Κυριακή, 5 Μαρτίου 2017

PROBLEMS WITH CAR-T CELLS?

Juno Therapeutics has finally decided to pull the plug on its investigational drug known as JCAR015, and announced that it will cease further development of the product.
The drug was being developed to treat adults with acute lymphoblastic leukemia (ALL). It used a technology known as chimeric antigen receptor (CAR) T-cell therapy, which has created a great deal of excitement in the sci
The CAR T-cell approach, which involves taking T-cells from patients, engineering them, and then reinfusing them back into the patient, has produced dramatic results in clinical trials in leukemia and lymphoma patients.
However, clinical trials with JCAR015 have been fraught with problems.
As previously reported by Medscape Medical News, the phase 2 ROCKET trial, which was being conducted in adults with relapsed or refractory B-cell ALL, was put on hold last July by the US Food and Drug Administration after two patients in the study died.
The two patients died of cerebral edema, which appeared to be treatment related. The deaths occurred after fludarabine was added to the preconditioning regimen, which had consisted only of cyclophosphamide.
The company said at the time that the addition of fludarabine to the preconditioning regime increased the incidence of severe neurotoxicity. The company eventually restarted the trial using preconditioning with cyclophosphamide alone.
However, three more deaths from cerebral edema occurred, bringing the total number of deaths to five.
The company has now decided to stop the trial.
"Juno, in collaboration with partner Celgene, has made a strategic decision to cease development of JCAR015 at this time," the company said in a statement, as reported to Reuters.
The company is continuing development of other CAR T-cell products.
Cerebral Edema Seen Only With This CAR T-Cell
Speaking to Medscape Medical News during the annual meeting of the American Society of Hematology in December 2016, two experts in the field noted that deaths from cerebral edema have been seen only with this one CAR T-cell product.
Elizabeth Budde MD, PhD, assistant professor in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope Hospital in Duarte, California, 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."
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 (JCAR015) in a particular trial (the ROCKET trial).
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.
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 (Actemra, Genentech), 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."

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