Erik Ness

For Mari Casanova, it started with a weird, dry cough. Her doctor wasn’t alarmed and suggested cough medicine. But a few weeks later, the morning after a Pilates class in November, Casanova felt an unusual lump in her armpit. At first she wondered if she had pulled a muscle. Then she realized it was the size of small lemon, so she cleared her schedule and headed to her neighborhood hospital in Chicago.

A needle biopsy indicated cancer, but for nearly two months, her doctors couldn’t pin down the origin. Finally, they located a spot, about the size of the back of an earring, in her right lung. She received a diagnosis of small cell lung cancer (SCLC). Her doctors said the lump in her arm was already spreading, and she was scheduled to begin three months of chemo 10 days later. A second opinion didn’t happen. “I didn’t have time to get the right doctor,” she says.

On the treatment side, SCLC has been described as “a graveyard for drug development” in several studies, including one published in Frontiers in Oncology in 2020, where chemo alone was the standard for more than 40 years. And on the patient communication side, it was even more retro: Casanova’s doctor never told her she was facing one of the most aggressively dangerous cancers known. “Yeah, he forgot the part about death,” she says.

An aunt had died from breast cancer years ago, but otherwise, Casanova had no close personal experience with cancer. “I said, ‘This is going to be easy for me’ because I had no clue what chemo was,” she says. “‘In three months, I’m going to be fine. I’m going to beat this.’ I had no fear because I didn’t understand that I could die.”

She tolerated the chemo well. Meanwhile, her sister Martha had questions and had been doing some research. She came along for what was supposed to be the last appointment. And when Martha started to ask hard questions, the doctor shooed her away with a gesture and left the room. Casanova collected her records and found another oncologist.

“And the first thing he did was explain to me that I could die.” She pauses a bit at the memory. “Yeah, in a very sweet kind of way.” He laid out a treatment plan: one more round of chemo and some radiation for the spot on her lung and to prevent brain metastases.

Casanova was fortunate in that patients with SCLC are often very overwhelmed by their symptoms. “They usually come in in pretty significant distress,” explains Dr. Stephen Liu, director of thoracic oncology at Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C. “This is not a subtle finding.”

“My approach is to be very upfront, very open, very honest,” Liu says. “Small cell lung cancer is an exceptionally lethal subtype of lung cancer. And I try to prepare patients for the journey that we’re going on.” Because it moves so fast, SCLC is almost always picked up at an advanced stage, and there’s almost no role for surgery. Median survival for people receiving treatment like Casanova was only 10 months.

“It’s a heartbreaking, terrible disease,” adds Trudy Oliver, a lung cancer researcher at Huntsman Cancer Institute and an associate professor of oncological sciences at the University of Utah in Salt Lake City. “It’s why we’re in the lab trying to find things that will make a difference

so that it doesn’t have to feel like such a such an overwhelming death sentence.”

According to the Centers for Disease Control and Prevention, lung cancer is the third most common cancer in the United States after skin and breast/ prostate cancers, but most of that is non-small cell lung cancer (NSCLC). Its treatment has improved dramatically over the past two decades, marking one of the great success stories of modern oncology. SCLC makes up approximately 15% of lung cancers overall, or nearly 30,000 cases annually. Most SCLC can be linked to cigarette smoking. Its poor prognosis leaves few survivors, and the added burden of tobacco’s social stigma means that SCLC hasn’t benefited much from patient advocacy. But for more than a decade now, a dedicated cadre of researchers has been trying to crack one of the most challenging types of tumors in oncology.

“There was a period of time when small cell was largely ignored,” says Dr. Charles Rudin, medical oncologist and chief of thoracic oncology at Memorial Sloan Kettering Cancer Center in New York City. “People really felt like this disease was too hard and nothing worked.” That sort of negative reinforcement led to less research focus. Rudin’s lab undertook one of the first major projects to turn this around: sequencing the small cell cancer genome. That knowledge base led to trying to define new targets for SCLC and accelerated the critical process of defining subsets of disease. “There’s an opportunity to tease apart the biology of this disease and start to develop better and more focused therapeutic approaches,” Rudin says. “It’s not an uncommon disease at 15% of lung cancer. And there are few therapies that work, so patients are super eager to try something that’s going to change their fate. I think it really was just waiting for people to come to the table and start to work on it.”

Oliver took up this challenge after learning that existing mouse models of SCLC were slow, with tumors developing in the second year. The wait slowed research and limited its value in such short-lived organisms. Engineering a mouse to study a particular cancer is complex science. But after years of work, her lab succeeded: Its mice would get sick in just a few months. In the process, the researchers unlocked some small cell secrets.

“The tumors looked and behaved a little differently,” Oliver says. “That was really our first clue that not all SCLC behaves the same way.” Working with a group in Germany, she discovered her model was very sensitive to a particular class of drugs. SCLC could no longer be viewed as one disease, and that makes a difference in the clinic.

Dr. Lauren Averett Byers, an associate professor in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, also jumped into the SCLC challenge. Her group is also focused on defining — and attacking — the molecular subtypes of SCLC.

Among the first things Byers worked on was defining SCLC’s differences at an elemental level. SCLC is considered a neuroendocrine tumor, which is a cancer that begins in neuroendocrine cells with similar traits to hormone- producing cells and nerve cells. Its fundamental biology is rooted in how the cells of the nervous and hormonal systems work. NSCLC features a number of highly accessible biologic targets that have allowed major therapeutic advances. SCLC is more cryptic, Byers says. “It wasn’t going to be as straightforward.”

As computational biology advanced, one approach was to let the data talk. Her team deployed a battery of algorithms to analyze the growing library of SCLC tissue samples. “How many types of small cell lung cancer are there?” she asks. “Let’s not be biased by what we think we know. Let the data tell us.”

A year after Casanova began her SCLC treatment, John Williams was running a snowblower on his block. He was a few miles away, also in Chicago, and a heavy snow had been falling that January night.

Now 77, Williams is fit and retired, and he takes pleasure in helping out his neighbors. He had already cleared the sidewalks and was finishing a neighbor’s driveway when it suddenly became difficult for him to breathe. He struggled to make it back to his house and collapsed into a chair. A few days later, he was still having breathing issues and was admitted to the hospital. They drained two liters of fluid from his lungs and ran a battery of tests: a PET scan, CT scan, an MRI, blood tests and a needle biopsy.

A few days later, Williams met with an oncologist, who told him he had SCLC and started talking about palliative care. She forecasted he had two to four months, maybe a year.

“This can’t be me,” he thought, his mind shifting into overdrive. “I’m the active, ‘go get ’em’ kind of guy.” But it was him, and the very next day, he was getting chemo. And not just chemo. In March 2019, the Food and Drug Administration (FDA) approved Tecentriq (atezolizumab) as part of the first immunotherapy-plus-chemotherapy regimen for SCLC. But the data that would lead to this approval had been released in September 2018, and Williams’ doctors were already putting it to use. Williams laughed when his infusion nurses couldn’t pronounce the drug name and suggested they call it “Bob.”

“This is what I call a really major stroke of luck,” he says, and he spent a lot of time thinking about his circumstances. “I’ve got absolutely no control over the doctors, the medication, the progression of the disease. I can do nothing. The only thing I can control, really, is my attitude. I can be negative or I can be positive,” he says. “So I focused on the positive from that point forward. And that’s an extremely difficult road because there’s so much negativity around.”

He can’t prove it, but he thinks the combination worked. “I’m thinking that the Tecentriq and attitude had a major, major effect on my physiology.”

Williams was playing golf by the time the season opened a few months later. He lost his hair and discovered — to the detriment of his golf game —that eyebrows actually serve a purpose: They help keep the wind out of your eyes.

In fact, once the fluid was gone from his lungs, he felt no symptoms of his cancer. One of the major challenges comes with the tumor location; SCLC can quickly encroach on major airways and blood vessels. This challenge is mitigated by the disease being responsive to so many types of chemotherapy. “You can see double-digit response rates to over a dozen different chemotherapy drugs or two- or three-drug combinations,” Liu says. “You can actually get response rates that are quite high.” Although patients might feel like things have gone back to normal, maintaining that response and preventing relapse is the real challenge. “We can’t rest on the laurels of that initial response,” Liu says. “We have to prepare for what will be in many cases an inevitable relapse.”

Tecentriq improved those odds for the first time in more than 30 years. It didn’t move the bar much, adding just a couple of months, but Liu still considers it a breakthrough. “I appreciate that it’s not necessarily the breakthrough that everyone wanted, that the survival gains aren’t of the magnitude that people are waiting for, that patients deserve,” he says. “I’d consider it the first step; hopefully, the first step of many. When we add immunotherapy to chemotherapy, we improve survival. There’s no doubt about it.”

In 2020, a second immunotherapy agent, Imfinzi (durvalumab), was granted FDA approval in combination with chemo. It is not the same as Tecentriq, but both are anti- PD-L1 agents with very similar survival results. In Liu’s mind, they are equivalent.

Rudin also acknowledges that although Tecentriq and Imfinzi don’t extend survival tremendously, they represent a significant advance. “A subset of patients between 10% and 15%, maybe 20%, do derive significant benefit from immunotherapy. That can be transformative for those patients,” he says, providing hope even for patients with advanced stage disease. “That gives us an important proof of principle that this is a disease that can be amenable to appropriate therapy.”

A quick look at the numbers makes it easy to tell when a subset of patients in a clinical trial is doing significantly better, raising expectations like an A student breaking the curve. The real challenge comes in finding out why. Often the idea behind a drug points the way, and simply testing biomarkers for the drug pathway yields the answer.

SCLC hasn’t been so transparent, which is part of what drove Byers’ computational group. As expected, their analysis confirmed three of the major variations the field has been defining. But the project also unmasked a fourth group, which they described as inflamed SCLC. It hadn’t been on anybody’s radar. “It was incredibly exciting because we’ve really struggled in SCLC to understand who gets the most benefit from immunotherapy,” she says. Although obvious biomarkers haven’t worked out, this new, computationally defined group appears to survive almost twice as long as the other groups treated with chemo plus immunotherapy.

Inflamed SCLC had higher markers of immune infiltration and of important immune checkpoints. Immunotherapy works by manipulating the body’s immune system, and now researchers have a footprint to work with. “There are obviously many questions and things left to test,” Byers says.

Tecentriq worked for Williams for an estimated 10 months (from February to December 2019), then he was put on Abraxane (paclitaxel). In the autumn of 2020, his cancer returned and is now trying to take hold in his liver. Relapse is a scary time for all patients with cancer, but particularly for patients with SCLC. “Our first shot is always our best shot, and part of that is because when small cell lung cancer does relapse, it does so unforgivably,” Liu says. Many patients never get more than first-line treatment.

But once again, Williams is just in time for another new treatment. Zepzelca (lurbinectedin) received FDA accelerated approval in June 2020, the first approved use of the new agent. It is exciting for patients with SCLC because the only other approved chemo drug at this stage is topotecan, known for its extensive list of uncomfortable and brutal side effects. Zepzelca presents its own difficulties but is generally easier to handle and can be effective against cells that have developed early resistance to platinum-based chemo.

Zepzelca is a welcome addition to a limited armamentarium, though its future was clouded when its phase 3 trial came up short of expectations in December 2020. “We see a lot of patients with recurrent disease,” Rudin adds. “We’re exploring many of the new therapeutic targets in patients with recurrent disease.”

Oliver describes the unique challenge of SCLC using M&M’s. Imagine your newly treated cancer is a bag of blue M&M’s, and you’re fortunate to have a cancer drug that wipes out blue M&M’s. “If my bag of M&M’s was all blue, I could wipe out that bag pretty quickly,” she says. But if your bag contains five colors of M&M’s, the blue drug is going to be limited. With SCLC, what actually happens is that some blue M&M’s die, but others change color. “That ability to evolve and change rapidly and easily? That’s a massive challenge,” Oliver says.

“That’s how they escape or adapt,” Byers adds. Researchers need to figure out how they’re switching colors and how to block that. They can also refine the classic cancer strategy of combining drugs that hit more than one color. “I think that’s doable,” she says. As hard as drug development has been for SCLC, she says it may be one of the most amenable tumors for developing a so-called liquid biopsy: using genetic information available in blood to target the disease.

“My hope is that within the next five years, we will start having biomarker testing to guide treatment,” Byers says.

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Articles

In recent years, research in treating small cell lung cancer has broadened, bringing emerging therapies like immunotherapy to the forefront.

No Small Challenge: Emerging Therapies in Small Cell Lung Cancer

He and his wife were driving home from a late July wedding in 2019 when it really began to hit

him. Back in Rochester, New York, he collapsed, and then endured three days of chest pains, a terrible cough and night sweats. He barely left his bed. “Everything started to seem a little bit harder to me,” he says. “I’ve always kind of overexerted myself with everything I do. Just thought I was overworking myself.”

Owens’ wife, Allison, was eight months pregnant. Like many other 31-year-olds, Owens didn’t even have a doctor. But once Allison dragged him to urgent care, things escalated quickly. His blood pressure was through the roof. Another doctor suspected thyroid issues and ordered imaging, which revealed a 6-inch mass in his chest. Owens headed to the hospital for bloodwork and didn’t check out for a month.

For many cancers, diagnosis unfolds at what feels like a glacial pace. Weeks elapse between appointments. There’s ample opportunity for research, worry and second opinions. But T-cell acute lymphoblastic leukemia (T-ALL) hits like a landslide.

“In most instances, it is a very urgent situation where we need to hospitalize people and get them going on treatment,” says Dr. Mark Litzow, head of the acute leukemia group at Mayo Clinic in Rochester, Minnesota.

“All these procedures are coming at them,” says Owens’ oncologist, Dr. Kristen O’Dwyer. She’s clinical director of the acute leukemia program of the Wilmot Cancer Institute at the University of Rochester Medical Center in New York. “I have to do a bone marrow biopsy, get a central line and a lumbar puncture, an echocardiogram. If it’s a young man, there’s fertility preservation. All these things in a matter of 48 hours, so I can get them starting on treatment. And they have to trust me,” O’Dwyer adds, “which is huge, especially for a young patient who is like, ‘I don’t have cancer. I’ve just been really tired because work has been crazy.’”

Acute lymphoblastic leukemia (ALL) — sometimes known as acute lymphocytic leukemia — is an aggressive cancer of the blood and bone marrow. “Our bone marrow produces many billions of cells every day,” says Litzow. Stem cells in the marrow produce immature cells called blasts that, when healthy, will develop into one of many different blood cells. In this constant state of division, mistakes happen. Biological safety mechanisms catch most of these, but sometimes abnormal cells escape and take over. “Instead of maturing and producing red blood cells, white blood cells and platelets, it just keeps making more of itself,” Litzow says.

Most ALL (85%) derives from defects in B lymphocytes, cells that normally mature into the antibody-producing white cells that help fight off infection. Cure rates for B-ALL are high and getting higher. T-ALL arises from T lymphocytes, which are important cells in the immune system for fighting infections and other immune functions.

The most common childhood cancer, ALL also afflicts adults. T-ALL is a subset of ALL and is a rare cancer: An estimated 6,150 new cases of ALL were diagnosed in 2020 in the United States; just 25% of these cases were in adults with T-ALL. It’s largely a disease of adolescents and young adults (aged 15 to 39). Although incidence diminishes with age, it’s a trade-off: Cure rates for children are high and decline as patients get older.

In young children, certain genetic mutations found in B-ALL tend toward good outcomes. In teenagers, these “good” mutations decline and high-risk elements gain. “By the time you’re looking at young adults, you very rarely see the good-risk genetic subtypes,” says Dr. Stephen Hunger, director of the Center for Childhood Cancer Research at the Children’s Hospital of Philadelphia. “The high-risk genetic subtypes are much more common.”

Treatments began to emerge for ALL in the late 1960s. When some patients recovered from early-generation chemotherapy regimens and others did not, doctors learned from the differences. Children, for example, did better than adults. In the 1970s it became possible

to distinguish between ALL from B lymphocytes and T lymphocytes. The more common B-ALL responded well to therapy, while patients with T-ALL fared much worse.

Treatment for B-ALL delivered on this promise and has reached exceptional levels thanks to new antibody therapy and CAR-T cell therapy. Treatments for T-ALL have not kept pace, though in the past few years improvements have led to cure rates approaching 90% in children and 70% in young adults.

ALL treatments are relatively similar, with one big difference: If the first line of treatment fails, backup for T-ALL is very limited, with Arranon (nelarabine) being administered with mixed results in patients. “For patients who do not achieve remission, or (who) relapse after achieving remission, it is nearly impossible to find an effective treatment,” says O’Dwyer.

T-ALL treatment regimens are difficult and complex, and adapted to a patient’s individual risk. Patients with a better prognosis need less intensive therapy, while those with less favorable prospects require more intensive treatments. “We’re trying to get a balance between avoiding toxicity and maximizing cure rates,” Hunger explains.

For T-ALL, the therapeutic regimens may include a half dozen or more drugs. Many of these specifically target the cancer — cyclophosphamide, vincristine sulfate, Adriamycin (doxorubicin), daunorubicin, cytarabine, mercaptopurine, thioguanine and Oncaspar (pegaspargase). Steroids like prednisone and dexamethasone are used liberally, as they are directly toxic to lymphocytes and therefore slow the disease and influence the immune system in useful ways. Other agents offer more immune modulation and help dampen side effects like neurotoxicity.

Some are given intravenously and others orally; a few are delivered both ways at different times. It’s often hyperfractionated, which means smaller doses are given at shorter intervals. Intrathecal therapy — fed into the spinal fluid via lumbar puncture — is used in all patients to prevent central nervous system relapse. Radiation is also possible for pockets of disease in places like the testicles where chemotherapy does not penetrate well.

A patient will typically experience many of these in a rotation of therapeutic cocktails that typically last 2.5 years. After diagnosis, there’s typically a monthlong hospital stay. Called induction, its goal is to hit the cancer hard and induce remission, while closely monitoring results.

How the cancer responds to treatment is pivotal, and the ultimate measure of patient response is called minimal residual disease (MRD). By taking a bone marrow sample and using high-tech scanners, it’s possible to detect minute levels of malignant blast cells. The more blast cells, the higher the risk of relapse. It’s an important metric, because how patients respond to the initial therapy is very predictive of the likelihood of successful treatment.

After induction, the next phase, known as consolidation, can last from eight months to more than a year. Some courses during this time are very intense — many consecutive days of treatment — while others are devoted to recovery. Some patients receive a stem cell transplant, a challenging round of treatment, immune isolation and recovery all by itself. The last year to 18 months is maintenance therapy, typically delivered orally.

Two different schools of practice have emerged for how to combine and sequence these treatments. They use similar ideas and ingredients, but are assembled in slightly different ways, as oncologists have strong preferences based on training and experience.

The two regimens go by the clumsy names hyper- CVAD and augmented Berlin-Frankfurt-Münster (aBFM). Because of the acute nature of T-ALL and the length of treatment, a patient’s treatment may be limited to the regimen practiced by their provider.

O’Dwyer says aBFM is common in most academic cancer centers. Hyper-CVAD, meanwhile, is more commonly used in community oncology, with the notable exception of The University of Texas MD Anderson Cancer Center in Houston. “They’re always doing a hyper-CVAD,” she says. “The results are, of course, excellent.”

But O’Dwyer has some opinions about the limits of hyper-CVAD in a community setting, where it is often used to treat both B-ALL and T-ALL, along with other blood cancers. Because T-ALL is rare, her concern is the lack of experience with some of the more complicated elements, like administering Oncaspar, an enzyme that breaks down a key amino acid fueling leukemia cell growth. It’s a difficult drug because of side effects — infusion reactions, severe toxicities, blood clots and pancreatitis. Experience helps guide safe use. “It’s such an important component for the cure of this disease that it’s really required,” she says.

Intrathecal therapy is also a challenge for those who don’t deliver it regularly. “We can get it done efficiently and quickly and safely. It’s harder to do that in the community,” O’Dwyer says. So that her patients can travel less, she partners with community oncologists for more straightforward aspects of treatment and handles the more complex elements in house.

“The plan should be developed in discussion with someone who does this a lot,” says O’Dwyer. “I think T-ALL is rare enough that, when at all possible, patients should be referred. It’s high stakes, upfront. You want to get it right the first time because you have so little salvage option.”

Emily Robbins was 22 when a lump in her neck knocked her world off track. In the previous few months, she’d run her first full marathon, had graduated from college and was barely into the second month of her first full-time job. Even as she was wheeled into the Wilmot Cancer Institute, she could not fathom the diagnosis. “I guess my body just didn’t want to hear that,” she says.

Robbins is not a child, but she has been treated as one — and that’s a good thing, because children tend to do better in ALL generally. Partly that’s due to favorable genetics, but partly it’s because they handle the difficult regimen better.

But as oncologists have gotten better at delivering their difficult medicine and managing side effects, they’ve pushed the treatment limits to extend pediatric treatment to adults. Results of a rigorous trial consisting of 295 patients, ranging in age from 17 to 39 years, were published in 2019. Only 3% of patients died of treatment-related causes, and only two patients died after remission. Just

as important, the amount of time before complications occurred almost doubled, to 6.5 years.

This new standard of care, which is also a new framework for future research, had been reported in a national meeting shortly before Robbins got sick and was the model for her treatment. But it’s not child’s play. The first month of hospital-based treatment was rough, though not in the same way as she had imagined. “I slept almost all day,” she says. “What was really hard was how weak my body got.” Because of the length of the treatment, she says, the side effects and the drugs that caused them all blend together for her.

While many children go back to school during the maintenance phase and resume a normal life, the oral chemo caused nausea for Robbins. She tried to return to work, but it didn’t go well. She was still tired and had lots of side effects. “I pushed myself too hard,” she says. “My advice would be just to give yourself a break.”

The length of treatment really defines the experience. “I don’t know what normal is,” she says. “I don’t remember. I can’t compare my life to what normal was for me. I can’t imagine anyone younger going through it. Thinking of someone young having to get that kind of intense treatment is just scary to think about.”

“We’ve done a lot to improve cure rates for T-ALL, which is very rewarding,” says Hunger. “But you know, it’s still pretty nasty treatment that you wouldn’t wish on your worst enemy. The upper age limit for who will tolerate those regimens is a bit of a moving target. Certainly, at the age of 40, we definitely would consider — unless somebody had a lot of other medical problems — giving a pediatric- intensive regimen.” But as T-ALL occurs in patients past their 50s, the outcomes decline. They have higher-risk disease, don’t tolerate the aggressive treatment as well and have a higher risk of complications.

For many cancers, the enormous strides in the ability to read genetic code have unlocked a range of new therapies. However, those targets have led to a dead end. “They haven’t translated into clinical use at all,” says O’Dwyer.

Indeed, the latest improvement comes from Arranon, a drug first conceived of in the 1950s, then brought to fruition in the 1970s. Arranon inserts itself into T-cell DNA when it gets copied. The error triggers cellular self- destruction. It was first approved in 2005 for patients who had failed two rounds of conventional treatment.

But Arranon has serious and sometimes fatal neurologic toxicities. “It was a hard drug to move forward,” says Hunger, who was involved in the clinical trials. “We had to go through nearly a decade of studies just to first prove to ourselves and everybody else that it was safe to give

to patients.” Eighty percent to 85% of patients are cured without it and 85% to 90% are cured with it. “Clearly it improves the overall outcome, but only marginally, which is most of what we’re looking at these days,” he says. “These advances take place because patients decide to trust physicians and enroll in clinical trials to test new therapies. It’s a partnership between patients and physicians.”

CAR-T cell therapy, the much-heralded new immunotherapy, has provided unprecedented remission rates for patients with B-ALL. T-ALL has been more puzzling because the therapy manipulates the very same T cells that go haywire. With the cancer intimately entangled in the biology of the cure, wires get crossed, and the wrong T cells get killed. Scientists are working on solutions, and O’Dwyer expects a lot more patients to be treated for T-cell malignancies at various research hospitals this year.

Despite the promise of CAR-T cell therapies, the next round of trials toward incremental improvement in standard therapy is being shaped now, building off the Arranon-enhanced pediatric regimen.

Among the agents on the near horizon are Velcade (bortezomib), Darzalex (daratumumab) and a tag team of Venclexta (venetoclax) and navitoclax. Velcade is already used to treat multiple myeloma and mantle cell lymphoma, and other blood cancers. Like many chemotherapy agents, Velcade triggers natural self-destruct sequences common to all cells.

Darzalex is also used in the treatment of multiple myeloma and several rare lymphomas. It targets CD38, a protein common on T-ALL cells. Venclexta has already been approved for use in chronic lymphocytic leukemia.

O’Dwyer and her colleagues are hoping to test Darzalex and Venclexta/navitoclax in parallel, flipping patients from one treatment to the other depending on results. “We’ll get a lot of information based on those two approaches,” she says.

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Oncologists and researchers are racing to identify new therapies to help better treat a rare form of acute lymphoblastic leukemia.

A ‘T-ALL’ Order: Treating T-Cell Acute Lymphoblastic Leukemia

Type “revolutionary new cancer” into your favorite search engine and you can almost hear the hype machines engage.

Headlines promise revolutionary vaccines, tests, drugs and imminent clinical trials. But despite the many extraordinary advances in this golden age of oncology, few are truly revolutionary. Then there is CRISPR, a technology that has emerged only in the last decade, empowering us to edit the genetic code of almost any living thing. The technology, which uses software to mimic a geneediting process that bacteria use to fight off viruses, can make a gene stop working, repair damaged DNA, or even insert an entirely novel piece of DNA. Science, the flagship journal of the American Association for the Advancement of Science, published a special issue this August on revolutionary technologies. CRISPR led off its short list.

Testing of CRISPR in humans is just beginning, but the possible uses of the technology are vast, with an array of potential benefits, pitfalls and ethical implications. CRISPR is already being used by a food company to give bacterial cultures used in cheese and yogurt more immunity against viruses. In the future, the technology could be used to create better crops or livestock, make synthetic copies of microbes used to manufacture drugs, modify the fertility of pest species so they become less prevalent, eliminate diseases in animals, people or societies, or even design babies with specific characteristics, such as enhanced intelligence or height, in some cases creating traits passed on to future generations.

LUKAS DOW, Ph.D., uses CRISPR to build genetic models of cancer on which medicines can be tested. - COURTESY CORNELL / PHOTO BY ROBYN WISHNA

While genetic engineering has been feasible in the laboratory for some time, CRISPR makes it comparatively easy. “We never really had tools that were powerful enough to do it in a reasonable time frame at a reasonable expense,” says Lukas Dow, Ph.D., assistant professor of biochemistry in medicine at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine in New York City. That explains why, in the time it typically takes someone to earn a Ph.D., CRISPR has not just emerged but infiltrated labs worldwide. Its capabilities for genetic manipulation are more sophisticated than even those celebrated in last year’s biggest cancer news, the FDA’s approval of Kymriah (tisagenlecleucel) and Yescarta (axicabtagene ciloleucel), known as chimeric antigen receptor (CAR)-T cell therapies. These expensive but powerful medicines use genetic engineering to enhance the human immune system by training T cells to selectively seek and destroy cancer. That’s a revolution, too, yet the engineering itself is much less refined than CRISPR technology.

“There is so much anticipation and expectation that some people seem to have formed the impression that CRISPR is already curing diseases and in the clinic,” says Michel Sadelain, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center in New York City. Sadelain hopes it won’t be long before that happens. He is constructing what could be the first U.S. trial using CAR-T cells designed with the help of CRISPR, scheduled to begin in 2019. “There is no doubt that CRISPR is a major advance,” says Sadelain, “but there is still a whole body of work to do on its safety.”

CRISPR has had, and will continue to have, growing pains. Early concerns about precision, called off-target effects, have been allayed as techniques improve and more assessment data is collected. “We have been lulled into the view that editing is small and local and controllable,” Allen Bradley of the Wellcome Sanger Institute in England told the journal Nature Methods in July. “(T)he reality of DNA repair in a cell is much more complex.”

MICHEL SADELAIN, M.D., Ph.D., has made it his life's work to engineer human immune cells. - COURTESY MEMORIAL SLOAN KETTERING CANCER CENTER

In June 2018, two articles sharing study findings in Nature Medicine said that the anticancer gene P53 often prevents CRISPR from successfully editing human cells, and when the technology does make an edit, it may be in cells that lack P53. When those edited cells multiply in the body, their malfunctioning P53 increases the risk that cancer might develop.

Scientists who work with CRISPR say that part of the reason for the research was to reveal any such complexities and increase understanding of how the technology works.

Still, the studies hit the mainstream media, including an article in the New York Post with the headline “Futuristic gene-editing technology may cause cancer.”

“That really couldn’t be further from the truth,” Dow says with a sigh. “There’s been a lot of hype about CRISPR’s potential to cure disease. Some people even say (it could) cure all disease. The same hype cycle drives fear.”

Because fungi fight bacteria, we discovered antibiotics, which may be the most important medical breakthrough of the 20th century. Because bacteria are under constant attack from viruses, we now have CRISPR, perhaps the most intriguing medical breakthrough of this century.

The new technology takes advantage of a natural immune response of the same name that bacteria use to fend off viruses. The mechanism was first seen in E. coli in 1987. You may recall that nucleic acids — DNA and RNA &mdash; are each made from just four molecules. Scientists assign each of these a letter, so your genetic code can be read as a 3 billion—character string of just these four letters. Viruses are also constructed largely of RNA or DNA, and they do damage by hijacking the DNA of their host. Inside bacteria, CRISPR works to ward off these viral interlopers, even saving samples of viral DNA, like mug shots, to allow the bacteria to recognize future intruders.

CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats. It refers to palindromes, or repeating patterns, of DNA that are found in most single-celled organisms known as archaea and in nearly half of bacteria. The palindromes are like bookmarks for the virus snippets that the bacteria capture and keep “on file” so they are able to recognize any dangerous viruses that come along later. When the bacteria detect such a virus, they send a Cas (CRISPR-associated) enzyme to destroy it by cutting it up.

Our limited ability to decipher DNA meant that we didn’t even notice these curious palindrome patterns in bacterial DNA until the late 1980s. It took another 20 years to see the purpose in the pattern. Now that scientists understand how bacteria use CRISPR to repel viruses, they are harnessing the technique for use in the lab and clinic. In the decade since the technology emerged, CRISPR techniques have proliferated, spurring a host of research, investments, patent battles and sci-fi scenarios.

CRISPR’s importance in cancer is fundamental. The disease is first and foremost a corruption of the body’s DNA, a cruel hitch in our genetic code. In the past 20 years, our ability to read that code has expanded exponentially, driving many advances in treatment and understanding. CRISPR now makes it feasible to write, and rewrite, that code.

To do so, scientists use computers equipped with special software to indicate what they would like to accomplish with CRISPR and are given instructions on the materials they should mix in a test tube to get the desired reaction. According to MIT Technology Review, to use the technology on people, several methods have been proposed that will be tested in clinical trials: gels or creams that go on the skin; drinks or foods; ear injections; CRISPR-engineered skin grafts; and a technique like that used in Kymriah and Yescarta that removes cells from a patient, engineers them in a lab and reinfuses them.

Dow’s lab focuses on gastrointestinal tumors, primarily colon and pancreatic cancers, and searches for the genetic drivers of disease. There can be thousands of mutations in a tumor, but many of them have little or no role (so-called passengers). What mutations drive a tumor to form and grow? What makes it susceptible to a drug and then able to evolve resistance to that drug?

“If you take apart a car and want to understand what every component of the engine does, it’s very difficult, because often you just take a piece out and it stops working,” Dow says. Tumors are the same way. For several decades now, cancer scientists have been painstakingly building genetic models of cancer in mice and yeast and from cancer cells themselves. They’ll simplify a cancer by knocking out noncritical parts — something akin to the air conditioner. Then they’ll systematically remove and restore other genes to try to figure out whether they might be the cancer’s spark plug or accelerator.

“It’s a way for us to home in on the individual parts of a very complex machine and find out exactly what those things do,” says Dow.

CRISPR allows that work to proceed far more quickly and with much more precision. “By building these more accurate models, our hope and our goal is that we will build systems that are more predictive of human disease,” Dow says. Being able to predict response or resistance patterns means that researchers can more precisely target drugs: “The goal has always been to develop better treatments with the hope of getting curelike responses.”

Cancer is a disease of enormous complexity. In 2000, Douglas Hanahan, Ph.D. (who developed one of the first mouse models of cancer), and Robert Weinberg, Ph.D. (who discovered the Ras cancer-causing gene), published “The Hallmarks of Cancer.” One of the most cited papers in oncology, it outlined six biological processes defining cancer; in 2011 they updated it to 10. In 2018, a group of Australian cancer researchers looked at CRISPR research through the “Hallmarks” lens and found active CRISPR research in all 10 areas of interest. “This system has the potential to dramatically accelerate progress in cancer research,” they concluded.

CRISPR feels so powerful right now because it comes on the heels of a tremendous effort to sequence cancer genomes. Researchers now have easy access to the complete genetic code of thousands of tumors of nearly every cancer type. “We now know in many different tumor types all of the mutations that occur,” says Kathryn O’Donnell, Ph.D., assistant professor at the University of Texas Southwestern Medical Center Department of Molecular Biology and Simmons Cancer Center in Dallas. “Finding the ones that really matter — sifting the drivers from the passengers &mdash; is really important.”

KATHRYN O'DONNELL, Ph.D., uses CRISPR to speed up research into how lung cancer develops and grows. - O'DONNELL: COURTESY UT SOUTHWESTERN

O’Donnell’s lab focuses on mechanisms of tumorigenesis in lung cancer, and CRISPR cuts months, even years, off discovery timelines. Not too long ago, the development of a mouse model might have taken researchers years of collaboration. Now it can be accomplished in months.

Some of O’Donnell’s work right now focuses on an overactive cell surface protein in lung cancer called Protocadherin-7, encoded by the PCDH7 gene. Using CRISPR to knock out that gene in a lung cancer mouse model shows a significant reduction in tumorigenesis. Now O’Donnell and her colleagues are trying to figure out how to turn this knowledge into a target for potential therapy. It can be tough to balance her excitement with her necessary critical thinking. “We as scientists need to be cautious and cautiously optimistic,” she says. “I think more research is needed, and we always need to be rigorous and careful as we proceed.”

Genetic engineering has long been the dream of cancer researchers. In the early 1990s, Sadelain began his life’s work of engineering human T cells while he was a fellow at the Massachusetts Institute of Technology in Cambridge. His advisers found his vision without merit, and it took twoand- a-half years to achieve even limited proof of concept. With CRISPR, he says, he could now teach a high school student how to engineer a batch of T cells in an afternoon.

Kymriah and Yescarta are both created using a retrovirus to introduce the desired genetic modification to the T cells. Though powerful enough, the technique has limited precision. Genes won’t even necessarily wind up on the same chromosome. That works well enough; the successes with T cell engineering so far show that. But location does matter to genes. Genes work in a context, and that context is their chromosome, their neighborhood. If you insert the same genes in different places, they don’t work in the same way, explains Sadelain. In fact, there are rare cases of genetic insertion leading to leukemia because it occurred next to a critical growth gene.

Sadelain has been working with CRISPR to better target the modification. “We expected to find chromosomal position effects, and we did,” he says. But they were pleasantly surprised to discover just how big a difference it made: In a mouse model of acute lymphoblastic leukemia, CAR-T cells generated by CRISPR “vastly” outperformed the conventionally generated CAR-T cells at every dose level. The next question is, will it work the same way in humans?

Meanwhile, Khalid Shah, Ph.D., director of the Center for Stem Cell Therapeutics and Imaging at Brigham and Women’s Hospital in Boston, wants to use CRISPR to help cancer cells to kill cancer.

Some cancer cells that circulate in blood have a selfhoming tendency that causes them to return to tumor sites. Harnessing this behavior could deliver a Trojan horse inside the walls of a difficult-to-reach tumor. Working with mice, Shah and his colleagues used CRISPR to edit these brain and breast cancer cells, inserting molecules that would initiate cell death. The mice showed a “marked survival benefit.” Shah hopes to bring that technique to clinical trials in humans in the next three to four years.

“Cellular based therapy — CAR-T cell therapy, cancer cell therapy &mdash; may become the norm in the next 20 years,” Shah predicts.

CRISPR may also help realize the long-held dream of early cancer diagnosis by detecting miniscule amounts of tumor DNA in a patient’s blood serum or urine.

But most patients who benefit from CRISPR technology won’t get such paradigm-breaking treatments and probably won’t even know. Their doctors will make simple decisions, informed by CRISPR, to guide treatment at an early stage. If it hasn’t happened already, it probably will soon, and it may even go unnoticed by patients. It won’t be long before every branch of cancer research is built on conclusions derived from CRISPR clues.

If CRISPR clears the safety bar set by clinical trials, many more exciting developments could usher in a new era. CRISPR has encouraged blue-sky thinking about treatment for many cancer types. Several trials are already under way in China, where T cell—engineering drugs created with CRISPR have been used in patients. One lab has even repaired a gene in embryos that otherwise would have caused Marfan syndrome, providing “proof of principle for the technical feasibility of gene therapy,” the researchers stated in a paper explaining the findings.

“CRISPR enables precision genetic engineering,” Sadelain says. “That allows you to do more precise experiments, more precise engineering, and we all hope that it’s going to make more precise medicine.”

We’ve never been completely comfortable with genetic engineering as a society, and that’s probably as it should be. Our modest accomplishments continue to set off loud debates across a range of human enterprises: medicine, war, conservation, agriculture, religion.

CRISPR raises the stakes, moving us from mostly speculative fiction to scientific reality. What changes can we make? What changes should we make? What changes dare we make? Might a monster someday be created? “Genetic engineering and claims about genetic disease and genetic problems have a deep, dark history,” says Arthur Caplan, Ph.D., the Drs. William F. and Virginia Connolly Mitty Professor of Bioethics at New York University. “Genetics has been the subject of gross and horrific abuse. We can’t ignore that fact.”

While many people believe humans have no business messing with genetic code, Caplan is not one of them. “I don’t worry about the slippery slope. I think eliminating and preventing diseases makes a lot of sense. I think it would be almost impossible to argue against it.”

But CRISPR is particularly challenging because of the rapid pace of discovery it’s enabling. “Speed is important, but speed kills,” he cautions. While some people worry that bioethics may slow progress, Kaplan doesn’t agree. In fact, history suggests that ethical prudence has significant value. In September 1999, scientists at the University of Pennsylvania broke several ethical guidelines, leading to the death of a patient in an early gene therapy clinical trial. That put the field on hold for 10 years, says Caplan.

He believes CRISPR is a long way from proving that it can efficiently and reliably edit embryos. Consider the Chinese Marfan repair: At what point do we allow that embryo to come to term? Caplan has some thoughts about what shortcuts not to take: “You have to demonstrate that you can do it safely in animals,” he says. “The offspring have to be healthy. And you do have to be able to show that your tool is as accurate as you say it is.”

Caplan would like further safeguards to backstop CRISPR’s rapid rise. A global registry of genetic engineering efforts is needed, because the technology is already widespread. And he hopes that journal editors will not reward rash or racing behavior. A bioethics framework should also strengthen mechanisms for emergencies and desperate measures, tools that can benefit some cancer patients. “We’ve done that with drugs; we should be able to do it with gene editing,” he says. We also need to settle some outstanding business questions. Two major institutions are already embroiled in an epic patent dispute over CRISPR techniques. As more companies and institutions add their incremental improvements, freely using the technology could become more difficult.

And then there is the cost: Even the doctors involved in CAR-T cell research were stunned when Novartis set its initial price point for Kymriah at nearly a half million dollars. CRISPR may bring prices down, but will it be a meaningful price cut?

“Do not tell me about helping humanity until you tell me how you are going to make it affordable,” says Caplan. “Justify your prices. Tell me how you got to them.” And he suggests that this accounting should probably recognize that these discoveries are largely built upon generous public funding of genome mapping. “Paying twice never made me happy,” he says.

CRISPR technology can edit the genetic code of most living things. How will it be used to prevent and treat cancer, and what are the ethical considerations?

Evolution Revolution: CRISPR in Cancer Care

Prisoners are among the only U.S. citizens with a constitutional right to health care.

That irony will anger some and perplex others, but prisoners are by definition wards of the state. When we take someone’s liberty, we also take responsibility for their food and shelter, their security and health. But behind bars, perhaps even more than in America at large, health care is inconsistent in its availability and quality.

Many prisons and larger jails have created their own medical systems, such as those in Wisconsin and California, and may subcontract specialist health care with university and private facilities. But as of 2012, more than 20 states — often chasing the promise of cost control &mdash; had hired private contractors like Corizon Health and Correct Care Solutions. “Every state, every jurisdiction, is like its own individual fiefdom,” says Brie Williams, M.D., director of the Criminal Justice & Health Program and the Criminal Justice and Aging Project of Tideswell at the University of California, San Francisco. “When you’ve seen one prison or jail, you’ve seen one prison or jail.”

Corizon agreed in emailed comments screened by its lawyers.

“Nothing is withheld, but not everything is doable, because every institution is different. I can’t emphasize this enough: There is no typical,” Richard Kosierowski, M.D., director of oncology services for Corizon, said. “Care is not that different from what a patient in the community would experience. The difference is that, because of security costs and needs, it is a very complex method of delivery.”

Humane and curative care surely happens in prisons. Some prisoners get their first regular health care, leading to prevention and early diagnosis. The hospice movement is taking root, offering both compassionate end-of-life care and redemptive work for some inmates.

But there are too many disastrous cases, caused by no or slow investigation into cancer’s red flags: unexplained pain, massive weight loss, palpable tumors. Horror stories about prisoners dying bit by bit before the eyes of unresponsive prison workers make alarming headlines, and some end up in court.

Overall, the sprawling U.S. penal system is simply too diverse for blanket statements. Despite comprising less than 5 percent of the world’s population, the U.S. detains more than one-fifth of the world’s inmates. In 2017, there were 1,719 state prisons, 102 federal prisons, 901 juvenile correctional facilities, 3,163 local jails and 76 Indian Country jails, together holding 2.3 million in custody, according to the nonprofit Prison Policy Initiative. Prisons hold state and federal inmates, typically for sentences longer than a year, whereas jails are for those serving shorter sentences in counties and cities. Their walls contain a growing number of patients with cancer, some of whom read 

® and send occasional letters about their circumstances.

Despite the wide range of experiences, unifying themes have emerged: the powerlessness of prisoners to drive their own health care and the staggering increase in the age of the prison population. From 1981 to 2016, according to the American Civil Liberties Union (ACLU), the number of state and federal prisoners aged 55 and above soared from 8,853 to 124,900. The 2030 projections top 400,000.

Mostly, the incarcerated are ignored. The rare public spotlight on prison health oscillates between outrage over human rights and alarm over cost.

Garnering less attention is the dilemma of a prisoner who, expecting release in a few years, receives a potentially terminal diagnosis. The extra test, second opinion and clinical trial are largely out of reach. Judge and jury did not intend for this individual to die in prison, but will the difference between care inside and out become a death sentence? And if treatment fails, should dying behind bars be part of the punishment, too?

“I’m not sure we’re a better society for letting them die alone and uncomfortable,” says Michele DiTomas, M.D., M.S., who runs a hospice for the California Department of Corrections and Rehabilitation. “I think we are a better society if we help people die with forgiveness and closure and comfort.”

Correctional institutions are required to address inmates’ health problems.

That principle achieved the force of law in 1976, when the Supreme Court ruled on Estelle v Gamble, which began when a Texas prisoner was injured by a falling 500-pound cotton bale. Gamble lost his case, but the landmark decision stands: “Deliberate indifference by prison personnel to a prisoner’s serious illness or injury constitutes cruel and unusual punishment contravening the Eighth Amendment.”

Medical care must meet community standards, but the legal record paints an unsettling picture of our constitutional commitment since then.

Take, for instance, the cases described in recent letters from the Prison Law Office, a nonprofit California firm that works to improve conditions for incarcerated people, to the Arizona Department of Corrections (ADC).

“This is the tenth time my office has written to you about delays,” begins one letter. “We remain deeply concerned about the serious and ongoing errors and delays in his medical care,” ends another.

When a 37-year-old woman with a family history of early breast cancer asked for a mammogram in April 2017, the Perryville, Arizona, prison denied the request, saying she was too young and lacked symptoms.

However, no physical exam was conducted, and on May 27, she reported a golf ball-size lump in her right breast. A diagnostic mammogram requested on June 8 was performed July 7. An Aug. 4 biopsy led to a surgical consult on Aug. 30, after which the doctor wrote: “Patient needs oncology consult ASAP!!” A biopsy after a Sept. 29 surgery revealed that the patient was BRCA mutationpositive with triple-negative breast cancer, but she did not see an oncologist until Nov. 15. Delays continued into January; by then, the woman also had a uterine mass and a new lump in the opposite breast.

These letters exist because, in 2014, the ADC settled a class action lawsuit on behalf of 33,000 Arizona prisoners alleging a systematic violation of their 8th amendment rights against cruel and unusual punishment because of both inadequate health care and the correction department’s punitive approach to mental illness. Without admitting guilt, the ADC agreed to a settlement requiring it to meet more than 100 health care performance measures.

Yet the ADC hasn’t entirely met the terms of that settlement. At a federal hearing in February, the judge threatened fines for about 1,400 violations disclosed in December and January alone. In March, the judge threatened ADC with contempt charges. Meanwhile, the corrections department has both blamed Corizon and rewarded it financially.

Prisoners sue their jailers frequently — sometimes frivolously, sometimes with just cause. But jailhouse lawyering should not be confused with the dozens of class-action lawsuits that have spotlighted health care deficiencies in correctional systems at every level, compelling reform efforts in many states. “Anything that we know about correctional health care is based primarily on litigation,” says Josiah Rich, M.D., M.P.H., of the Center for Prisoner Health and Human Rights at Brown University in Providence, Rhode Island.

A 2006 class action filed by the ACLU against Wisconsin for health care failings at the women’s Taycheedah Correctional Institution provides one example. That action was dismissed with the ACLU’s blessing in 2016, after the state worked to improve conditions for its prisoners. “The impetus for the improvements at the prison was the litigation,” said Larry Dupuis, legal director of the ACLU of Wisconsin, at the time. “But the medical leadership team has demonstrated a commitment to improving the quality of care that we expect them to maintain in the future.”

In a wide-ranging interview, James Greer, director of the Bureau of Health Services at the Wisconsin Department of Corrections (WDC), touched on many cancer-related issues, from drug prices and psychological support to compassionate release and the development of a prison hospice staffed by 50 trained inmates, where families can visit anytime. He also touted new strategies to treat HIV and hepatitis C, classes for yoga and mindfulness, and a pilot program in counseling about prediabetes.

DAVID FATHI, director of the ACLU's National Prison Project - PHOTO BY JENNIFER HEFFNER

“Aging is one of the big issues in corrections across the country,” Greer adds. Wisconsin is getting ready to build the state’s first nursing-home unit, a 60- to 70-bed facility at a minimum-security complex. “We’re going to ask for another one, probably, in the next budget. We have close to 700 prisoners over 65,” he says.

Piecemeal victories like Wisconsin are important, but they do not convince David Fathi that U.S. prisoners get proper care.

“Health care in prisons varies from barely adequate to almost nonexistent,” says Fathi, director of the ACLU National Prison Project, which supports prisoners’ legal rights. “Prisons are closed institutions, and prisoners are an unpopular and politically powerless group. It’s a recipe for neglect and abuse.”

For one thing, prisoners remain at the mercy of their caregivers, who may be either engaged and empathic or overworked and disconnected.

JACK BECK, of the Correctional Association of New York, says the prison environment is not conducive to good health care. - PHOTO BY BEN HIDER

“They are inmates first and patients second,” says Jack Beck, Prison Visiting Project director of the Correctional Association of New York, which has legislative authority to inspect the state’s prisons. “Unfortunately, many providers become totally biased. They don’t trust or believe their patients. The environment is not conducive to good health care. The resources are not adequate to good health care.”

The path to informed advocacy is also blocked.

Prisoners generally do not have access to the internet, severely limiting their ability to research treatment options. Outside family members can assist, but they are not typically permitted to accompany prisoners to appointments and, even with proper privacy clearance, can struggle to get complete information.

What’s more, the advocacy now common in cancer treatment runs counter to the correctional culture of control. Prisoners often don’t even know when their appointments are. “Self-advocacy in prison is punished,” says Laura Whitehorn, who spent 14 years in a federal prison during the height of the AIDS epidemic and became a health advocate after her release. A friend of hers in prison who found breast lumps actually withheld that information during a parole hearing. “To advocate for yourself is seen as trying to make yourself more than a prisoner,” Whitehorn says.

Meanwhile, corrections, like everybody else, is struggling with rapidly climbing health care costs.

A 2017 analysis of state prison health spending by The Pew Charitable Trusts shows remarkable variation in spending per inmate in 2015 — from $2,173 per year in Louisiana to $19,796 in California. The 49-state median was $5,720. Care for federal prisoners cost $7,958 per capita in 2015.

Compare that with median health care spending across all U.S. residents, which was $8,045 in 2014. Louisiana’s median for citizens across its entire population was $7,815, much more than it spent the next year on health care per inmate, and California’s per capita health care cost was $7,549 in 2014, much less than it spent per inmate the following year. Arizona residents spent $6,452 per citizen overall in 2014, compared with $3,529 per prisoner in 2015.

Across the board, in fiscal year 2015, state correction departments spent $8.1 billion on prison health care services, about one-fifth of prison expenditures overall, according to Pew. The federal government paid another $1.3 billion. Neither Pew nor the government break down spending by disease, but Peter Lee, Pharm.D., M.B.A., vice president of clinical pharmacy services for Corizon Health, says its cancer spending jumped from about 3 percent of total costs in 2016 to about 4 percent in 2017. Federal spending on drugs also is accelerating steeply, attributed partly to cancer biologics.

Correctional budgets are already challenged by costly breakthrough treatments for hepatitis C, a disease 10 times more common in incarcerated populations than in the general public.

Some states already administer the drugs to prisoners; in at least nine states, class-action suits demand access. New York was an early adopter, spending about $140 million between 2014 and 2017. Furthermore, due to budget cuts and policy errors, the U.S. penal system has become the country’s default mental health provider, another big expense.

As more expensive targeted and immunotherapies for cancer become standards of care, the squeeze in correctional budgets could get even more serious. Some of these novel drugs cost $150,000 or more per patient, per year, or even $400,00 for a one-time treatment with chimeric antigen receptor T-cell therapy, and those often constitute just one element of overall treatment. Most experts interviewed by 

® didn’t specify whether prisoners have access to these expensive therapies, or, if so, how the system pays for them. In addition, care and monitoring of side effects can be particularly challenging — a troubling scenario for a generally undereducated patient base and understaffed facilities.

That cancer is now the leading cause of death in federal prison is a surreal combination of simple aging and a throw-away-the-key approach to criminal justice that began in the 1980s and is now regretted by many jurisdictions. In the 1980s, U.S. incarceration rates climbed precipitously and prison terms lengthened. A backlash to this mass incarceration has been building in response to overcrowding, budget stress and accountability.

Some argue that rehabilitation seems less valued than a cheap prison labor force. Among the loudest voices are those critiquing the apparent racial and economic prejudice of the system, which locks up a greater percentage of black men than even South Africa did under apartheid. Poverty is also punished. Among black men, more than half of the poorest fifth are likely to be jailed at some point; for the top fifth, the probability tumbles to 14 percent.

Perhaps the most damning statistics were crunched by the Department of Education in 2016. Analyzing the period between 1979 and 2013, it found that public school spending rose by 107 percent compared with a 324 percent increase in corrections spending.

Race and poverty also fuel health disparities, with evidence of a vicious feedback loop between public health and corrections. A 2017 paper in leading medical journal 

titled “Mass incarceration, public health, and widening inequality in the USA” highlighted several studies suggesting “that states with large numbers of former inmates have poorer-quality health-care systems, lower life expectancy, and higher incidence of HIV infection and infant mortality than do states with few former inmates.”

As a group, prisoners have had historically poor access to health care even before incarceration: inadequate PAP tests for cervical cancer surveillance and little to no screening for breast, colorectal or prostate cancer. “It goes on and on,” Rich says. “The prevalence of cancers is going to be higher.”

Higher rates of HIV mean more HIV-related cancer.

Higher rates of hepatitis and alcohol abuse mean more liver cancer. Higher rates of smoking mean more lung cancer. Smoking and drinking combined mean more head and neck cancers.

Research comparing people in and out of custody suggests that prisoners over age 50 are more likely to have the health problems of people 10 to 15 years older. “As the prison population ages in this country, which it is doing due to extremely long sentences, it’s become even a needier population from a medical standpoint,” Fathi says. The trend has engendered bipartisan discourse over the failures of mass incarceration and how to reverse them.

“This is an obvious place where we can re-examine our over-reliance on mass incarceration,” Williams says, “and really question whether or not the criminal justice system, the correctional facilities, prisons and jails are the right place for these people.”

Do prisoners with cancer get appropriate care? There’s no single answer.

Erik Ness

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Evolution Revolution: CRISPR in Cancer Care

Just Treatment: Exploring Cancer Care for Prisoners

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