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Chimeric Antigen Receptor-CAR LYMPHOCYTES A NEW PROMISING TREATMENT

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There is palpable excitement here at American Society of Hematology (ASH) 55th Annual Meeting over results that are being reported with a new approach to treatment, engineered T cells. Although the results come from pilot clinical trials conducted in a small number of patients with leukemia and lymphoma, these are patients with very aggressive and refractory disease, and yet some of them have shown dramatic responses to the therapy, going into complete remission and no longer showing visible signs of tumor on computed tomography (CT) scans.
"It looks like the disease has disappeared after a single infusion of these engineered T cells," commented James Kochenderfer, MD, from the Experimental Transplantation and Immunology Branch of the National Cancer Institute (NCI) in Bethesda, Maryland.
However, he cautioned that there is a significant patient variation in both efficacy and toxicity with this approach.
Several groups in the United States are working on this approach to treatment, and some have teamed up with pharmaceutical companies. The T cells developed at NCI have been licensed to Kite Pharmaceuticals, and a similar approach developed at the University of Pennsylvania, which has the most clinical data so far, has been licensed to Novartis.
Some observers say that this pharmaceutical company involvement, as well as accelerated approval for an urgent medical need, could result in these therapies becoming available as early as 2016, but others forecast a longer development time and suggest the therapies will not be available for clinical use until 2020.
Like a Smart Bomb
The novel approach to therapy involves extracting T cells from the patient, subjecting the cells to chimeric antigen receptor (CAR) cell engineering, and then infusing the engineered T cells back into the patient.
The engineering, which takes about 10 days, changes the T cell in 2 ways. First, it adds a receptor that targets the CD19 antigen that is found on most leukemic cells; when the cells are inserted back into the patient’s body, they home in on this antigen, latch on and destroy the leukemic cell. Second, the process inserts a viral vector mechanism into the cells which – once the cells have latched on to the leukemia – triggers these T cells to expand and proliferate, so that they seek out and destroy all the remaining leukemic cells.
There is tremendous excitement over this approach, because it acts like a smart bomb, said 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. Whereas bone marrow transplantation is like 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, she commented to Medscape Medical News.
The clinical results have been dramatic and unprecedented in such advanced disease.
Results in Lymphoma
Dr. Kochenderfer presented results from 15 adult patients with advanced B cell lymphomas (abstract 168), including 9 patients with chemotherapy-refractory large cell lymphoma such as primary mediastinal B cell lymphoma and diffuse B cell lymphoma. They received reduced-intensity conditioning with cyclophosphamide and fludarabine and then an infusion of their own T cells that had been CAR engineered.
Thirteen of the 15 patients treated were evaluable for response, and 12 of those 13 responded: 7 patients had complete remissions, and 5 had partial remissions, Dr. Kochenderfer said. The remaining patients had stable disease.
Dr. Kochenderfer gave details of one of the patients who had a complete remission, showing CT scans with visible tumor in the liver and abdomen prior to the treatment, and none visible after treatment. This was a patient who had undergone 10 prior therapies, including many different combinations of rituximab plus chemotherapy regimens, and the disease progressed a month after chemotherapy finished, so she was "clearly refractory," he said.
"Our data provide the first true glimpse of the potential of this approach in patients with aggressive lymphomas that, until this point, were virtually untreatable," Dr. Kochenderfer told journalists at an ASH press briefing at which these novel therapies were highlighted.
"We are particularly encouraged by the partial and complete responses that we observed in a number of patients with diffuse large B cell lymphomas who had exhausted all other treatment options…and who are not generally thought to be good candidates for hematopoietic stem cell transplantation," he added.
However, he tempered his enthusiasm by adding that "this approach is still an early-stage experimental therapy."

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