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Leukemia Patients Receiving Engineered T-Cell Therapy Remain in Remission

By BiotechDaily International staff writers
Posted on 18 Dec 2012
Researchers report on the first successful and sustained demonstration of clinical use of gene transfer therapy with human T-cells programmed to specifically target cancerous tumors. The results may lead to a shift in the treatment approach for patients with Leukemia or similar types of blood cancers, which in advanced stages currently have the possibility of cure only with bone marrow transplants.

Nine of 12 leukemia patients initially responded to the therapy pioneered by scientists at the Perelman School of Medicine at the University of Pennsylvania (Philadelphia, PA, USA). Clinical trial participants, all of whom had advanced cancers, included 10 adult patients with chronic lymphocytic leukemia and two children with acute lymphoblastic leukemia. Two of the first 3 patients treated with the protocol, whose cases were published in August 2011, remain healthy and in full remission more than two years after treatment, with the engineered cells still circulating in their bodies. The researchers have now presented the latest results of the trial at the 2012 American Society of Hematology’s Annual Meeting and Exposition.

“Our results show that chimeric antigen receptor modified T-cells have great promise to improve the treatment of leukemia and lymphoma [and in the future] may reduce or replace the need for bone marrow transplantation,” said trial leader Carl June, MD, the Richard W. Vague professor in Immunotherapy. However, the procedure requires a lengthy hospitalization and carries at least a 20% mortality risk, and even then offers only a limited chance of cure for patients whose disease has not responded to other treatments.

The protocol for the new treatment involves removing patients' cells through an apheresis process similar to blood donation. The T-cells are then programmed using an HIV-derived Lentivirus vector with a gene encoding an antibody-like protein, a chimeric antigen receptor (CAR), expressed on the cell surface, and designed to bind the protein CD19. The modified cells are then infused back into the patient following lymphodepleting chemotherapy. The CAR expressing T- cells specifically focus on attacking cells that express CD19, which includes CLL and ALL tumor cells, and normal B cells. The high specificity limits systemic side effects typically experienced during traditional therapies. In addition, a signaling molecule built into the CAR initiates production of cytokines that trigger T-cell proliferation and so provide additional T-cells that target additional tumor cells.

In the patients who experienced complete remissions after treatment, the CAR T-cells exhibited vigorous proliferation after infusion, with the most robust expansion activity usually occurring 10-31 days after infusion. Each of these patients developed a cytokine release syndrome marked by fever, nausea, hypoxia, and low blood pressure, which doctors treated when needed with the anticytokine agent tocilizumab. Ultimately, the treatment eradicated large amounts of tumor in these patients. Tests of patients with complete responses showed that normal B-cells have also been eliminated; these patients are receiving regular gamma globulin treatments as a preventive measure. No unusual infections have been observed.

Related Links:
Perelman School of Medicine at the University of Pennsylvania
Leukemia T-cell therapy clinical trial



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