Cancerland

by David Scadden

  I once encountered deep skepticism while treating a cancer patient for whom no therapy was working. When I suggested a new, long-shot medicine, I could see her parents were gravely worried. When they asked if I was “experimenting,” I realized from their accents and age that they were probably acutely aware of and may have lived through the horrors of the Holocaust. They were not sure if they could trust me or the entire medical establishment. I tried hard to reassure them, but even as I did this, I feared that I was talking too much, as if I were trying to talk them into something and that in doing so, I was likely making things worse. We went ahead with the treatment, but it failed and their daughter died. I would never learn whether they felt I was sincere.

  Some people feel better after expressing these feelings, part of the job to remain calm and caring as they do. However, the words that are said can also be devastating. It is difficult to remain stoic and yet be authentic in such settings. Taking sometimes unfair words without giving in to the urge to protest is necessary. What sometimes comes out is a rote answer or false understanding, which is the last thing anyone needs from a doctor.

  In time, oncologists learn to be guided by the person at the heart of the crisis: the patient. There are many ways to communicate the same information, and when you share a medical foxhole with someone, you get a good idea of what will work for them. In some cases, patients understand they face death but will not acknowledge the facts using the precise words. On the other end are those who need to say, “I know I may die soon,” out loud, many times over. No matter where a person falls along the spectrum of reactions, love, friendship, psychotherapy, and pastoral care can be of enormous help. Everyone dies. Not everyone must cope with knowing that the event is imminent. These people deserve every bit of help we can offer.

  The three patients who agreed to take Carl June’s experimental treatment knew what they were getting into. They were told that augmented immune cells could run wild, as they had in one previous trial with a colon cancer patient who had suffered lung damage as a side effect and died. They also knew that as they underwent chemotherapy to destroy most of their existing immune system, which could otherwise inhibit the proliferation of the new ones, they would be vulnerable to potentially deadly infection. But patients who reach the end of conventional treatment options and are offered spots in a trial often seize the opportunity for multiple reasons. The chance for a cure, or even a somewhat longer life, is one big motivation. Another is a yearning, felt by many patients, to contribute something positive to others whenever the chance arises. Taking a chance on an experimental treatment can be seen as a great opportunity to serve in this way, and this service adds meaning to life.

  Nothing notable occurred when June’s patients had their T cells harvested and then underwent chemotherapy. (After many decades, transplant groups had reliable routines for managing the effects of the procedures so that the worst complications were avoided.) The lab-treated cells were infused back into the patients’ bodies and began to replicate, but days would pass before signs of change arrived in the form of fevers and chills. Speaking later to The New York Times, one of the men said he became so ill that he was moved into intensive care and his loved ones were warned that he might die. Another of the patients recalled, “I was sure the war was on. I was sure the CLL cells were dying.”

  He was right. As June would observe, each of the trial participants became “a bioreactor,” and the new T cells multiplied and went to work. Indeed, each one of the powerful T cells must have been capable of attacking and killing as many as one thousand cancer cells before it exhausted its abilities. Since the T cells were dividing, offspring cells would remain, which meant that CAR T therapy amounted to what June called “a living drug” that would last a lifetime.

  Unfortunately, hugely successful cancer-killing cells can create problems of their own. Chemicals created as by-products of the destruction of malignant cells—a process called lysis—caused the fevers and other symptoms in June’s patients. One developed cancer lysis syndrome. Early signs of this complication include exhaustion, emotional swings, and tremors. He hallucinated a vision of rain in the hospital corridor with his wife walking through it.

  Cancer lysis syndrome is the most common treatment emergency for patients being treated for blood and lymphatic cancers. The word lyse means “break apart,” and the syndrome begins, ironically, when a medicine that breaks apart cancer cells does its job too well. Each dying cancer cell contains lots of debris that’s not good for you. When a treatment destroys the equivalent of two or three pounds of cancer cells, the body can be overwhelmed. Unable to handle all the circulating poisons, the kidneys start to fail, and the chemicals affect other key organs, including the heart and brain.

  As the lysis syndrome accelerates, the basic chemistry in the body changes. If the kidney cannot filter properly, urine output plummets. The abnormal chemistry becomes toxic. Patients may vomit. They stop eating, develop cramps, and become disoriented. It’s all quite scary for the person who develops it and for the caregivers who try to help, because we know it can lead to death by kidney failure, seizures and cardiac arrest. Various medicines can be given to restore normalcy to the body’s chemistry, and some patients are put on dialysis. Most, but not all, patients survive.

  When June’s patient developed problems in his kidneys, the medical team went into action. The intervention worked. Over the long term, these patients would require regular injections of gamma globulin to help them fight off infection. This was necessary because in addition to destroying leukemia cells, the new T cells killed both the normal and malignant B cells.

  In the end, two of the men in the trial went into complete remission and the third improved significantly. (By one published estimate, the T cells destroyed a full two pounds’ worth of cancer cells in just one man’s body.) Reports of this success were published with exciting headlines. On its website, The New York Times even posted a video clip that showed an engineered T cell attacking a tumor cell in a lab dish. In the video, the immune cell appears to crawl all over the cancer cell until the contents of its target start to flow out, like the guts spilling out of a fish sliced open by a filleting knife. Soon, the words dead tumor appear on the video. It’s the kind of process anyone with cancer might hope to imagine taking place inside the body as a treatment takes hold and health is restored. In fact, many patients create movies of the mind that show their cancer cells dying, in just this fashion, and frequently meditate on the images. People did this long before anyone understood the mechanism of lysis. I don’t know if this common fantasy was informed by some mysterious mind-body connection, but the fact that people were actually right about the cellular struggle taking place inside them is more than a little intriguing.

  After his first small trial, Carl June broadened his effort gradually, refining his technique for delivering improved immune cells with impotent HIV. Unfortunately, his work provoked lots of over-the-top reporting in the popular press, where some found it impossible to resist shading the facts to suggest that patients were somehow endangered by the HIV virus vector. In 2013, a short film circulated online, making the claim that June had cured leukemia in a dying girl named Emily Whitehead by “injecting her with HIV.” More recently, a full-length TV documentary described several forms of cancer immunotherapy that utilized altered viruses, either as a gene delivery vector or to attack the tumor cells directly. It reported one trial that enrolled high-grade glioma patients who were given one dose directly to their brain tumors and saw remarkable remissions in 12 percent. Eighteen months after treatment, they showed no signs of recurrent tumors. Moving as they were, the stories of the adults featured in the documentary were eclipsed when Emily Whitehead appeared in the film. Just five years old when she was first diagnosed with leukemia and eight when she received the experimental treatment, she was a compelling figure on the screen, and the story of her rescue from an apparent death sentence was breathtaking.

  Emily’s story was retold on webs
ites around the world, but, too often, the scientific details, including precise information about how the HIV was defanged and T cells were utilized, were ignored or glossed over. Without careful reading and, in some cases, additional research, it was easy for lay readers to conclude that doctors were giving people active and dangerous versions of the virus that causes AIDS. This caused more than a little confusion for people with cancer, their families, and caregivers. Eventually the official website of the authoritative British organization called Cancer Research UK published an article knocking down these fears. It was titled “No, Doctors Did Not ‘Inject HIV into a Dying Girl’ to Treat Her Cancer.”

  With work continuing apace, bringing more people with more different kinds of cancer into viral vector trials, a variation on this concept further challenged scientists’ ability to communicate with the public. At Duke University, a team led by Matthias Gromeier used an altered polio virus and a common cold virus to create a hybrid that would be attracted to a protein secreted by cancer cells. (This was work he began while studying with virologist Eckard Wimmer at the State University of New York–Stony Brook.) The group at Duke wanted to use their engineered virus to pierce a chemical cloak that prevents the immune system from recognizing glioma cells and doing their job. In theory, the virus would destroy some of the malignant cells and remove this disguise, which would make them vulnerable to the immune system.

  As the Duke team proved in the lab, the hybrid virus would home in on the “scent” of cancer, invade only the malignant cells, and destroy them. To the team’s excitement, the hybrid virus also triggered T cells to swing into action and polish off those virus-infected cancer cells that survived. But even though they had confirmed that the idea worked, they would have to prove it was safe to literally drop the virus into the brains of people with glioma. This safety review lasted seven years, and included an intense effort to show that a fat molecule derived from beef, which was used in the treatment, would not cause bovine spongiform encephalopathy (the so-called mad cow disease). The Duke team also had to test the virus on the brains of three dozen monkeys (no serious adverse reactions were observed) before the FDA permitted its use with even one person.

  In 2012, a small group of people with glioma became the first human subjects to receive the treatment, which came to be known as PVS-RIPO, for recombinant oncolytic poliovirus. The drug was administered directly into their brains, via tiny holes drilled through the skull and catheters directing the medicine to the tumor site. After the surgery, which caused little trauma, patients did experience the symptoms of infection as the virus went to work. Some patients would become quite ill, with swelling in their brains causing problems with speech and movement.

  At the time, median survival for people first diagnosed with glioma who received standard care was a little more than fourteen months. Half of patients died before this date, and half lived longer. Given that PVS-RIPO was an experimental drug, no one knew what to expect. Then tests done on patient number one, a twenty-year-old college student named Stephanie Lipscomb, showed that after a brief period of tumor growth, her cancer had started to recede. Indeed, she responded so well that, in less than two years, that single dose of the virus had wiped out all signs of the tumor in her brain. Other patients saw similar progress, with the imaging of their brains showing that tumors were literally dying, bit by bit, and collapsing.

  Because they were conducting a so-called phase I trial, which is intended to test the safety of new therapies, the Duke scientists adjusted the virus dose they administered, hoping to determine the maximum dose that could be given without a severe adverse effect. Some patients who received high doses developed fatal complications. However, half did well, and two years after the trial, the scientists reported higher rates of survival than what would be expected for patients with the disease. They also determined that the optimal treatment did not require giving patients the most drug they can tolerate, as is often the case with chemotherapy. Instead, they discovered that higher doses not only increased side effects but inhibited the immune response they were trying to provoke. Paradoxical as this finding may seem, it cannot be considered a surprise. The immune system is a complex mechanism, and it’s possible that, like a watch, it can be overwound with too much stimulus and simply refuse to work.

  In 2017, as I write, Stephanie Lipscomb has earned a nursing degree and is healthy and well. She chose to work in oncology. Two other patients, who otherwise would have surely died, were alive three years after treatment. People around the world are clamoring for the therapy tested at Duke, but more work remains to be done before good protocols could be established for its wide use. The U.S. Food and Drug Administration gave the therapy “breakthrough” status, which meant that it could be studied further and evaluated on an accelerated basis. This regulatory category had been created in response to criticism of the FDA by people who feared that people were suffering and dying as promising therapies were considered in a process that was unnecessarily slow. For their part, FDA officials were doubtless worried about a disaster like thalidomide, a drug used mainly outside the United States for the relief of morning sickness that caused fetal deformities. Nevertheless, fifty years after thalidomide became a global scandal, the agency sought to make exceptions to its painstakingly slow process. When PVS-RIPO got breakthrough status, the group at Duke began work on phase II and phase III trials, which would involve many more patients. However, at of the start of 2017, they were not yet enrolling patients.

  In the meantime, Carl June was reporting truly astounding results from his CAR T cell / HIV vector work. He teamed with a pediatric oncologist scientist, Stephan Grupp, to treat children who fell into the small portion of acute lymphoblastic leukemia (ALL) that doesn’t respond to chemotherapy. Of the first thirty-nine children treated, several of whom had undergone bone marrow transplants, thirty-six went into remission. June has seen similar success with CLL and has received substantial new support for his work. (Penn has even opened a new Center for Advanced Cellular Therapeutics.) June’s targets include some very-difficult-to-treat diseases, including pancreatic cancer, which is the only form of cancer with a five-year survival rate below 10 percent. (A member of June’s research team died of pancreatic cancer in 2010.) He has also begun to work on ovarian cancer. This is another tough one when it comes to therapy. His wife was diagnosed with it in 1996 and died after five years of off-and-on treatment. Given the fact that Carl began his work on cancer immunotherapy many years before these losses, no one can say that his work was the result of his personal experience. But it is also true that no one is untouched by cancer and, sadly, the losses that remind us of why we do this work.

  EIGHT

  GENE HACKING

  With engineered T cells providing some spectacular results for people who were otherwise out of options, new ways to modify cells opened up additional opportunities. Carl June’s addition of a chimeric antigen receptor to T cells worked, but had to made individually for each patient. It was the ultimate personalized therapy. But like anything bespoke, it is expensive and hard to make widely available. Companies are doing it, but other innovations are entering the field.

  New technologies for editing genes rather than just adding them are now in the clinic. DNA is the written text for all living things. Over the eons, life-forms have developed a wide array of tools for cutting, repairing, and editing genes: a virtual sewing kit for life. The scissors are called nucleases. They can be directed to cut particular parts of the genome. One group of these, called TALENs (transcription activator-like effector nucleases), do so with great precision and, when the cut is repaired, it can be made to do so in a way that inactivates the targeted gene. TALENs have been used to cut out the genes in a T cell that guide its normal function, so that they only respond to the new chimeric antigen receptor that is put into them. That means a CAR T cell could be made that can be given to anyone. It could become an “off the shelf” rather than a customized, patient-specific cell. In 2015, Cellectis scie
ntists used TALENs to create such “universal” T cells that would work in every body. This process could be particularly helpful to get around the problem, presented most often by children with cancer, of patients who don’t have enough T cells of their own to use in therapy.

  In the summer of 2015, a call from Great Ormond Street Hospital in London (formerly called the Hospital for Sick Children) gave the Cellectis scientists a chance to test their idea. Researchers at GOSH possessed a vial of frozen T cells enhanced by Cellectis, but it was meant for experiments, not treatment. (A scientist at University College London was collaborating with Cellectis.) The doctors in London said they were desperate to save a one-year-old baby named Layla Richards, who, in her short life, had undergone chemotherapy and a bone marrow transplant, which failed to cure her acute lymphoblastic leukemia, which had been diagnosed fourteen weeks after she was born. Even though it had been tested only in mice, British regulations permitted the use of the treatment on an emergency basis if all of those involved gave permission. Her parents and doctors saw it as the only hope. Cellectis executives weighed the risk, which included the damage that failure would do to their reputation and stock price, and agreed to go forward.

  Layla received a one-milliliter dose of enhanced T cells, which had been donated by a stranger. Thirty days later, tests turned up no sign of leukemia. Two years later, she was still cancer-free and thriving. It was still too early to use the word cure, but as she recovered, Cellectis and its collaborators planned trials that would involve groups of patients. When the media spread word of the success, Cellectis’s stock soared while the value of tech companies pursuing personalized forms of cell-based therapies sank. Investors seemed to believe that thanks to gene editing, Cellectis could produce an off-the-shelf treatment that would be far less expensive to make than the type of bespoke cures devised at the University of Pennsylvania. The verdict is still out. Cellectis has since had a major setback when a patient died. Other gene-editing methods are proceeding quickly to clinical testing.