Zosia Chustecka

December 05, 2016

UPDATED WITH INTERVIEW December 9, 2016 // SAN DIEGO, California ― After several years of excitement over clinical trial results with chimeric antigen receptor (CAR) T-cell therapy, commercial products are now approaching the market.

Two companies are planning to file for registration by early 2017. Because the products fill unmet medical needs, they were given priority designation, so they could be approved before the end of next year.

Novartis' product is CTL019, an anti-CD19 CAR T-cell therapy. The product, which is currently named tisagenlecleucel-T, was developed for use in the treatment of relapsed and refractory acute lymphoblastic leukemia (ALL) in pediatric patients. Results from a global registration trial (known as ELIANA), which were presented here at the American Society of Hematology (ASH) 2016 Annual Meeting (abstract 221), show an 82% complete remission rate and are detailed below. The data will be used to file for approval in the United States in early 2017 and in Europe later in 2017, the company said.

Kite's product, Kte-C19 (anti-CD19) CAR T-cell therapy, which is currently named axicabtagene ciloleucel, is for use in patients with refractory diffuse large B-cell lymphoma. Data from a pivotal phase 2 study (ZUMA-1) will be presented here on the last day of the ASH meeting (abstract LBA-6) and will be reported then. The data from this trial have already been submitted to the FDA on a rolling registration that should be finished by early 2017. The company said it plans to file in Europe in 2017.

But a third company has hit problems. Juno was also planning to file for approval in 2017 of its product JCAR015 on the basis of results from the ROCKET trial. JCAR015 is intended for treatment of adult patients with relapsed or refractory B-cell ALL. However, that trial is now on clinical hold after the deaths of five patients from cerebral edema.

Setback for Juno: Deaths From Cerbreal Edema

All three products utilize anti-CD19 CAR T cells, but they differ with respect to the transgene construct and manufacturing processes. These differences may explain why the Juno product, but not the others, has been associated with deaths from cerebral edema, commented Marcella Maus, MD, PhD, director of cellular immunotherapy at the Cancer Center in Massachusetts General Hospital, Boston. However, she pointed out that the Juno product is being used in a different patient population – adults with ALL ― whereas the Novartis product is intended for use in pediatric patients.

The two main severe adverse events seen with CAR T cell therapies are cytokine release syndrome (CRS), which is treated with the interleulin-6 blocker tocilizumab, and neurologic toxicity (encephalopathy, aphasia, seizures), Dr Maus commented. From the data, she said it appears that CRS is more common with the Novartis product, whereas the Juno product has more neurologic toxicity. Usually these neurologic symptoms are mild and reversible, and MRI scans of the brain appear normal. There have been no been previous reports of cerebral edema, but it seems that in some patients in the Juno trial, "this neurological toxicity tipped over into something more serious and irreversible."

Elizabeth Budde MD, PhD, assistant professor in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope Hospital in Duarte, California, agrees. She is one of a new breed of immunotherapists, working in a specialty that emerged only in the past few years as novel ways of manipulating the immune system to fight cancer have been developed.

Dr Budde has been involved in several trials of CAR T cells. In an interview with Medscape Medical News, she emphasized the importance of close monitoring with an experienced eye, "as these patients can crash at any time."

One of the concerns with treating the adverse events of these therapies is the fear that this may interfere with the efficacy of CAR T cells, but by now, accumulated data show that this does not occur with use of tocilizumab to treat CRS. Tocilizumab is now used early on and is effective at reversing CRS. A trial is planned in which tocilizumab will be used prophylactically to prevent CRS from developing, she said.

There is still some concern that the use of corticosteroids to treat neurologic symptoms may dampen CAR T-cell efficacy, and she wonders whether, in the Juno cases, there was a delay in starting steroids. She again emphasized that close monitoring is needed – she and other members of her team are on call 24 hours a day, and the nursing staff has been intensively trained on what to look out for in these patients. This neurologic toxicity can be life-threatening, she said, and so quick intervention is needed. She mentioned one patient who started to become confused, had trouble speaking, and stopped recognizing the nurse. This patient was immediately treated with steroids, even though this was a deviation from the clinical trial protocol. "The patient is more important that the protocol," she said.

Dr Budde speculated that in the Juno studies, there may have been a delay in treating neurologic symptoms with steroids, and as a result, symptoms progressed and then developed into cerebral edema. She emphasized that cerebral edema has not been reported for the other two CAR T-cell products (from Novartis and Kite) and that the deaths in the Juno trial should not cast a cloud over the field. This is a problem that seems to be confined to a particular product in a particular trial (JCAR015 in the ROCKET trial).

CAR T Cells in Multicenter Studies

Dr Maus was impressed by the global registration study that was undertaken for the Novartis product. That study involved 25 centers in the United States, Europe, Canada, Australia, and Japan. Each patient in the trial underwent leukapheresis, and blood extracts were sent to a Novartis facility in the United States, where the personalized CAR T-cell therapy was manufactured for each individual. The therapies were then returned to the treating centers for administration to the patients.

The Kite study was similar and was conducted in 22 centers in the United States. The investigators report that the average turnaround time from patient apharesis to receipt of the product was 17 days.

"This is a tremendous feat," commented Dr Maus. This is very complex therapy, she noted, with complicated chain of custody for the product. In addition, adverse events require unusual management in comparison with other leukemia treatments, so the fact that the trial was conducted across so many sites is "remarkable," she said.

Commenting specifically on the Novartis trial, Dr Maus said the responses seen in pediatric ALL patients are "groundbreaking." They are not quite as high as has been previously seen in single-center studies, but the 82% complete remission rate is "quite remarkable."

These patients have few other options, Dr Maus commented. These are really sick patients – six died of their disease before they underwent infusion. Half of the patients had already undergone a stem cell transplant, and she suspects that the remainder were ineligible for transplant, because either the disease would not go into remission or donors were unavailable.

There has already been much excitement over the early clinical results with CAR T-cell therapy in leukemia. Experts have said that results showing that this approach can eradicate the disease are "landscape changing."

"This whole field has just exploded. It probably represents one of the most exciting therapeutic strategies to be tried in any form of leukemia, let alone ALL, in the last decade or so," commented Daniel DeAngelo MD, PhD, assistant professor at Harvard Medical School and the Dana-Farber Cancer Institute in Boston.

The new data now being reported confirm the efficacy seen in earlier studies and show that this novel approach is feasible across many different centers. The new results provide details of the adverse events that can be expected.

Details of Novartis Global Registration Trial

Details of the global registration ELIANA study were presented at the ASH meeting by Stephan Grupp, MD, PhD, from the Center for Childhood Cancer Research, Children's Hospital of Philadelphia, in Pennsylvania.

The trial enrolled 87 pediatric and young adult patients with CD19-positive B-ALL (average age, 12 years; range, 3 to 23 years). There were five manufacturing failures, six patients died before undergoing infusion, and three patients discontinued therapy before infusion because of adverse events. A total of 62 patients underwent infusion.

Dr Grupp presented efficacy data on the first 50 patients who underwent infusion and for whom 3 months' follow-up data were available. Of these, 41 patients (82%) achieved complete remission and were found to be negative for minimal residual disease at 3 months.

The 6-month relapse-free survival rate was 60%, and the 6-month overall survival rate was 89%.

Safety data were reported for 62 patients. The majority of adverse events occurred in the first 8 weeks and then subsided, Dr Grupp reported. Adverse events of grade 3 or 4 that were suspected to be product related were seen in 74% of patients in the first 8 weeks and in 10% of patients after 8 weeks.

The most common adverse event was CRS, seen in 79% of patients (grade 3 in 27%, grade 4 in 27%). The average time to onset of this syndrome was 3 days (range, 1 to 22 days), and the average duration was 8 days (range, 1 to 36 days). More than half (59%) of the 49 patients who developed CRS were admitted to the intensive care unit; 20% underwent invasive ventilation, and 10% underwent dialysis. Dr Grupp described this adverse event as "manageable" and noted that no deaths occurred.

In addition, decreased in appetite was experienced by 39% of patients, pyrexia occurred in 37%, hypotension in 33%, elevations in liver enzyme levels in 31%, hypokalemia in 26%, and hypoxia in 23%. Cytopenias that had not resolved by day 28 were seen in 37% of patients, infections were seen in 40%, and transient neuropsychiatric events occurred in 45% (grade 3 in 15%).

Two deaths occurred within 30 days of infusion, one from ALL and one from cerebral hemorrhage. No cases of cerebral edema were seen, Dr Grupp noted.

Dr Grupp concluded that the product CTL019 offers a new option for pediatric and young adult patients with relapsed/refractory B-cell ALL.

"This Therapy Is Not for the Fainthearted"

Commenting on CAR T-cell therapy generally, ASH president Charles Abrahms, MD, said that because of the serious adverse events, "this therapy is not for the fainthearted, but we can usually carry patients through." Until recently, this therapy had been given within a university setting, with specially trained personnel who had experience with the technology and its adverse effects.

These new multicenter studies show that CAR T-cell technology can be used in a broader setting, Dr Abrahms commented.

However, Dr Budde commented that these therapies will never reach a community setting. These are complex therapies with potentially very serious adverse effects, and they should be used in comprehensive medical centers with experience in stem cell transplantation, she said. The centers must also have excellent intensive care units, Dr Grupp noted in his presentation.

In addition, the clinicians caring for these patients should be dedicated immunotherapists, Dr Budde said: there needs to be a dedicated team of physicians and nurses who have undergone extensive education in how to care for patients receiving CAR T cells.

This is a treatment approach that does carry risk, but it also offers for many refractory and relapsed patients the only chance of remission, and perhaps also a chance of cure, Dr Budde said. Some of the patients in the earlier CAR T-cell trials (including pediatric patients with ALL) remain free of disease after 4 years. Although some went on to receive a transplant, others have remained disease free for 4 years (and counting) after just one infusion of CAR T cells.

In those patients, one dose of CAR T cells eradicated the disease.

The ELIANA study was funded by Novartis. Dr Grupp has served as a consultant for Jazz Pharmaceuticals, Novartis, and Pfizer. Several coauthors are Novartis employees.

American Society of Hematology (ASH) 2016 Annual Meeting. Abstract 221, presented December 3, 2016.


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