Δευτέρα, 14 Δεκεμβρίου 2015

CAR T-CELLS EFFECTIVE EVEN AFTER TRANSPLANTATION

ORLANDO, Florida — The novel approach of using chimeric antigen-receptor (CAR) T-cells in the treatment of hematological malignancies continues to create much excitement, as the unprecedented responses and the continuing deep remissionspromise a way of eradicating the disease. Building on early studies in small numbers of patients, pivotal trials of CAR T-cells are now under way in leukemia and lymphoma.
But the pioneers of this technology are continuing to push the envelope, and a new application of CAR T-cells are being reported here at the American Society of Hematology (ASH) 57th Annual Meeting by James Kochenderfer, MD, from the Center for Cancer Research at the National Cancer Institute in Bethesda, Maryland, who was one of the first to report success with CAR T-cells in lymphomas.
Some observers have suggested that the CAR T-cell approach could be an alternative to or used as a bridge to stem-cell transplantation, but a study that Dr Kochenderfer presented here shows that the approach can also be used in patients who have already undergone a transplant but continue to progress.
Progressive disease after transplant is a leading cause of death in these patients, Dr Kochenderfer commented. These patients have often failed many therapies, and the transplant is seen as a last resort, he commented at a press briefing. If the disease continues to progress, there is not much else that can be offered to such patients. One approach that has been tried, but without much success, is donor lymphocyte infusions (DLI), but these have had inconsistent efficacy and are associated with significant morbidity and mortality from graft-vs-host disease, he explained.
His team used a novel twist on this approach: they also used donor lymphocytes (from the original donor of the stem-cell transplant) but then genetically modified the T-cells to express an anti-CD19 CAR.
Patients in this study received a single infusion of these anti-CD19 CAR T-cells, without any chemotherapy. "This was a big difference with previous trials," he noted, as "we used large amounts of chemotherapy in some of the other trials." Giving the CAR T-cells on their own allowed much higher doses to be given, some 10-fold greater than the doses used in previous trials in combination with chemotherapy, he noted.
The trial involved 20 patients with B-cell malignancies that progressed after transplant. Overall, nine of the 20 patients had a complete response (CR) or partial response (PR).
The best responses were seen in patients with acute lymphocytic leukemia, with four out of five of these patients achieving a CR, although two of these patients later relapsed. Good responses were also seen in chronic lymphocytic leukemia (CLL), where one of five patients had a CR, one had a PR, two patients had stable disease, and one patient had progressive disease.
The remaining patients had lymphoma. Five patients had mantle-cell lymphoma, where one of five patients had a CR, which is ongoing; one patient had a PR; and three patients had stable disease. Another five patients had diffuse large B-cell lymphoma, where one of five patients had a CR, three patients had stable disease, and one had progressive disease.
The responses were very rapid, seen within 7 to 10 days of the infusion of CAR T-cells, and there was no acute graft-vs-host disease, Dr Kochenderfer reported. One patient had continued worsening of preexisting chronic graft-vs-host disease, and another developed chronic graft-vs-host disease in the eye, but months after the infusion when there were no CAR T-cells left in the body.
In his presentation, Dr Kochenderfer highlighted two cases where the responses were dramatic. He showed before and after MRI scans showing a patient with CLL had a large adenopathy that disappeared, and a patient with lymphoma who had two large masses in her head, which also both disappeared.
Patients who responded had significantly higher levels of peak CAR T-cells than those who did not, he noted.
Patients with high burden of disease experienced severe cytokine-release syndrome, with fever, tachycardia, and hypotension, he noted, but this was reversible, he added. Some patients reported muscle pain and biochemical markers suggesting muscle damage, which is a first in these trials with CAR T-cells, he added.
While the results are from a small number of patients, they are exciting because they show that this novel approach using CAR T-cells achieved regression in malignancies that were progressing after transplant, in patients with very advanced disease, and this was achieved with one infusion, without chemotherapy and without graft-vs-host disease, he said.
Dr Kochenderfer reported consultancy with Bluebird Bio. Disclosures for the coauthors are listed in the abstract. 
American Society of Hematology 57th Annual Meeting; Orlando, Florida. Abstract 99, presented December 5, 2015.

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