CAR cell engineering offers hope for patients with hard-to-treat blood disorders

The use of chimeric antigen receptor (CAR) cell engineering was described in several studies presented at the 2013 American Society of Hematology (ASH) Annual Meeting, December 7-10, 2013, in New Orleans, Louisiana.

CAR cell engineering involves extracting T cells from a patient's blood and positioning a receptor that recognizes CD19, a protein present in most leukemia cells, on the surface of the T cells. Next, the T cells are programmed to proliferate when they attach to the protein target. The engineered T cells are then infused into the patient, ready to seek out and destroy cancer cells.

CAR targeting is reserved for patients with leukemia who have failed all other treatment options. The risk of adverse reactions is lower because the cells are derived from the patient and are less likely to attack host tissue than foreign cells.

The fate of the engineered cells over time was studied in pediatric and adult patients with acute or chronic lymphocytic leukemia who underwent CAR treatment. Patients with the greatest expansion of T cells (more than 5% of their T cells) were most likely to achieve complete response, and those with less robust but detectable cell expansion, had a partial response to treatment. The engineered T cells could be detected many months after infusion and continued to be functional in complete responders. The study author explained that this treatment worked dramatically and in a sustained manner in patients with relapsed, treatment-resistant leukemia.

A second study treated 22 children and five adults with relapsed acute lymphocytic leukemia that was treatment-resistant by reengineering their T-cells with CAR targeting. A total of 19 of the children and all five adults achieved a complete response. One patient has been in remission for a year and had CAR-bearing cells detected at 18 months postinfusion. None of the patients experienced immediate infusion-related reactions or graft-versus-host disease, although some patients developed cytokine release syndrome (high fever, muscle pain, nausea) from successful T-cell expansion. Stephan Grupp, MD, PhD, of Children's Hospital of Philadelphia and the University of Pennsylvania School of Medicine, the study author, stated that the engineered cells expand and then persist in patients, allowing for long-term disease control. Furthermore, the study allayed previous concerns that infused cells survive only for a limited time.

A third study involved 15 patients with advanced B-cell malignancies, including eight with large B-cell lymphomas, who were treated with cyclosphamide and fludarabine followed by infusion with their own T cells engineered to express anti-CD19. Six patients achieved complete remission and six achieved partial remission. Acute reactions such as fever, low blood pressure, focal neurologic deficits, and delirium resolved in less than 3 weeks. This is the first report of successful treatment in patients with chemotherapy-refractory primary mediastinal B-cell lymphoma and diffuse large B-cell lymphoma. The study author explained that these aggressive lymphomas were virtually untreatable, and that this approach offers an option for patients who are not good candidates for hematopoietic stem cell transplantation.

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