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Blood, 15 October 2007, Vol. 110, No. 8, pp. 2838-2845.
Prepublished online as a Blood First Edition Paper on July 3, 2007; DOI 10.1182/blood-2007-05-091280.
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Submitted May 21, 2007
Accepted June 29, 2007
Complete responses of relapsed lymphoma following genetic modification of tumor-antigen presenting cells and T-lymphocyte transfer
Catherine M. Bollard*, Stephen Gottschalk, Ann M Leen, Heidi Weiss, Karin C Straathof, George Carrum, Mariam Khalil, Meng-fen Wu, M Helen Huls, Chung-Che Chang, M Victoria Gresik, Adrian P Gee, Malcolm K Brenner, Cliona M Rooney, and Helen E Heslop
Center for Cell & Gene Therapy, Baylor College of Medicine, The Methodist Hospital & Texas Children's Hospital, Houston, TX
Department of Immunology, Baylor College of Medicine, The Methodist Hospital & Texas Children's Hospital, Houston, TX
Department of Pediatrics, Baylor College of Medicine, The Methodist Hospital & Texas Children's Hospital, Houston, TX
Department of Medicine, Baylor College of Medicine, The Methodist Hospital & Texas Children's Hospital, Houston, TX
Department of Pathology, Weill Medical College of Cornell University, TMHRI, The Methodist Hospital, Houston, TX
Department of Pathology, Baylor College of Medicine, The Methodist Hospital & Texas Children's Hospital, Houston, TX
Department of Virology, Baylor College of Medicine, The Methodist Hospital & Texas Children's Hospital, Houston, TX
* Corresponding author; email: cmbollar{at}txccc.org.
Epstein Barr Virus (EBV) associated tumors developing in immunocompetent individuals present a challenge to immunotherapy, since they lack expression of immunodominant viral antigens. However, the tumors consistently express viral proteins including LMP2, which are immunologically "weak" but may nonetheless be targets for immune T cells. We previously showed that a majority of cytotoxic T lymphocytes (CTL) reactivated using EBV-transformed B lymphoblastoid cells lines (LCL) contained minor populations of LMP2-specific T cells and homed to tumor sites. However, they did not produce remissions in patients with bulky disease. We have now used gene transfer into antigen presenting cells (APC) to augment the expression and immunogenicity of LMP2. These modified APC increased the frequency of LMP2-specific CTLs by up to 100 fold compared to unmodified LCL-APCs. The LMP2 specific population expanded and persisted in vivo without adverse effects. Nine of ten patients treated in remission of high-risk disease remain in remission, and five of six patients with active relapsed disease had a tumor response, which was complete in 4 and sustained >9 months. It is therefore possible to generate immune responses to weak tumor antigens by ex vivo genetic modification of APC and the CTL so produced can have substantial anti-tumor activity. This study is registered at http://www.cancer.gov/clinicaltrials (Protocol IDs: BCM-H-9936, NCT00062868, NCT00070226)
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