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Training cells as cancer killers

With the August approval by the Food and Drug Administration of a new therapy to treat young patients with a form of leukemia, the University of Colorado Anschutz Medical Campus is positioned to contribute to a revolution in patient care.

The therapy, from Novartis, carries an exotic name that is bound to become more familiar in the days ahead: chimeric antigen receptor T cell, or CAR-T. It’s not a drug or radiation, but rather a new line of attack that relies on reengineering a patient’s own cells to recognize, attack and kill cancer cells. The target in the Novartis therapy is acute lymphoblastic leukemia (ALL), the most common form of cancer in children.

The trial of the therapy, called Kymriah, targeted ALL patients 25 years or younger with high-risk leukemia who relapsed after standard therapy, including bone marrow transplants and chemotherapy, or whose disease was resistant to treatment. More than 80 percent achieved remission within one month of therapy.  The longest TCAR treated patient is more than five years from treatment and she remains in remission.

“It’s a tremendous leap forward,” said Lia Gore, MD, head of Pediatric Hematology, Oncology and BMT at Children’s Hospital Colorado. “It’s a landmark change in how we will treat disease, in this case cancer.”

Children’s Colorado is one of 30 or so hospitals nationwide approved to administer the Kymriah therapy. Treatment will not be available outside an approved center.

Seek and destroy

Gore is principal investigator in a separate trial of a similar immunotherapy from Kite Pharmaceutical. Like Kymriah, the Kite therapy takes a page from nature’s book to turn the tables on cancer.  Both treatments target a protein called CD19 that ALL cells commonly express. Clinicians harvest T-cells, key building blocks of the body’s immune system, from the patient then send them to a facility where they are genetically modified, grown, and expanded in the lab under special conditions. In effect, the T-cells are retrained to seek, identify and destroy an enemy – in this case the cancer cells marked by CD19.

The manufacturing facility grows the reengineered cells by the millions, then ships them back to hospital clinicians, who infuse them back into the patient in a process similar to a blood transfusion. The cells grow and expand in the patient, and the immune system uses its newly weaponized T-cells to not only fight the cancer but in an encouraging number of cases rid itself of it.

“It works somewhat like a vaccine, in that the body mounts an immune response to the cancer cells,” Gore said.

Promising as it may be, don’t look for immunotherapy clinics to sprout in strip malls. Nor is the treatment, or the body’s response to it, akin to routine vaccination.

“It requires a high level of expertise,” Gore said, including teams to collect the blood cells, equipment to store and ship them, a dedicated lab to generate the cells and return them to clinicians to infuse the reengineered cells, and expertise to manage patients who receive the therapy – which is not without risks of its own.

One serious side effect of the therapy, for example, is cytokine release syndrome, a reaction to the specialized T-cells that can drive dangerously high fevers, low blood pressure, fluid retention, and neurologic problems, Gore said. The reaction is “evidence that the immune system has been activated to try to fight the cancer cells,” she added – a good thing – but it will frequently require intensive care.

Patients who receive the therapy also require extensive follow-up care, noted Kelly Maloney, MD,  program leader for Leukemia/Lymphoma at Children’s Colorado. Maloney manages follow-up care for several patients who participated in the Novartis trial at other hospitals. The follow-up includes monitoring blood counts as well as liver and kidney function, and providing follow-up reports to the trial-site hospitals. Patients also require lifetime immunoglobulin infusion therapy to replace healthy infection-fighting cells that are killed along with cancer cells by the CAR T-cells, Maloney explained.

New hope

While the complexities make for a clinical challenge, the selection of Children’s Hospital Colorado as an approved site for the Kymriah therapy is an exciting prospect for young patients and their families, Maloney said. Kymriah has produced remarkable remission numbers in kids who have frequently relapsed, leaving them with slim hopes of recovery, she said.

“For years and years, we’ve seen kids relapse after their first remissions,” said Maloney, who finished her fellowship training in 1998. These tough cases have required bone marrow transplants and multiple, increased doses of chemotherapy in attempts to turn the tide.

“In the past, with these multiply relapsed patients, there was nothing left for us to offer,” Maloney said. “It’s easier to have glimmers of hope now for families. The therapy is likely to move earlier in therapy in some patients so it’s not going to come with second and third and fourth relapses. It’s going to move up to a targeted, first-relapse therapy.”

Growing Cells
Cells in a biosafety hood in the Verneris Lab. The flasks contain T cells and natural killer cells that have been growing in the laboratory under various conditions for two or three weeks.

“The future is very bright for these patients,” agreed Michael Verneris, MD, program leader of BMT and Cellular Therapy at Children’s Colorado. Verneris was the local principal investigator for the Novartis trial at the University of Minnesota before moving to Colorado late last year.

The 80-plus-percent remission rates for the trial patients are especially notable because their conditions were so grave, Verneris said. “Kids enrolled in this trial had life spans that we measured in weeks and months,” he said.

Home-grown, natural-born killers

The Anschutz Medical Campus is poised to become a bigger player in the burgeoning immunotherapy field, Verneris said. For example, it’s home not only to the researchers and clinicians who will drive new therapies forward but also to the biotechnology facilities capable of growing the massive stocks of blood cells necessary to administer the therapies.

Those players include Children’s Hospital Colorado – and, on the adult side, UCHealth University of Colorado Hospital – the University of Colorado School of Medicine; Clinimmune Labs, a massive blood collection, processing and storage facility owned by CU; and the Gates Center for Regenerative Medicine, which is supported by the CU, UCHealth, and Children’s Hospital Colorado. The center conducts the stem cell research and biomanufacturing that helps to drive the development of immunotherapies and other cell-based approaches to treating disease.

The search for the next-generation of cancer therapies is also underway in Verneris’s lab on the fourth floor of Research Complex 1 North on the CU Anschutz campus. He and his colleagues are working to transform simple skin cells into cancer-fighting warriors. The technology, developed about a decade ago, involves genetically reprogramming the cells to return them to their embryonic state. At this point, these induced pluripotent stem cells (iPSCs), as they’re called, are blank slates awaiting an identity through genetic prodding.

Jessica Lake, MD
Jessica Lake, MD, a pediatric hematology/oncology/bone marrow transplant fellow at CU, counts natural killer cells before an experiment in the Verneris Lab.

Verneris is working to create white blood cells called natural killers (NKs) from iPSCs.  In the body, NK cells live up to their name. Their mission is to seek out and destroy invaders that attack healthy cells. In the lab, Verneris and his team are growing their own NKs from iPSCs and testing their cancer-killing power. The goal: create a potent weapon that can be mass-manufactured and infused in patients – an “off-the-shelf” therapy, as he describes it.

“Companies are charging toward this,” Verneris said. “It’s an incredibly exciting time.”

Wide application – and more questions

For Gore, the immunotherapy approach has great power because it can be broadly applied. Researchers are already looking at using it to fight acute myeloid leukemia, a form more aggressive than ALL, with a lower survival rate, she said. It’s being investigated to treat brain tumors, sarcomas and other cancers. Kymriah focused on CD19 because the protein is common in this type of leukemia, and therefore a good therapeutic target, Gore said, “but there are antigens on the surface of every cell.” Many of them could one day find themselves in the crosshairs of a patient’s newly charged immune system.

For now, however, a central question and challenge from the Novartis trial remains. Why did the Kymriah therapy work much better for some patients than others? It turns out, Verneris said, that in some, the CAR T-cells did not “persist.” That is, they worked well initially in killing the cancer cells, but then diminished in number, allowing cancer cells to reclaim the battlefield.

“The question is, where did they go in the body?” Verneris said. “We want them to stay in the blood.”

For that reason, Kymriah cannot be called a cure for everyone, Gore added. It’s a problem that requires ongoing research. One possible confounding factor, Gore said, is leukemia and other cancer cells’ ability to mutate and develop their own resistance mechanisms to fight off the CAR T-cells.

Because of these uncertainties and the quest for new knowledge about the disease and the people it strikes, clinicians and researchers will monitor Kymriah patients for at least 15 years, Gore said. “We need to evaluate its long-term effects.”

Paying the price

Another uncertainty and source of controversy is the cost of the therapy, pegged at $475,000 to hospitals directly.  This charge does not represent the total cost to patients and insurers for receiving this therapy, Gore said, although Novartis has said the charge will be dropped if it doesn’t work in the first month.

Maloney acknowledged the issue of cost will be a point of contention but emphasized that it plays no role in her clinical decision making.

“My job as a physician is to provide the best therapy for my patients,” she said. “I can’t put the decision on a cost-benefit ratio. All my patients’ lives are precious and they all deserve the best chance of survival.”

A further complication is that some patients will require a bone marrow transplant after CAR-T therapy and some will not, Gore added. The cost of a transplant is roughly $150,000 to $200,000 at the low end, but complications and long-term care can drive that to $1 million and higher, she said. If, on the other hand, a patient doesn’t need a transplant after the CAR-T therapy, “the overall cost [of the therapy] is probably going to be less over a lifetime.”

For Verneris, that points to the need to identify as accurately as possible which CAR T-cell therapy patients will likely also need a transplant.

“We know that some patients have been in remission up to five years with CAR-T. They are probably cured,” he said. But for patients who had shorter remissions, the “door opens to BMT,” he added. “The challenge is figuring out who needs the transplant and who doesn’t.”

These questions don’t dampen the excitement that immunotherapy is generating in the pediatric hematology world at large or, especially, at Children’s Hospital Colorado, Maloney said.

“Having more access [to CAR T-cell therapy] and having a family able to stay local is super-important for the psycho-social part – having people around them who can support them for what can be a tough therapy at times,” she said.

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How patients and doctors prepare for end of life care for blood cancer patients

Clay Smith, MD, chief of the Division of Hematology at CU, enjoying a day in the mountains. Smith completed the advance care planning process three years ago to lessen the burden of decision-making on his family and encourages his patients to do the same.
Clay Smith, MD, chief of the Division of Hematology at CU, enjoying a day in the mountains. Smith completed the advance care planning process three years ago to lessen the burden of decision-making on his family and encourages his patients to do the same.

Clay Smith faces death many days.

Smith is associate chief of the Division of Hematology at the University of Colorado School of Medicine and director of the General Hematology, Blood Cancers and BMT Programs at UCHealth University of Colorado Hospital. He and his colleagues regularly treat and manage the care of patients with blood cancers such as leukemia, multiple myeloma and lymphomas.

While many survive through stem cell transplants, chemotherapy and radiation, the treatments can be painful, debilitating and isolating. Many don’t survive. The Leukemia and Lymphoma Society predicts that more than 58,000 people in the United States will die from blood cancers or complications from them this year.

Clay Smith has seen his patients die. Many of them struggled, along with their families and loved ones, in their final days to accept and come to terms with the prospect of death.

Until recently, however, Smith admits he didn’t directly face the reality of death himself.

“I’ve been in the field for 33 years,” he said. “In the early parts of it, I focused on medicine and science. I didn’t think about my own mortality.”

New perspective

That changed three years ago. Smith, now 58, began to consider the difficult moments he witnessed as a physician: patients and loved ones grappling with agonizing decisions, such as whether to continue treatments in the face of incapacitating physical decline or whether to remove a ventilator.

“I didn’t want my kids to struggle with that,” said Smith, who has two sons. “It was my responsibility as a parent to be sure my sons were never left with making those decisions.”

With that, Smith set up a living will, durable power of attorney (DPOA) and an advance-care directive to ensure that his wishes for end-of-life care were clearly stated. Reduced to the simplest terms, Smith said he will choose quality of life over quantity and reject extraordinary lifesaving measures.

No bright lines

Smith’s experience exposes one of medicine’s knottiest issues – and one that is felt especially keenly in the blood cancer field, where many patients teeter on the edge of recovery and decline, sometimes for years. Too often, Smith said, providers, patients and families view end-of-life discussions and advance care planning as code words for abandoning hope that disease can be conquered.

“When we talk about ‘getting our affairs in order,’ it’s sometimes mixed up with the idea that we are no longer devoting our energy to curing disease or prolonging life,” Smith said. “We can do both.”

The idea behind advance-care planning, he said, is that people should make decisions about how they wish to spend their final days before they become too ill to do so and the emotional turmoil that frequently accompanies dying engulfs their loved ones.

That’s just a matter of personal protection, Smith noted. As he put it, “Nobody buys car insurance thinking they are going to wreck.”

Jeanie Youngwerth, MD, Director of the Palliative Care Service at UCH, said Smith is a “great role model and advocate for advance-care planning.  He speaks openly, guiding patients in having the gift of conversation with families about their values and wishes.

Families often struggle with important decision making because advance-care planning conversations never happened, Youngwerth added. “It’s important to help patients and families prepare before times of crisis and make a plan that is based on their values.”

The provider dilemma

But providers aren’t exempt. They too grope for the best ways to meld lifesaving clinical care with advance-care planning. That is particularly true for those treating blood diseases, said Tanisha Joshi, PhD, a counseling psychologist and assistant professor of Medicine at CU. Joshi is “embedded” with Smith’s team and meets regularly with them, not only to discuss their patients’ needs, but also how their patients’ struggles affect them.

The challenges are twofold, Joshi said. First, the course of treatment for blood cancers can be very unpredictable – in general, more so than for solid tumors. Patients can hover at the edge of death, then recover. Others may show encouraging signs, then quickly go downhill. In addition, patients very often spend long stints in the hospital, particularly after stem cell transplants, which leave them immunocompromised and therefore at very high risk of infection. If the donor cells come from another individual, patients may also fall prey to graft-versus-host disease, wherein the body attacks what it perceives as foreign bodies.

Yet at the same time, rapid medical advances, such as immunotherapy, continue to offer hope and may spur both patients and providers to pursue care aggressively.

These uncertainties raise the risk of compassion fatigue and burnout for providers, Joshi said. They may also create conflicts among them in discussions of care plans.

“Nurses, psychologists, social workers and physicians may see cases in different ways,” Joshi said. Some may see aggressive, lifesaving care as fulfilling a duty to do everything possible on behalf of the patient; others may see that as futile and instead advocate for easing the patient’s suffering and improving quality of life in the final days.

“It places an emotional load on the team,” Joshi said.

Delicate balance

Elissa Kolva, PhD (left) and Tanisha Joshi, PhD, lead a CU study that aims to examine how end-of-life care is delivered at UCHealth University of Colorado Hospital and the effect that difficult blood disease cases have on providers.
Elissa Kolva, PhD (left) and Tanisha Joshi, PhD, lead a CU study that aims to examine how end-of-life care is delivered at UCHealth University of Colorado Hospital and the effect that difficult blood disease cases have on providers.

The volatile mix led Joshi and Elissa Kolva, PhD, assistant professor of Medical Oncology at CU, to launch a study of  patients at UCH. Kolva will be analyzing the type of care provided to patients, including the site of death; end-of-life counseling provided, if any; presence of advance care and do-not-resuscitate directives; numbers of emergency department visits and hospital readmissions; access to primary care, and more.

Joshi is conducting 60- to 90-minute interviews with providers, including physicians, advanced-care practitioners, inpatient and outpatient nurses, social workers, psychologists and survivorship coordinators. She will probe their perceptions of the care they provide and search for patterns in their responses. What were the challenges? How did it impact them personally? How do they take care of themselves emotionally? Did they have enough training to deal with difficult situations? What are the patient stories that stand out to them?

The work is ongoing and data analysis will follow, but the ultimate aim is to get a clearer picture of how the team is providing end-of-life care and the effect it is having on them. Joshi calls it “bringing torches to a dark tunnel. We want to understand what is the landscape.” The study’s title speaks to answering an even more fundamental question: “When Is Enough Enough?”

Kolva notes that research supports that providers treating blood disorders have trouble answering that question. In one survey for example, 55.9 percent of hematological oncologists who participated said they believed end-of-life discussions began “too late.”

“Our project builds from that finding,” Kolva said. “We want to provide a level of comfort for hematologic oncologists to have end-of-life conversations.”

Entering those conversations can be very difficult for providers, Kolva acknowledged. The power of medical technology, in the form of a new treatment or trial or another transplant, can make the prospects for a patient’s recovery tantalizingly close. “Most providers have seen a miraculous case,” Kolva said.

But providers must guard against allowing their commitment to treatment override patients’ values, she added. Jehovah’s Witnesses, for example, will not submit to blood transfusions. Use of stem cells collected from discarded umbilical cords may conflict with some individuals’ moral standards. Others may believe faith will deliver them from disease. These and other factors can influence end-of-life discussions, even as they challenge providers’ own beliefs, Kolva said.

“We love to pretend we know how people will feel at the end of life,” she said. “None of us know. We have to continue to check our feelings as providers when we feel we are pulling in one direction.”

For his part, Smith believes Joshi’s and Kolva’s work will lead other providers to think about the unthinkable, just as he did three years ago.

“This work will open conversations about the practice of advance-care planning and prompt providers to think more broadly about discussing end-of-life care,” he said.





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Study finds an association between proximity to oil and gas development and childhood leukemia

Young Coloradans diagnosed with acute lymphocytic leukemia are more likely to live in areas of high-density oil and gas development compared to young Coloradans diagnosed with other types of cancer, according to researchers at the Colorado School of Public Health at CU Anschutz. The researchers observed no association between non-Hodgkin’s lymphoma and high-density oil and gas development.

Dr. Lisa McKenzie
Dr. Lisa McKenzie

“Over 378,000 Coloradans and millions of Americans currently live within a mile of at least one oil and gas well, and petroleum development continues to expand into residential areas,” said lead investigator Dr. Lisa McKenzie, assistant research professor at the Colorado School of Public Health. “The findings from our registry-based case control study indicate that young Coloradans diagnosed with one type of childhood leukemia are more likely to live in the densest areas of oil and gas sites. More comprehensive research that can address our study’s limitations is needed to understand and explain these results.”

Funded by the CU Cancer Center and published today in the journal PLOS ONE, the study shows children and young adults between the ages of 5 and 24 with acute lymphocytic leukemia were 4.3 times more likely to live in the densest area of active oil and gas wells than those with other cancers. The study focused on rural areas and towns in 57 Colorado counties and excluded urban areas of more than 50,000 people.

According to the report, U.S. oil and gas development has grown rapidly over the past 15 years and this industrial activity has the potential to emit toxic substances into air and water, including carcinogens like benzene.

According to current research, over 15 million Americans now live within 1.6 kilometers (1 mile) of oil and gas development. There are hundreds of oil and gas wells within one mile of a home in Colorado’s most intensive areas of oil and gas development. The study indicates that people living in areas of oil and gas development may be at an increased risk for health effects, including cancers, resultant from such industrial exposures.

The report concludes that future research should incorporate information on oil and gas development activities and production levels, as well as levels of specific pollutants of interest like benzene, near homes, schools and day care centers. It recommends such research consider specific ages and residential histories, compare cases to controls without cancer and address other potential confounders and environmental stressors.

Data for the study was obtained from the Colorado Central Cancer Registry and the Colorado Oil and Gas Information System. The study included 743 young Coloradans aged 0-24 years living in rural Colorado and diagnosed with cancer between 2001 and 2013.

Researchers used information from the Colorado Oil and Gas Information System to build a geocoded dataset with coordinates of all oil and gas wells in rural Colorado and determined dates for when each well was active.

Geocoded residential addresses of cancer patients at the time of diagnosis were linked to active well locations in the year of diagnosis and active well locations in each of the 10 years preceding the cancer diagnosis. They then took the inverse of each distance and summed the inverse distances to calculate inverse distance weighted oil and gas well counts within a 16.1 km radius of each participant’s residence at cancer diagnosis for each of the 10 years prior to the date of the cancer diagnosis. The inverse distance weighted well count method gives greater weight to the wells nearer the home. Age, race, gender, income, elevation of residence and year of cancer diagnosis all were considered in the analysis.

The study was limited by the low occurrence of leukemia and non-Hodgkin lymphoma in rural Colorado, lack of specific age at cancer diagnosis and the fact that all study participants had been diagnosed with cancer. The study also was limited by the lack of information on specific activities at the well sites, place of residence before cancer diagnosis, other sources of pollution around the residence and individual characteristics such as common infections and family history of cancer.

The other study authors are William Allshouse, Tim Byers, Berrin Serdar and John Adgate of the Colorado School of Public Health at CU Anschutz and Edward Bedrick of the College of Public Health at the University of Arizona.

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