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CD28 Costimulation Provided through a CD19-Specific Chimeric Antigen Receptor Enhances In vivo Persistence and Antitumor Efficacy of Adoptively Transferred T Cells

Divisions of ¹ Molecular Medicine, ² Cancer Immunotherapeutics and Tumor Immunology, ³ Hematology and Hematopoietic Cell Transplantation, and ⁴ Pediatric Hematology/Oncology and ⁵ Department of Biostatistics, Beckman Research Institute and City of Hope National Medical Center, Duarte, California; ⁶ Medizinische Klinik und Poliklinik II, Bayerische Julius-Maximillian Universität Würzburg, Würzburg, Germany; and ⁷ Division of Pediatrics, University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Laurence J.N. Cooper, Division of Pediatrics, University of Texas M.D. Anderson Cancer Center, Unit 907, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-563-3360; Fax: 713-563-0604; E-mail: ljncooper{at}mdanderson.org.

Chimeric antigen receptors (CAR) combine an antigen-binding domain with a CD3- signaling motif to redirect T-cell specificity to clinically important targets. First-generation CAR, such as the CD19-specific CAR (designated CD19R), may fail to fully engage genetically modified T cells because activation is initiated by antigen-dependent signaling through chimeric CD3-, independent of costimulation through accessory molecules. We show that enforced expression of the full-length costimulatory molecule CD28 in CD8⁺CD19R⁺CD28^– T cells can restore fully competent antigen-dependent T-cell activation upon binding CD19⁺ targets expressing CD80/CD86. Thus, to provide costimulation to T cells through a CD19-specific CAR, independent of binding to CD80/CD86, we developed a second-generation CAR (designated CD19RCD28), which includes a modified chimeric CD28 signaling domain fused to chimeric CD3-. CD19R⁺ and CD19RCD28⁺ CD8⁺ T cells specifically lyse CD19⁺ tumor cells. However, the CD19RCD28⁺ CD8⁺ T cells proliferate in absence of exogenous recombinant human interleukin-2, produce interleukin-2, propagate, and up-regulate antiapoptotic Bcl-X_L after stimulation by CD19⁺ tumor cells. For the first time, we show in vivo that adoptively transferred CD19RCD28⁺ T cells show an improved persistence and antitumor effect compared with CD19R⁺ T cells. These data imply that modifications to the CAR can result in improved therapeutic potential of CD19-specific T cells expressing this second-generation CAR. (Cancer Res 2006; 66(22): 10995-1004)

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