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Sep 18, 2007

Investigators Engineer T Cells against B-Cell Malignancies

  • Modified T cells can be effective in fighting cancers associated with B cells such as acute lymphoblastic leukemia (ALL), according to researchers at Memorial Sloan-Kettering Cancer Center (MSKCC). By administering repeated doses of T cells designed to express an artificial receptor that recognizes human B cells, the researchers say that they were able to eradicate cancer in 44% of mice bearing human ALL tumors.

    “The immune system has evolved to police the body for infections and diseased cells, but it has a difficult time recognizing malignant cells since they largely appear normal to the immune system,” points out lead study author, Renier J. Brentjens, M.D., Ph.D., medical oncologist in the leukemia service at MSKCC. “The idea is that we can take a patient’s own T cells, re-educate them by inserting a gene into them that will enable them to produce a receptor to recognize B cell cancers, and then return them to the patient where they should be able to attack and kill the tumor cells.”

    To get T cells to recognize B cells, the MSKCC created a gene that encodes for a cell-surface protein, or a chimeric antigen receptor, designed to specifically bind to CD19, a molecule found on the surface of B cells and B-cell cancers. This chimeric gene, according to Dr. Brentjens, formed from active portions of several immune system-related genes, creates the chimeric antigen receptor protein called 19-28z, which does not require other costimulatory signals to fully activate T cells.

    Dr. Brentjens and his colleagues infected healthy T cells with modified retroviruses containing the gene that codes for 19-28z. The T cell’s internal protein-making facilities then produced the chimeric receptor as if it were one of its own natural antigen receptors, they state.

    The investigators compared T cells engineered with 19-28z to T cells engineered with a first-generation chimeric antigen receptor, lacking the costimulatory signal found in 19-28z. They report that the second generation 19-28z receptor was superior to the first and that this T-cell therapy works best when administered to mice through multiple weekly injections.

    “The repeated boosts of new T cells during therapy to improve T-cell persistence enhances the efficacy of these T cells in eradicating cancerous B cells,” says Dr. Brentjens. “This concept of T-cell persistence being critical to treatment efficacy is one we are further investigating in current and upcoming clinical trials.” The scientists add that they have an ongoing study using these T cells in CLL and have recently begun the planning stages for a trial in patients with ALL.

    The current findings were published in the September 15 issue of Clinical Cancer Research.



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