The UCHealth University of Colorado Cancer Center – Anschutz Medical Campus is part of the latest clinical trial testing a new and promising line of attack against lethal blood cancers.

The trial, sponsored by Seattle-based Juno Therapeutics, targets patients with diffuse large B cell lymphoma, an aggressive variety of the blood cancers classified as non-Hodgkin lymphomas. The disease causes the body’s B cells – a type of lymphocyte, or white blood cell, that normally act as infection-fighting soldiers in the body’s immune system – to grow exponentially. The rogue cells travel to other parts of the body through the lymphatic system, where they collect and form malignant tumors.

Diffuse large B cell lymphoma, or DLBCL, is one of the most common forms of aggressive non-Hodgkin lymphomas, with some 72,000 cases diagnosed each year, said Manali Kamdar, MD, clinical director of Lymphoma Services for the Cancer Center. Patients with newly diagnosed DLBCL usually receive a combination of chemotherapy drugs to wipe out the cancer, Kamdar said, and nearly two-thirds of them are cured.

However, 30 to 40 percent either do not respond to initial therapy or relapse shortly thereafter. The standard of care for these patients is more intense chemotherapy, Kamdar said, followed by a transplant of the patient’s own blood-forming stem cells.

“Unfortunately, very few patients respond to salvage chemotherapy and even fewer are able to proceed to stem cell transplant,” Kamdar said. “These patients uniformly have shown to have a dismal prognosis.”

The toughest cases

It is these patients – specifically those who have tried at least two lines of treatment unsuccessfully – who are the focus of the Juno trial. It’s part of a fast-growing effort to develop therapies that re-engineer the body’s own cells to seek and destroy cancer cells.

The approach, broadly called CAR (chimeric antigen receptor) T cell therapy, aims to target cancer cells precisely rather than bludgeon them, along with healthy cells, as chemotherapy does. The target in the Juno trial is a protein expressed by DLBCL cells known as CD19. To develop an attack, clinicians first use apheresis to separate T cells, which recognize and fight viruses in the body, from the patient’s blood. They send the T cells to Juno facilities, where they are injected with a virus that genetically reprograms them to recognize the CD19 protein using specially developed receptors: CARs.

The reprogrammed cells thus become dedicated DLBCL fighters, but before they can help the patient, their forces must grow by millions. Juno does so at its manufacturing plant, then sends the re-engineered T cells back to the treatment provider – in this case the Cancer Center. The patient receives a series of three chemotherapy treatments to eliminate the lymphocytes that would perceive the new T cells as invaders and attack them. With that accomplished, clinicians infuse the patient with the CAR T cells, which go on the attack against the DLBCL cells waving their CD19 red flags, binding to the protein and killing the cells.

CAR T cell therapy has generated great excitement recently. Kymriah, a Novartis-developed therapy for children and young adults up to age 25 with acute lymphoblastic leukemia (ALL), received FDA approval in August. It too targets the CD19 protein. More than 80 percent achieved remission within one month of therapy.  The longest ALL CAR T-treated patient is more than five years from treatment and she remains in remission. Kymriah could receive approval to treat DLBCL soon.

Yescarta, from Kite Pharma, in October became the first FDA-approved CAR T therapy for patients with DLBCL who relapsed after two previous treatments of other kinds. The target once again is CD19.

Forging new frontiers

“What was once science fiction is becoming reality,” said Enkhtsetseg Purev, MD, PhD, a hematologic oncologist and principal investigator for the Juno trial at the Cancer Center. Early results of the therapy, dubbed JCAR017, have been encouraging, she said. About 80 percent of the roughly 30 DLBCL patients enrolled nationwide had responded after 30 days to the CAR T treatment, while 60 percent had achieved a “complete response” and gone into longer-term remission.

William McDuffie, 67, of Cheyenne, Wyoming, hopes to be among the success stories. McDuffie, the Cancer Center’s first JCAR017 trial patient, worked as an office manager in a manufacturing plant and enjoyed relatively good health until February 2015, when he began experiencing night sweats. He lost weight abruptly, shedding 65 pounds in only two months. He said he also began to “get loopy,” with strange dreams and hallucinations.

“It was scary,” said his wife Grace.

In August 2015, McDuffie spent more than three weeks in the hospital in Cheyenne, where he was diagnosed with DLBCL. By then it had spread under both clavicles and into his spleen. He improved after chemotherapy treatment, but relapsed after 10 months. His oncologist referred him to Kamdar, who ordered a second round of chemotherapy known as RICE, a combination of four drugs. That too failed after several rounds, and a PET CT scan showed that the lymphoma continued to progress.

By that time, McDuffie had had enough of chemo, which combined with the disease to leave him weak and without an appetite. He was fatigued and unsteady, making his daily walking difficult. The simple act of walking through a doorway became a potential misadventure. Grace took over bill-paying and all the daily household chores as his health steadily declined.

There was a ray of hope: the JCAR017 had officially opened at the Cancer Center. McDuffie said he was aware of the budding studies of CAR T cell therapy, having read articles about it in The Economist and the New York Times, and decided it was worth a try.

In late September, the Cancer Center’s Apheresis Unit collected McDuffie’s T cells. They went to the Juno manufacturing facility and returned to the Cancer Center three-and-a-half weeks later, packaged and frozen in vials. After three days of lymphocyte-suppressing chemotherapy, McDuffie rested for a day, then received the CAR T cells in two infusions performed in mid-October on the Blood and Marrow Unit at UCHealth University of Colorado Hospital. He spent the next two weeks there for recovery and observation.

Speaking with a visitor in the Cancer Center in early November, McDuffie discussed forthrightly the ordeals of the past two-and-a-half years – the physical and mental challenges of the disease and the many infusions, scans and biopsies that came as part of the battle against it. He’d regained most of the weight he’d lost and was hopeful the trial had given him another chance at life.

“I feel fine,” he said, as he awaited a November 14 PET scan that would reveal if the CAR T cell treatment had cleared the cancer from his body. He was also encouraged that he’d thus far avoided what up to now has been a serious side effect of CAR T cell therapy: cytokine release syndrome (CRS), a reaction to the specialized T-cells that can drive dangerously high fevers, low blood pressure, fluid retention, and neurologic problems. The Juno therapy aims to reduce the incidence of CRS in patients.

“We believe that the Juno therapy is probably as potent as the other CAR T cell therapies, with not as many side effects,” Kamdar said.

Hope mixed with challenge

As the CRS problem illustrates, the burgeoning CAR T cell therapy field that is both ripe with possibilities and rife with risk. For example, a host of studies are underway to develop therapies that target other proteins expressed by cancer cells, such as CD20 and CD22. These might be administered individually or in combination, Purev said, to treat a widening number of blood cancers.

In addition, the strong clinical results of Kymriah and Yescarta and the early promise of JCAR017 suggest that CAR T cell therapy, now used to treat only the sickest patients, might be used more broadly, said Clay Smith, MD, associate chief of the Division of Hematology at the University of Colorado School of Medicine and director of the UCHealth Blood Disorders and Cellular Therapies Center.

“We now have a whole new form of treatment that is poised to revolutionize how we deliver care – and it’s only the tip of the iceberg,” Smith said. “We may be able to use CAR T cell earlier to prevent disease from progressing. I think that’s likely to happen.”

The implications of such a change are significant, added Jonathan Gutman, MD, associate professor of Hematology at the CU School of Medicine. “We are hopeful that this strategy may ultimately be able to replace transplant as a much less complex, toxic, and risky procedure than stem cell transplant,” Gutman said.

On the other hand, it’s a therapy that will be challenging to scale. Only a relative handful of medical centers are equipped to handle it. Approved sites will need to master the logistics of performing apheresis, collecting and shipping the T cells, receiving and storing the reengineered versions and infusing them back to the patient. They will also need to monitor and manage patients’ long-term care for up to 15 years.

Purev noted that the Cancer Center and University of Colorado Hospital are well positioned to meet these requirements. Longer-term, work is underway with the Gates Center for Regenerative Medicine and ClinImmune Labs, both located on the University of Colorado Anschutz Medical Campus, to make the manufacture and storage of CAR T cells a home-grown operation, she added.

An in-house cell-manufacturing program is an important step in pushing cell-based therapy forward both locally and nationally, Gutman said, and one that requires a “huge institutional commitment” from UCHealth, CU and Children’s Hospital Colorado.

One turn in a long road

Even deeper resources will be required to plumb the mysteries of the immune system, however. Smith pointed out that the bold headlines accompanying immunotherapy stories today belie decades of trial and error in basic science and research that preceded them. Work to genetically modify immune cells date back to the late 1980s, notably through the work of Steven Rosenberg, MD, PhD, longtime chief of surgery at the National Cancer Institute. It wasn’t until 2010 that Rosenberg and colleagues reported successfully using a patient’s genetically reengineered T cells to recognize CD19 expressed by B cells. In 2014, Rosenberg published a paper describing how modified T cells could be used to effectively treat metastatic melanoma and renal cancer.

In the three decades between, Smith said, work proceeded sporadically, with “waves of excitement, followed by excess hype and disappointment.” Fortunately, he added, Rosenberg and a small group of other researchers kept plugging away, making incremental advances that eventually revealed not only how to modify T cells, but also how to grow them in sufficient numbers without causing them to lose their cellular identities – that is, their natural inclination to fight invaders, including cancer cells.

But their work opened the door to new questions. For example, a key challenge today for CAR T cell therapy is understanding why, in some patients, the treatment works for a time but fails to persist. In these patients, the modified cells mysteriously vanish, usually within three months, Kamdar said.

Perhaps even more difficult is the question of what constitutes therapeutic success for CAR T cell patients. The percentage of DLBCL patients in the Juno trial who have gone into complete remission thus far is “unheard of,” Kamdar said, “but that clearly begs the question, given that stellar response rate, will it be durable?”

The question is particularly pointed because remission is a prerequisite to a stem cell transplant, and is today considered the best chance at a cure for relapsed DLBCL, Kamdar said. If a patient remains in remission after CAR T cell therapy, do providers watch and wait, thereby sparing a painful and expensive transplant but also risking a relapse that precludes a transplant?

“As the years unfold we will have more insight as investigators that we can actually [use to] provide real data-driven results for patients so they can make an informed decision,” Kamdar said.

Perhaps a cure, but at what price?

Inevitably, any new, potentially break-through therapy leads to questions of cost. For Kymriah, the cost is pegged at close to a half-million dollars to the hospital alone and does not reflect the total cost of care. Stem cell transplants drive the price tag still higher. Assuming just a fraction of those with DLBCL alone were to receive CAR T cell therapy, the costs today could easily mount into the billions, Smith said – an obviously unsustainable number.

That’s the “huge caveat,” he cautioned, in all discussions of the future of cancer treatment, which includes not only CAR T cell work but also discovery of new ways to detect and target the genetic fingerprints of tumor cells, including their DNA and RNA mutations, their signaling pathways, their waste products and more.

Analyzing an “ocean of data” that contains the clues to developing precision drugs and therapies for an individual’s specific cancer is “exciting stuff” that will be, at least for the foreseeable future, “horribly expensive,” Smith said.

“We have to find ways to take the technology we have and make the therapies simpler and cheaper and multiply that across society,” he said. “It’s hugely important that we not only make sure that therapies work but that we also devote the same energy to making them affordable.”

Purev, in turn, notes that insurers will have a huge stake in the answers to these questions and will have a significant say in the availability of the new therapies, including CAR T cell. The as-yet unanswered question of whether a stem cell transplant following treatment truly sustains remission or simply adds to the cost of care is just one example, she noted.

“Payers will have to be convinced that it is worth it,” Purev said.

For William McDuffie, these questions, however relevant they may be to the future of medicine, are abstractions. For now, he is poised on the precipice of hope. On November 15, he and Grace learned the encouraging results of his PET scan. It showed that the JCAR017 therapy had reduced the tumors in his body by about fifty percent.

Both Purev and Kamdar said they remain hopeful, noting that many patients treated with CAR T therapy continue to respond after the 30-day mark. McDuffie is slated for a second PET scan Dec. 11, but will not need any further treatment before that time.

“We are hopeful he will continue to show a deeper response on the next PET scan,” Kamdar said.

As McDuffie waits, more people like him are looking for hope. The second JCAR017 trial patient at the Cancer Center received the therapy Nov. 17, Purev said. A third patient, she added, is scheduled to have T cells collected the following week for shipment to Juno. All these patients, and those to come, will add to the store of knowledge that helps to define the ever-changing face of modern medicine.

On a related note, researchers from the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, selected to estimate the cost-effectiveness of the newly approved CAR-T therapies, have found the clinical benefit of CAR T therapy may justify the expensive price. Attached is a video of Melanie Whittington, Ph.D., who was involved in creating a report about the value of CAR-T.