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 Blood, 15 February 2005, Vol. 105, No. 4, pp. 1622-1631.
Prepublished online as a Blood First Edition Paper on October 26, 2004; DOI 10.1182/blood-2004-03-1208.

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IMMUNOBIOLOGY

Enhanced antilymphoma efficacy of CD19-redirected influenza MP1–specific CTLs by cotransfer of T cells modified to present influenza MP1

Laurence J. N. Cooper, Zaid Al-Kadhimi, Lisa Marie Serrano, Timothy Pfeiffer, Simon Olivares, Adrian Castro, Wen-Chung Chang, Sergio Gonzalez, David Smith, Stephen J. Forman, and Michael C. Jensen

From the Divisions of Pediatric Hematology-Oncology, Molecular Medicine, Hematology and Hematopoietic Cell Transplantation, and Bioinformatics, Beckman Research Institute and City of Hope National Medical Center, Duarte, CA.

To enhance the in vivo antitumor activity of adoptively transferred, CD19-specific chimeric antigen receptor (CAR)–redirected cytotoxic T lymphocytes (CTLs), we studied the effect of restimulating CAR+ CTLs through their endogenous virus-specific T-cell antigen receptor (TcR) by the cotransfer of engineered T-cell antigen–presenting cells (T-APCs). Using influenza A matrix protein 1 (MP1) as a model antigen, we show that ex vivo–expanded CD4+ and CD8+ T-APCs expressing a hygromycin phosphotransferase-MP1 fusion protein (HyMP1) process and present MP1 to autologous human leukocyte antigen (HLA)–restricted, MP1-specific CD4+ and CD8+ CTL precursors. The MP1-specific CTLs are amenable to subsequent genetic modification to express a CD19-specific CAR, designated CD19R, and acquire HLA-unrestricted reactivity toward CD19+ leukemia and lymphoma tumor targets while maintaining HLA-restricted MP1 specificity. The restimulation of MP1xCD19 dual-specific CTLs in vivo by the adoptive transfer of irradiated HyMP1+ T-APCs resulted in the enhanced antilymphoma potency of bispecific effector cells, as measured by elimination of the biophotonic signal of established firefly luciferase–expressing Burkitt lymphoma xenografts in nonobese diabetic/severe combined immunodeficiency (NOD/scid) animals compared with control groups restimulated by Hy+MP1neg T-APCs. Engineered T-APCs are a novel and versatile antigen-delivery system for generating antigen-specific T cells in vitro and enhancing the in vivo effector functioning of CAR-redirected antitumor effector cells.


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