[HTML][HTML] Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial

R Brentjens, R Yeh, Y Bernal, I Riviere, M Sadelain - Molecular Therapy, 2010 - cell.com
R Brentjens, R Yeh, Y Bernal, I Riviere, M Sadelain
Molecular Therapy, 2010cell.com
Most patients with B-cell malignancies will die from their disease or are incurable. For this
reason, innovative therapeutic approaches are direly needed. Patient T cells may be
genetically modified to target antigens expressed on tumor cells through the expression of
chimeric antigen receptors (CARs), which are antigen receptors designed to recognize cell
surface antigens in a human leukocyte antigen–independent manner. 1 CD19, which is
expressed on most B-cell malignancies—including most non-Hodgkin's lymphomas, acute …
Most patients with B-cell malignancies will die from their disease or are incurable. For this reason, innovative therapeutic approaches are direly needed. Patient T cells may be genetically modified to target antigens expressed on tumor cells through the expression of chimeric antigen receptors (CARs), which are antigen receptors designed to recognize cell surface antigens in a human leukocyte antigen–independent manner. 1 CD19, which is expressed on most B-cell malignancies—including most non-Hodgkin’s lymphomas, acute lymphoblastic leukemias, and chronic lymphocytic leukemias (CLLs)—is an attractive antigen for this approach. 2 It is present on normal B-lineage cells from the early pre–B-cell stage until plasma cell differentiation. In a model of CD19+ acute lymphoblastic leukemia, we found that that a CAR termed 19-28z, which comprises the CD28 cytoplasmic domain in addition to that of the CD3 ζ-chain, 3 induced better responses than a ζ-chain-based receptor. 4 In preclinical in vitro studies, we demonstrated that human T cells that express CD19-specific CARs efficiently lyse human CD19+ tumor cell lines and that CLL patient–derived T cells effectively lyse autologous tumor cells. 2, 4 These results, and others, 5 supported a phase I clinical trial treating refractory CLL patients with autologous T cells modified by retroviral gene transfer of the 19-28z CAR. We have thus far enrolled six patients in this clinical trial. The cohort of subjects treated with modified T cells alone at the first dose level of T cells tolerated therapy well without dose-limiting toxicities. However, the first subject (subject 4) enrolled in the second cohort of patients, in whom cyclophosphamide lymphodepleting
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