Sep 22, 2014
By Shira Klapper, Senior Writer/Editor
Researchers at the National Cancer Institute (NCI) carried out a study in which T-cells from patients with diffuse large B-cell lymphoma (DLBCL) and other B-cell malignancies were genetically engineered to express proteins that bind with antigens on malignant B cells, thus killing them. The treatment, given to 15 patients who had not responded to second-line chemotherapy, brought about a complete remission in eight patients and a partial remission in four patients. Among the four patients with DLBCL who had a complete response (CR), three are still alive, with ongoing survival-times ranging from nine to 22 months from treatment. The phase I study, “Chemotherapy-refractory Diffuse Large B-cell Lymphoma and Indolent B-cell Malignancies Can Be Effectively Treated with Autologous T Cells Expressing an Anti-CD19 Chimeric Antigen Receptor,” is reported in the Journal of Clinical Oncology (JCO), online, ahead of print, August 25.
The study’s findings are especially important for the one-third of patients with diffuse large B-cell lymphoma (DLBCL) whose disease is refractory, that is, unresponsive, to second-line chemotherapy. These patients have historically faced a poor prognosis. According to James N. Kochenderfer, MD, an investigator at the National Cancer Institute (NCI), “Patients with DLBCL whose disease is refractory to second-line chemotherapy have median survival times of only a few months. They have very limited treatment options because if chemotherapy doesn't work, they're generally not eligible for bone marrow transplants. There’s definitely a need for new treatments in DLBCL, particularly since it is the most common B cell malignancy.”
Infusing genetically engineered cells
What makes this study unique is that the patients’ own cells were genetically modified and then re-infused back into the patients’ blood to produce T-cells that express chimeric antigen receptors (CARs), proteins that can recognize antigens on malignant B cells, bind with them, and kill them. In this study, the targeted antigens were CD19, which are expressed on malignant and normal B cells.
“Basically we harvest blood cells from patients and modify these cells in the lab by genetically engineering them to express the CAR that specially targets the CD19 protein,” said Dr. Kochenderfer. “The T cell is genetically modified to express a new protein, an artificial protein that specifically binds to CD19, and thereby to lymphoma cells. When the CARs bind to the lymphoma cells, they give the T-cells the ability to recognize the cancer cell and destroy it. We’re actually permanently changing the patients’ cells to make them able to kill cancer." This is the first study to successfully treat DLBCL with anti-CD19-CAR T-cells.
Patients did experience several serious side effects, including fever, delirium and other neurological disorders, upon receiving the T-cell infusion, but those toxicities resolved in less than three weeks.
Plans for clinical use
Dr. Kochenderfer said that several pharmaceutical and biotechnology companies have already taken a strong interest in developing CAR cancer treatments and are now starting multi-center trials to test various treatments.
“Our hope is that we can make this treatment practical enough that it can be integrated into the standard treatment of relapsed DLBCL,” said Dr. Kochenderfer. “And I think that’s a realistic goal.”
James N. Kochenderfer, MD, is an Investigator in the Experimental Transplantation and Immunology Branch at the Center for Cancer Research at the National Cancer Institute, in Bethesda, Maryland.
Click here to read the abstract.
Click here to read the PDF.
Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2014. Published online ahead of print 8.25.2014.
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@ 2014 American Society of Clinical Oncology