"We believe that when this treatment is approved, it will save thousands of children's lives around the world," Emily's father, Tom Whitehead, said at the meeting. This will turn "blood cancers into a treatable disease where even after relapse most people survive," he predicted.
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.
The engineering changes the T cell in two ways. First, it adds a receptor that targets the CD19 antigen that is found on most leukemia cells. When the cells are returned to the patient's body, they home in on this antigen, latch on, and destroy the leukemia cell. Second, the process inserts a viral vector mechanism into the cells that, once the cells have latched onto the leukemia cell, triggers these T cells to expand and proliferate, so that they seek out and destroy all the remaining leukemia cells.
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. Dr Brenner was speaking in an interview arranged by the American Society of Hematology at the request of Medscape Medical News.
It is not yet clear whether the cells will persist for the rest of the patient's life, because the data currently available reflect only a few years, Dr Brenner said, but he noted that with bone marrow transplants, which were first performed in the 1960s, the effects last a lifetime.
It is not clear whether CAR T cells will also last a lifetime or whether will they gradually disappear over decades. It is also not clear how long immunosurveillance may be needed, he said.
While policing the blood, these cells wipe out any leukemia B cells that may reappear, but there can be a downside. In some patients, this has also led to depletion of healthy B cells, a condition known as known as B cell aplasia. "This is not a major problem, at least not so far," commented Dr Greenberg, because this deficiency can be corrected by giving immunoglobulin supplements, in some cases long term.
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 cytokine release syndrome, 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%).
Although these side effects are severe, they are not more severe than those associated with bone marrow transplants, although the side effects are different, Dr Brenner commented. "You certainly get severe multiorgan toxicity and also neurological toxicity after a transplant."
Bone marrow transplants are very acute medicine, and CAR T cells are also very acute medicine, he continued. Both can have very severe side effects, and although those side effects are different in type, they are not different in intensity, he said.
"Incredibly exciting" is how experts are describing the new development with chimeric antigen receptor (CAR) T cells, as the first of these novel therapies approaches the market.
After last week's unanimous vote in favor of recommending approval by the USA Food and Drug Administration (FDA), it now seems likely the first of these products will be on the market before the end of the year.
That product is tisagenlecleucel-T (previously known as CTL019). It was initially developed at the University of Pennsylvania and was subsequently licensed to Novartis. It will be indicated for pediatric relapsed/refractory acute lymphoblastic leukemia (ALL).
"But this is just the tip of the iceberg," said Lee Greenberger, PhD, chief scientific officer of the Leukemia and Lymphoma Society. An early supporter of this research, the society has contributed $21 million during the past 2 decades to the University of Pennsylvania and Children's Hospital of Philadelphia.
More of these products are coming through for use in other blood cancers. Next to the market is Kite's axicabtagene ciloleucel (KTE-C19) for lymphoma. Products aimed at other leukemias and for multiple myeloma are under development. There have also been early results with this approach in solid tumors, Dr Greenberger noted.
"This is incredibly exciting, with unbelievable potential," he commented in an interview with Medscape Medical News.
"It's a one-shot therapy that looks to be curative," he said.
The first patient treated with tisgenlecleucel 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 says.
"It's still early days," he added, noting that in the trial that was pivotal for approval, the overall survival (OS) rate was 12 months. That rate was 80%, which 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 transplant.
These are patients with few options and a very poor prognosis, Dr Greenberger said: for these patients, the therapy is lifesaving.
That was the point made by parents of treated children who spoke at the FDA advisory meeting. "We were discussing hospice," recalled the father of Emily Whitehead, who at the age of 6 years was the first patient to receive tisagenlecleucel. Now a healthy teenager, she has been free of leukemia since May 2012 and was at the meeting with her parents. The family have been vocal advocates of the novel therapy and have formed a foundation to raise awareness and funding.
They are severe side effects, he emphasized, and they need to be overseen by clinicians with experience in this field, and suitable facilities are required. Patients may need to be treated in the intensive care unit, for example, and some patients may need to undergo intubation.
This is not a therapy that will ever be used in a community setting, both Dr Brenner and Dr Greenberg predicted. It needs specialist clinicians and facilities, they said.
At the advisory meeting, Novartis said that if the product is approved, it would be rolled out gradually. It will initially be made available to centers that had already been involved in the pivotal clinical trial. It will then to made available to centers in which personnel had undergone rigorous training. The company estimated that the therapy will be available in only about 30 to 35 centers in the United States.
Smart Bombs vs Carpet Bombing
Overall, bone marrow transplant causes a bigger shock to the system than 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. 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.
"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, that was 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.
In addition, 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."
Because it is a one-time treatment and is potentially curative, there has been speculation as to how high a price tag will be put on the therapy. Estimates of $300,000 to $500,000 have been mentioned, and the cost may be even higher.
But bone marrow transplant is also expensive. According to Medigo, the average cost of an allogeneic bone marrow transplant in the United States is around $800,000; the cost of an autologous transplant is around $350,000. Perhaps a more relevant comparison (because of the pediatric indication for tisagenlecleucel) are the estimates given for a child requiring a bone marrow transplant; in such cases, the cost ranges between $75,000 and $200,000.
Seeing the first CAR T-cell therapy move toward the market is "very exciting," Dr Brenner commented. "We've been doing this for years at a lower level at academic centers, and now finally to have the resources of a large pharmaceutical company makes a huge difference, because what they can do that academic centers cannot do is scale up these processes and make them available to a larger number of people who need them."
Having industry involved has also streamlined a complicated production process and has shortened the manufacturing time. Whereas patients at the beginning of the clinical trial needed to wait 44 days between giving blood and undergoing CAR T-cell infusion, the process now takes only 22 days from "vein to vein," Novartis said at the meeting.
For the future, there is hope that it may be possible to make "off the shelf" products that would require no waiting time, Dr Greenberg commented. There is also work underway to incorporate a "genetic switch" into the CAR T cell, which would make it possible to "turn off" the therapy by taking another drug. This could be useful when side effects become very severe, he suggested.
There is a tremendous amount of work ongoing involving other blood cancers, all of which appear suitable to this approach. There is also hope that the therapy could be made to work against solid tumors, Dr Greenberg said. This first product that is heading to market is "just the tip of the iceberg," he repeated.
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