First CAR T-Cell 'Living Drug' Approved by FDA 

Zosia Chustecka

August 30, 2017

UPDATED AUGUST 31 // The first T-cell therapy that uses chimeric antigen receptor (CAR) technology has been approved today by the US Food and Drug Administration (FDA), paving the way for the other products using this novel approach that are in development.

"We're entering a new frontier in medical innovation with the ability to reprogram a patient's own cells to attack a deadly cancer," said FDA Commissioner Scott Gottlieb, MD.

The product is tisagenlecleucel-T (Kymriah, Novartis), approved for use in pediatric and young adult patients (age 3 to 25 years) with relapsed or refractory acute lymphoblastic leukemia (ALL).

Novartis announced that the product will be priced at $475,000, which has caused some sharp intakes of breath across the oncology community, but it has also been pointed out that this is a 'one-off' therapy that is potentially curative. In successful cases, the one-time treatment eradicates the leukemia. The nearest parallel is bone marrow transplants, which cost around $800,000 for an allogeneic bone marrow transplant in the United States and around $350,000 for an autologous transplant, although costs vary widely.

"The approval of CAR T-cell therapy for pediatric leukemia marks an important shift in the blood cancer treatment paradigm," commented Kenneth C. Anderson, MD, from the Dana-Farber Cancer Institute, Boston, Massachusetts, and president of the American Society of Hematology.

"We now have proof that it is possible to eradicate cancer by harnessing the power of a patient's own immune system. This is a potentially curative therapy in patients whose leukemia is unresponsive to other treatments and represents the latest milestone in the shift away from chemotherapy toward precision medicine."

The FDA describes the new product as a cell-based gene therapy, and more specifically as a genetically modified autologous T-cell immunotherapy, prepared individually for each patient.

"New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses," Dr Gottlieb commented. "At the FDA, we're committed to helping expedite the development and review of groundbreaking treatments that have the potential to be life-saving."

The FDA approval comes hot on the heels of a unanimous vote in favor of recommended approval from 10 experts convening at a recent Oncology Drugs Advisory Committee meeting, as reported by Medscape Medical News. At that meeting, David Lebwohl, MD, head of the CAR T Cell Global Program at Novartis, said that he had been involved in hematologic drug development for 20 years but has "never seen anything like this before."

The product achieves a consistently high overall rate of remission and has "the potential to be a definitive therapy — many patients do not require further therapy…. This is truly a paradigm shift in a setting of enormous medical need," he told the meeting attendees

The data that led to approval come from one multicenter clinical trial of 63 pediatric and young adult patients with relapsed or refractory B-cell precursor ALL. The overall remission rate within 3 months of treatment was 83%.

"Kymriah is a first-of-its-kind treatment approach that fills an important unmet need for children and young adults with this serious disease," said Peter Marks, MD, PhD, director of the FDA's Center for Biologics Evaluation and Research. "Not only does Kymriah provide these patients with a new treatment option where very limited options existed, but a treatment option that has shown promising remission and survival rates in clinical trials."

Risk for Severe Adverse Events

However, the new approach carries with it a risk for adverse events that can become severe, and even life-threatening, and this is restricting use of the therapy to specially certified centers.

The product has a boxed warning for cytokine release syndrome (CRS), a systemic response to the activation and proliferation of CAR T cells causing high fever and flu-like symptoms, and for neurologic events. Both CRS and neurologic events can be life-threatening, the FDA warns.

In clinical trials, CRS has been treated successfully with an interleukin-6 blocker, tocilizumab (Actemra, Genentech), which is already marketed for use in rheumatoid arthritis. The FDA has now expanded its indication to include treatment of CAR T cell–induced severe or life-threatening CRS in patients 2 years of age or older. The agency noted that in clinical trials among patients treated with CAR T cells, 69% of patients had complete resolution of CRS within 2 weeks after one or two doses of tocilizumab.

Other severe side effects seen with CAR T-cell therapy include serious infections, hypotension, acute kidney injury, fever, and hypoxia.

The FDA noted that most symptoms appear within 1 to 22 days following infusion of Kymriah. Because the CD19 antigen is also present on normal B cells, and Kymriah will also destroy normal B cells that produce antibodies, there may be an increased infection risk for a prolonged period.

Because of the risk for CRS and neurologic events, Kymriah is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use, the agency noted.  

The agency has also mandated that hospitals and their associated clinics that dispense Kymriah be specially certified. As part of that certification, staff involved in the prescribing, dispensing, or administering of Kymriah are required to be trained to recognize and manage CRS and neurologic events.

Additionally, the certified healthcare settings are required to have protocols in place to ensure that Kymriah is given to patients only after verifying that tocilizumab is available for immediate administration. The REMS program specifies that patients be informed of the signs and symptoms of CRS and neurologic toxicities following infusion — and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Kymriah.

One Shot, Potentially Curative

This is incredibly exciting, with unbelievable potential," commented Lee Greenberger, PhD, chief scientific officer of the Leukemia & Lymphoma Society, in a recent  interview, as previously reported by Medscape Medical News.

 "This is just the tip of the iceberg," he predicted.

Next likely to reach the market is Kite's axicabtagene ciloleucel (KTE-C19) for lymphoma, and CAR T cells aimed at other leukemias and for multiple myeloma are under development.

"It's a one-shot therapy that looks to be curative," he said.

The first patient treated with tisagenlecleucel has been leukemia free for more than 5 years, and 5 years is often used as the benchmark in cancer as to whether the patient has beaten the disease. "We are getting there, we are in that range," he said.

"It's still early days," he added, noting that in the pivotal trial that was the basis of approval, the overall survival (OS) rate at 12 months was 80% with tisagenlecleucel-T. This is double what has been previously reported (40% with blinatumomab and 20% with clofarabine monotherapy; the median OS durations were 16.6 months, 7.5 months, and 3 months, respectively).

"To get this sort of response in a relapsed/refractory ALL population is absolutely remarkable," Dr Greenberger commented.

For this patient population, CAR T-cell therapy offers a last chance — patients in the pivotal trial had already undergone a median of three prior therapies, and more than half had undergone hematopoietic stem cell transplantation.

These are patients with few options and a very poor prognosis, Dr Greenberger said. For these patients, the therapy is lifesaving.

"Living Drug" Made Individually for Each Patient

The product is made individually for each patient. After blood is taken from the patient, it undergoes a process that involves extracting T cells, subjecting the cells to CAR cell engineering, and then infusing the engineered T cells back into the patient.

Because they grow and expand in the body and then lie dormant, CAR T cells have been described as "livings drugs."

The "living drug" description is apt, said Malcolm Brenner, MD, PhD, founding director of the Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, who has been working with these therapies for the past 20 years.

"It's an important concept," he told Medscape Medical News.

"What you start off with isn't what you end up with," he added.

"I wouldn't say this is a new concept, as bone marrow transplant is also a living drug...but this is quite a different concept from usual drugs, which are gradually cleared out of the body."

"These cell therapies are potentially very long-lived...which is good, as you want to keep the leukemia at bay, but if you develop side effects, they can also last a very long time, and also, because the cells are growing and expanding, the side effects can become worse," he noted. "These therapies need very careful monitoring," he added.

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 has been involved in several trials of CAR T cells, and 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."

The worst of the side effects occur within a week or two of infusion, when the cells are expanding and attacking the leukemia. Some of the side effects can be very severe, even life-threatening. The two most concerning side effects are CRS, which was severe in about half of the patients in the pivotal trial, and neurologic toxicity, which developed in nearly half of the patients (44%).

In early trials with CAR T-cell products, these side effects resulted in several deaths, but clinicians have since learned how to manage these adverse events, for example by using tocilizumab for CRS and steroid for neurologic toxicity. There were no deaths due to treatment in the pivotal trial with  tisagenlecleucel-T.

Although these side effects are severe, they are not more severe than those associated with bone marrow transplants; however, the side effects are different, Dr Brenner commented. "You certainly get severe multiorgan toxicity and also neurological toxicity after a transplant."

Overall, bone marrow transplant causes a bigger shock to the system than does CAR T-cell therapy.

Preparing the body for transplant requires intensive chemotherapy and, in some cases, whole-body radiotherapy to wipe out the bone marrow before the transplant. Both are extreme therapies with severe side effects; indeed, this treatment itself can sometimes be fatal, Dr Greenberg commented.

"With CAR T cell therapy, you do need to make room for the cells, so there is also a chemotherapy pretreatment, but it is not nearly as toxic and as risky," said Dr Greenberg.

The difference between the two approaches was summarized in an interview with Mary Horowitz, MD, conducted previously by Medscape Medical News. Dr Horowitz is scientific director at the Center for International Blood and Marrow Transplant Research and chief of the Division of Hematology and Oncology at the Medical College of Wisconsin, in Milwaukee. She commented that whereas bone marrow transplant is like carpet bombing a city in order to destroy a specific building, CAR T cells are like smart bombs that seek out and destroy just the building.

Another difference is that after transplant, there is a high risk for infection and also a risk for graft-vs-host disease, both acute and long term, which may require immunosuppression, sometimes long term.

In contrast, CAR T-cell treatment is a "one-shot therapy," Dr Greenberg emphasized. "Yes, it's a shock to the immune system, and the adverse events during the acute phase can be severe, and even life-threatening, but once it's over, it's done. That's it. No more treatment."

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