February 2017 Edition Vol.12, Issue 2

CAR T-Cell Therapy on Fast Track for Commercialization in 2017

By Chase Doyle

San Diego—Though still plagued by toxicity concerns, chimeric antigen receptor (CAR) T-cell therapy is showing remarkable promise in hard-to-treat blood cancers with no other approved options, and commercial products are rapidly approaching the market.

The technology — which involves engineering a person’s own immune cells to recognize and attack cancer cells — is fulfilling a significant unmet need for patients: it’s shown activity in myriad hematologic malignancies, including chronic lymphocytic leukemia, several types of non-Hodgkin lymphoma, and, most recently, multiple myeloma.

The story at the 2016 ASH Annual Meeting, however, was scalability. In just a few short years, CAR-T cell therapy has jumped from single-institution studies of 10 to 20 patients to a global registration trial involving 22 centers and more than 100 patients.

More importantly, expansion of this highly personalized treatment has not reduced its efficacy. Rather, these pivotal studies show that CAR T-cell manufacturing, treatment logistics, and the management of adverse events can be successfully implemented across multiple sites.

Multicenter Trial a “Tour de Force”

Because the technology for generating engineered cells is not widely distributed, T cells must be extracted from each patient and shipped to a central lab, where they are modified and grown to clinically useful levels, before being shipped back to the clinic and re-infused in patients.

It’s a complicated chain of custody for even a small number of patients, but lead investigator Stephan Grupp, MD, PhD at the Perelman School of Medicine at the University of Pennsylvania, noted that orchestrating treatment at the scale of the ELIANA trial, was nothing less than a “tour de force”.1

Funded by Novartis, ELIANA is the first global CAR T-cell trial in ALL. The study enrolled 87 pediatric and young adult patients with CD19­-positive, relapsed/refractory B-cell ALL in 25 centers in the United States, Europe, Canada, Australia, and Japan.

Dr. Grupp presented at ASH efficacy data on the first 50 patients who underwent infusion and had 3 months follow-up data available. Of those, 41 (82%) achieved complete remission and were found to be negative for minimal residual disease at 3 months. The remissions lasted at least 6 months in 60% of patients, and the 6-month overall survival rate was 89%.

“These global multicenter trial data build on earlier encouraging research conducted at a single trial site and advance the case for CTL019 as a potential treatment for children and young adults with relapsed or refractory B-cell ALL,” said Dr. Grupp.

Findings from ELIANA are intended to form the basis for FDA and European Medicines Agency approval of CTL019, the anti-CD19 CAR T cells used in the study. Novartis expects to complete submissions in early 2017.

Although these outcome data may not differ significantly from trials past, what’s thrilled investigators is the technology’s now proven scalability – the coordination of treatment in a multi-centered fashion, even among institutions with no previous CAR T-cell experience.

Marcela Maus, MD, PhD, Director of Cellular Immunotherapy at the Cancer Center in Massachusetts General Hospital in Boston, echoed Dr. Grupp’s exuberance, calling the study’s completion a “tremendous feat”.1

It’s not just the complexity of the product or its administration that impressed, either. Adverse events associated with the therapy require a dedicated team of physicians and nurses who have undergone extensive education in caring for patients receiving CAR T cells.

Although the responses seen in pediatric ALL patients may not be as high as previous single-institution studies, said Dr. Maus, the 82% complete remission rate is still “groundbreaking” because the trial was managed across so many sites.

Phase II ZUMA-1 Trial

Engineered immune cells are also showing promise in aggressive forms of non-Hodgkin’s lymphoma. In the first pivotal, multicenter study of anti-CD19 CAR T cells in treatment-refractory non-Hodgkin’s lymphoma, interim analysis showed a nearly 6-fold higher rate of complete remission compared with historical outcomes.

Sattva S. Neelapu, MD, of The University of Texas MD Anderson Cancer Center, presented results of the phase II ZUMA-1 study (n=101), which met its primary endpoint with an overall response rate of 76% and a complete response rate of 47% following a single infusion with KTE-C19, a CAR T-cell therapy targeting CD19 (p<0.0001)2.

At 3 months, the durable complete response was 39%, reported Dr. Neelapu.

Manufactured by Kite Pharma, the KTE-C19 product demonstrated high-level activity against diffuse B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma.

The study, conducted in 22 centers across the United States and Israel, also demonstrated a similar mastery of logistics as in the ELIANA trial. In spite of geographic hurdles, investigators reported a 99% manufacturing success and an average “door-to-door delivery” time of 17 days.

“The rapid turnaround time from white blood cell extraction to receipt of product is crucial because these patients can’t afford to wait,” said William Go, MD, PhD, Senior Director of Clinical Development at Kite Pharma in an interview with OBR.

“In this trial, 91% of enrolled patients were successfully dosed. The patients who couldn’t receive treatment were typically too advanced with complications of their rapidly progressing disease,” he said.

Based on these findings, Kite Pharma initiated a rolling FDA submission for KTE-C19 as a treatment for relapsed/refractory aggressive B-cell non-Hodgkin’s lymphoma in patients who are ineligible for autologous stem cell transplant.

The primary analysis for this phase II study is expected in the first quarter of 2017 when all treated patients have at least 6 months of follow-up.

Toxicities Serious but Manageable

Despite these successes, CAR T-cells’ march of progress has not gone unabated.

Juno Therapeutics recently put its pivotal ROCKET trial on hold because of 5 deaths due to cerebral edema. Its lead product, JCAR015 in ALL, also utilizes anti-CD19 CAR T cells, but differs with respect to transgene construct and manufacturing processes.

According to Dr. Maus, these differences may account for the neurologic toxicities, but the product was also being tested in adults with ALL compared to pediatric patients in the Novartis trial.

Whether Juno will shift its focus to a different construct remains to be seen, but these high-profile deaths underscore the treatment’s potentially deadly side effects.

“This therapy is not for the fainthearted,” said ASH president Charles Abrams, MD, “but we can usually carry patients through.”

Of the 62 pediatric patients with ALL who underwent infusion in the ELIANA study, the majority of adverse events occurred in the first 8 weeks and then subsided, Dr. Grupp reported.

Grade 3 or 4 adverse events thought to be treatment 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 cytokine-release syndrome (CRS), seen in 79% of patients (Grade 3 in 27%; Grade 4 in 27%). 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.

In the ZUMA-1 study, although 86% of patients experienced a serious adverse event, only 12% experienced Grade 3 or higher CRS. In addition, said Dr. Neelapu, 27% of patients experienced a Grade 3 or higher neurologic event, but these were generally reversible and no cases of cerebral edema were observed.

A Chance for Complete Remission

Clearly, this new approach to treatment carries risk, but for many refractory and relapsed patients, CAR T-cell therapy also offers the only chance for remission, and sometimes even a cure.

“Unfortunately, there are limited FDA approved products for these refractory aggressive non-Hodgkin’s lymphoma patients. Normally at this stage, I would be answering questions about palliative care and helping patients get their affairs in order. That’s why this therapy is so meaningful for these patients. In our clinical studies of axicabtagene ciloleucel, we have observed complete remissions one month after a single transfusion of their own engineered immune cells,” said Dr. Go.

In the ELIANA study, half of pediatric ALL patients had already undergone a stem cell transplant and the remainder were ineligible.

“These are really sick patients,” said Dr. Maus, who noted that 6 patients died of their disease before they underwent infusion. “They have few other options.”

And yet, some pediatric ALL patients from earlier trials continue to remain disease free 4 years later after just 1 infusion of CAR T cells. Although the side effects can be serious, when handled at centers of experience equipped with excellent intensive care units, they have been generally manageable and reversible, said Dr. Go.

“There are about 200 comprehensive medical centers with experience in stem cell transplantation and they’re used to treating severe adverse events,” he said.

Dial-able Switches and Off-the-Shelf CARs

“Just as mobile devices have progressed from primitive Palm Pilots to the multifaceted and streamlined machines that dominate today’s communications, CAR-T technology will continue to evolve,” said Dr. Go.

“Think of these products as version 1.0,” he explained. “The science is advancing just as rapidly as smart phone technology.”

The future may be fast approaching, but for those on the leading edge, it’s not impossible to foresee. KITE Pharma has a vision for what the world of engineered immune cells can and will become.

“KITE doesn’t want to stop advancing therapy,” said Dr. Go. “After we focus on hematological malignancies and potentially solid tumors, we’ll work on dial-able switches to modify these cells while in the patient. Theoretically, if engineered T cells are too strong, you can dial them down; if they’re not strong enough, you can turn up the volume.”

“Once we understand that,” he added, “we may move to off-the-shelf technologies so we can have a renewable resource. There’s a lot more complexity in this area, but I believe this will happen over time.”


1. Grupp SA, et al “Analysis of a global registration trial of the efficacy and safety of CTL019 in pediatric and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL)” ASH 2016; Abstract 221.

2. Neelapu S, et al. “KTE-­C19 (anti­-CD19 CAR T Cells) induces complete remissions in patients with refractory diffuse large B-­cell lymphoma (DLBCL): results from the pivotal phase 2 ZUMA­1” ASH 2016; abstract LBA­6.

Post a Comment

OBR Archives

To view previous issues of OBR green you can visit our archives. The entire library of OBR green articles is searchable.