For the second time this week, clinical details of the remarkable responses in acute lymphoblastic leukemia (ALL) seen with chimeric antigen receptor (CAR)-modified T-cells have been published.
"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," said Daniel DeAngelo MD, PhD, assistant professor at Harvard Medical School and the Dana-Farber Cancer Institute in Boston.
"This is extremely exciting; landscape changing," he said in an interview.
Dr DeAngelo has not been involved in any of the studies reported so far, but said his institution is now planning to get involved in this research.
The latest study, published in the October 16 issue of the New England Journal of Medicine,comes from researchers at the University of Pennsylvania and the Children's Hospital of Philadelphia.
They report that 27 of 30 patients (90%) with relapsed/refractory ALL experienced complete remissions. Sustained remissions were observed in 19 patients (15 of whom had no other therapy), and some of the remissions have been sustained for up to 2 years.
This was a very heavily pretreated group of patients with few other treatment options and a poor prognosis.
"ALL is the leading cause of childhood cancer deaths," noted lead investigator Stephan Grupp, MD, PhD. "We are especially hopeful for those patients who remain in remission for 1 to 2 years without further therapy," he said in a statement.
This Penn group is collaborating with Novartis. The product used, an investigational CAR-modified T-cell directed against CD19, known as CTL019, was recently granted breakthrough status by the US Food and Drug Administration (FDA) on the basis of interim results from this study.
The results are similar to those reported earlier this week by researchers at the National Cancer Institute (NCI), who are collaborating with Kite Pharmaceuticals.
There is also a third group active in this field, which includes the Memorial Sloan Kettering Cancer Center in New York City, working in collaboration with Juno Therapeutics.
All three groups have used CAR T-cells in patients with relapsed and/or refractory ALL who have few other options, and they have all shown "very dramatic responses," Dr DeAngelo commented. He would not compare results from the different groups with one another, and said they should be regarded as three independent groups that are at the same level, adding that the research has been "exemplary."
However, he noted that these therapies have serious adverse effects, the most prominent of which is cytokine-release syndrome, which can be severe enough to need intensive care.
Dr DeAngelo cautioned that these are very complicated therapies, and patients can get very ill, so he envisages that this approach would be restricted to centers of excellence, and that patients would have to travel there, just as they do currently to receive a stem cell transplant. "I don't envisage at present these therapies being administered outside of academic centers and, furthermore, academic centers that have experience with this therapy," he said.
"Obviously, this will present logistical problems for patients, but it's not something that cannot be overcome," he added. At present, patients travel for stem cell transplants, he pointed out, and for allogeneic transplants there are only a handful of centers in the whole country.
Penn Study Details
The study by the Penn group involves two sets of patients: 25 of the 30 patients were children and young adults (aged 5 to 22 years; median, 11 years) and were treated at the Children's Hospital of Philadelphia, while the remaining five were adults (26 to 60 years; median, 47 years) treated at the University of Pennsylvania.
These patients had been heavily pretreated: 26 patients had B-cell ALL in a first to fourth relapse, three patients had primary refractory B-cell ALL, and one patient had relapsed T-cell ALL that expressed CD19. Eighteen patients (60%) had had a relapse after allogeneic stem cell transplant.
"Relapsed ALL is a considerable therapeutic challenge," the researchers write, "particularly in patients who do not have a second complete remission or have relapse after a stem cell transplantation."
"Salvage therapy induces remission in only 40% of children who have had two or more bone marrow relapses, and long-term survival is quite poor," they add.
The researchers note that for the most recently FDA-approved drugs for relapsed ALL, which include clofarabine, nelarabine, and liposomal-encapsulated vincristine, the product labelling indicates rates of complete remission of less than 25%, with a median documented duration of response of 4 to 9 weeks.
Against this background, the results that they report with CTL019 look pretty remarkable: 90% complete response rates, with durable remissions lasting for up to 2 years. But in the stilted speak of scientific journals, the researchers describe their results as "encouraging."
Dr DeAngelo was less restrained, and described the responses as "exhilarating."
It is not clear why three patients did not respond, the Penn group comments.
The team also gave some details of their experience with the cytokine-release syndrome, an inflammatory process marked by dramatic elevations of cytokine levels (including interleukin-6). "Because this cytokine release probably both results from and contributes to T-cell activation, some degree of cytokine-release syndrome is probably necessary for efficacy," they write.
All the patients in their study had cytokine-release syndrome, but for the majority it was self-limited, with high temperatures and myalgia that resolved spontaneously in a few days, they report.
However, 27% of patients had severe cytokine-release syndrome, with hypotension and renal insufficiency that required treatment in an intensive care unit. Several patients experienced neurologic toxicities (including encephalopathy), but these "fully resolved without further intervention or apparent long-term implications," according to a Novartis press release.
Similar to the NCI group, the Penn researchers used tocilizumab, an interleukin-6 receptor blocking antibody (already marketed for rheumatoid arthritis) as a first-line agent in the management of severe cytokine-release syndrome, and report that it produced a rapid and profound improvement.
Although there are theoretical reasons why tocilizumab could blunt the efficacy of CAR by interfering with a cytokine feedback loop, in this study there was no suggestion that it compromised efficacy, they write.
Difference in Subsequent Therapy
A big difference between the NCI and the Penn study was the subsequent therapy that patients received.
In the NCI study, many of the patients who responded (10 of 12) went on to receive a hematopoietic stem cell transplant — as this is the standard of care in refractory ALL patients who achieved a minimum residual disease-negative complete response, the researchers note. Hence, in the NCI study, the CAR-modified T-cell therapy was used as a "bridge" to transplant.
In the Penn study, only three patients who achieved remission went on to receive a stem cell transplant. There were a number of reasons, the researchers explain (e.g., lack of suitable donor, prior stem cell transplant, or family choice). Hence, this study allows for longer follow-up of the effects of CAR T-cell therapy alone, and also shows the potential that they hold for a one-off treatment.
This is a big question for the CAR T-cells. Is this approach sufficient on its own, or should it be followed-up by a transplant? There are also many other questions about where they should fit into therapy, Dr DeAngelo commented. At present, it has been used as salvage therapy in patients who have no other options, but should it be moved to earlier in the treatment schedule for patients who have had a second relapse or patients after a first relapse? Should it be used in patients who are in remission but have a high risk for relapse, or in patients in remission but with minimal residual disease?
"We have to consider the benefit vs risk ratio, and these are rather toxic therapies," he commented. "Right now, I don't see the standard of care for ALL changing. Patients will still get chemotherapy and will go on to a transplant, but the question is, what happens now when patients relapse?"
"At present, I see the CAR T-cells used for refractory patients or as salvage after second relapse," he said. "Until we have a better assessment of the toxicity profile, that is where I would feel comfortable using this approach."
"Smart Bomb, But Not That Smart"
The CAR T-cell approach has been likened to a smart bomb, which homes in on a specific target (the CD19 antigen found on most leukemic cells).
Whereas bone marrow transplantation is like the carpet bombing of a city in order to destroy a specific building, these CAR cells are like smart bombs that seek out and destroy just the building, commented Mary Horowitz, MD, 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, in a recent interview.
Dr DeAngelo laughed at the analogy, and pointed out that a transplant effectively replaces a patient's whole immune system, "and you hope that the new immune system will react to the cancer. It doesn't happen all the time, and that's why patients relapse after a transplant."
In contrast, with the CAR T-cell approach, you manipulate the patient's own immune system. "You force it into reacting to the cancer by introducing the CAR into the patient's own T-cells," he said. "You engineer the patient's own immune system into recognizing and destroying the cancer, but this revving up of the immune system also has side effects.... These bombs are smart, but they are not that smart," he said. They destroy cancer cells, but they also destroy normal cells that are very similar.
In the case of ALL, this is not too much of a problem, as it is a B-cell disease, and the destruction of the normal B-cells can be compensated for with immunoglobulin, Dr DeAngelo explained. But in the case of ALL, the cells are neutrophils, and "you can't function without those," he pointed out.
So ALL has offered the perfect setting in which to test the CAR T-cell approach, he said.
The study was supported in part by a grant from Novartis, by grants from the National Institutes of Health, the Leukemia and Lymphoma Society, the Jeffrey Jay Weinberg Memorial Foundation, and the Children's Hospital of Philadelphia Hematologic Malignancy Research Fund, and a Stand Up to Cancer–St. Baldrick's Pediatric Dream Team translational research grant.
N Engl J Med 2014;371:1507-1517. Abstract
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Cite this: CARs Motor Through Leukemia, Part 2: 'Landscape Changing' - Medscape - Oct 15, 2014.
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