that had been resected a few weeks before and performed a study to measure the levels of a protein called phospho-S6. Phospho-S6 increases when mTOR is active. It came back strongly increased. Mammalian target of rapamycin was active. This still didn’t mean that blocking it would be an effective treatment. There’s no blood test or known examination that would give us that information. There were likely lots of other communication lines also turned on. And we didn’t know why mTOR activation was increased. But the T cell–VEGF-mTOR connection was starting to feel like a bit more than a hunch. That was more than anything else. And it was enough. Time to go.

  There wasn’t time to set up a formal clinical trial, and we likely didn’t have enough data to support one then anyway. I don’t think I would have felt comfortable trying the treatment on another patient based on our limited data; there were too many unknowns. Would it work? Plus, who knew what problems could arise when you shut down one part of a volatile immune system like mine? Maybe it would actually trigger a relapse?

  I traveled down to the National Institutes of Health to speak with Dr. Tom Uldrick, a member of the CDCN Scientific Advisory Board, who had always impressed me with his data-driven approach to medicine and his focus on his patients. Not just focus, he advocated for and championed his patients’ needs. He was exactly whom I needed to talk to. Our bald heads (he pulls off the bald head much better than I do) glistened in the light-filled atrium of the institute’s Magnuson Clinical Center as we reviewed the data. The brochure for the center states “patients, the Clinical Center’s partners in discovery.” This could not have been more true than it was that day. Our meeting location was significant too. The atrium is famous for casual exchange of scientific ideas leading to medical breakthroughs that have occurred at the NIH. It literally sits between the NIH’s buildings dedicated to basic science research, clinical research, and patient care. Tom and I were at a similar intersection of research and patient care. We agreed, especially in the absence of other options, that treating with an mTOR inhibitor made sense. We considered newer versions of drugs similar to sirolimus, but Tom noted that sirolimus had almost twenty-five years of safety data behind it, and he was aware of it inducing regression of a particular type of tumor with increased blood vessel growth similar to my lymph nodes.*2 It just hadn’t been used to treat iMCD. Yet.

  There has to be a first for everything.

  Or, put another way: The fact that it hasn’t been tried yet doesn’t mean it won’t work.

  Or the fact that it’s your first or second delivery doesn’t mean the baby won’t be delivered safely.

  The T cell–VEGF-mTOR connection was our strongest hunch among a seemingly infinite number of alternative ideas. Maybe some of those options would be better. We needed more data to know. But time was running out and we had to begin testing something empirically. I felt strongly that I couldn’t let a lack of data prevent this first use. I had to be the guinea pig.

  Dr. van Rhee gave his blessing, and so in February 2014 I started testing sirolimus on the nearest subject I could find: myself. I decided to keep those monthly infusions of IVIg going too; it had done something during that last relapse, and I wasn’t ready to stop it just yet.

  Again, I was scared. I did notice improvement in several of my symptoms almost immediately after starting the sirolimus, but since most of my blood tests had already normalized, I couldn’t get any objective indication if it was working until my time between relapses was extended. At that point, I’d been averaging a relapse approximately every nine months. All I could do was track my symptoms and lab tests while I waited. Then I got just the boost of confidence that I needed. The Blood journal editors emailed Chris, Frits, and me to say that they would accept our paper with only a few minor edits. It was exhilarating to know that our work would be published and disseminated so broadly. For me personally, it was an important lesson: Never stop questioning and always follow the data. We might be on the right path about this disease being about immune system function above all else. And therefore maybe sirolimus would work. Only time would tell. I really just wanted to make it to May, because Caitlin and I had finally mustered up the confidence to place our save-the-date postcards and then the wedding invitations in the mail. There was no turning back.

  *1 It had also been studied in another rare disease called lymphangioleiomyomatosis. A mentor, colleague, and friend, Dr. Vera Krymskaya, actually made the key discovery that led to the clinical trial of sirolimus and its FDA approval for that disease.

  *2 In patients who developed Kaposi sarcoma after kidney transplantation, changing from cyclosporine to sirolimus allowed for continued immune regulation and regression of the blood vessel–rich Kaposi sarcoma tumors.

  THERE WERE TWO big questions as May 24 approached.

  Question One: Was the sirolimus treatment going to hold? I had doubts. These doubts were well-founded (if anything, my experiences over the past few years had given me an education in skepticism). As I said earlier—I’m an empiricist, and I knew better than to be fooled by one study, especially one of only a few weeks in a single patient (me). I understood all too well that breakthroughs can take years and there are twists and turns that no one can expect. The last few weeks had been some of the happiest of my life—I’d even taken that road trip with my closest friends to the Grand Canyon that Ben and I had mused about during my first hospitalization. Ben and I also celebrated the news that he and his wife were expecting their first child and wanted me to be his godfather; but that didn’t mean these moments would last.

  Question Two: Was I going to have any hair at my wedding? It’s not lost on me that the length of my hair should have been the least of my worries. But this second question occupied at least as much of my thoughts as the first one. I’m pretty sure Caitlin thought about it too, although she was politely quiet on the issue.

  It wasn’t vanity. I just wanted Caitlin to see Dave on our wedding day. She had so selflessly been with David Fajgenbaum, the patient, for so long. My baldness was a clear reminder of what I had just been through and what still simmered beneath the surface for me. I wanted to give her Dave. The Dave she had first fallen in love with (though with a lot less muscle than before), and the one I hoped she’d have for a very long time to come.

  Dave, who just happened to have really, really short hair.

  Of course, with hair growth I couldn’t take matters into my own hands, as I’d been doing and preaching about for medical research. In this one instance, Santa Claus was just going to have to deliver—I would sit and wait and hope. Every once in a while, that happens to work.

  With only days to spare, my hair started to grow back. On the day of the wedding, my groomsmen gathered in my hotel room to get ready. Grant was shaving next to me and offered to trim some of the hair that had grown on the back of my neck. I declined—every hair counted! It almost looked like I had a (severe) buzz cut when Caitlin and I walked down the aisle.

  May 24 was such a happy day. Our joy that it was finally happening was amplified by memories of when it almost never could have. It felt like we had all collectively walked through the one and only door in a long hallway that led to happiness. I couldn’t stop smiling the whole day. I was marrying the girl of my dreams—a woman who had recently been packing my body with ice like I was a coho salmon at Whole Foods. Here she was saying “in sickness and in health, until death do us part” and I didn’t have to guess that she really meant it; I knew she’d be there for me. She had the “in sickness” part down, so I figured the “in health” part would be in th
e bag too.

  Back when I was semiconscious, back in between the loud beeps of machines in the ICU, I had dreamed of getting to marry Caitlin even if it was the last thing I did before I died. But when the day finally arrived, I didn’t feel that desperation; I felt simply as though we were finally beginning the life we’d wanted to start earlier, and that we had so much more to do together.

  Almost everything about our wedding day was perfect. I was responsible for one misstep during the ceremony. I’m not sure what made me think it was time to go in for the kiss when I did, but right after we exchanged rings, I thought it, so, you know, I did it…and Caitlin had to stiff-arm me before I could get within range. Our guests burst out laughing. The priest laughed too and said, “Not yet, there will be time for that.” I guess I wasn’t used to the idea that I had time, lots of time, to do what I wanted. It was a feeling I was eager to relearn.

  My dad was responsible for another um…moment. The ceremony had ended and the dancing had commenced—and then the music suddenly stopped. I looked onstage and saw what I had been quietly fearing: My dad had taken the guitar from the band. Ever the entertainer, he was known to take the stage at events like this. We had even warned the band that he might try this. They had assured me they’d keep it away from him, that never in twenty-five years of weddings had they permitted a guest to play. I don’t know what he said (or how much of a tip he slipped them), but there he was, guitar in hand, beaming with satisfaction.