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Blood, 12 March 2009, Vol. 113, No. 11, pp. 2442-2450.
Prepublished online as a Blood First Edition Paper on October 29, 2008; DOI 10.1182/blood-2008-05-157222.
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Submitted May 20, 2008
Accepted October 15, 2008
Enhancing the in vivo expansion of adoptively transferred EBV-specific CTL with lymphodepleting CD45 monoclonal antibodies in NPC patients
Chrystal U Louis, Karin Straathof, Catherine M Bollard, Claudia Gerken, M Helen Huls, M Victoria Gresik, Meng-Fen Wu, Heidi L Weiss, Adrian P Gee, Malcolm K Brenner, Cliona M Rooney, Helen E Heslop, and Stephen Gottschalk*
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, The Methodist Hospital, Houston, TX, United States
Texas Children's Cancer Center, Baylor College of Medicine, Texas Children's Hospital, The Methodist Hospital, Houston, TX, United States
The Dan L Duncan Cancer Center, Baylor College of Medicine, Texas Children's Hospital, The Methodist Hospital, Houston, TX, United States
Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, The Methodist Hospital, Houston, TX, United States
Department of Pathology, Baylor College of Medicine, Texas Children's Hospital, The Methodist Hospital, Houston, TX, United States
Department of Molecular and Human Genetics, Baylor College of Medicine, Texas Children's Hospital, The Methodist Hospital, Houston, TX, United States
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Texas Children's Hospital, The Methodist Hospital, Houston, TX, United States
Department of Medicine, Baylor College of Medicine, Texas Children's Hospital, The Methodist Hospital, Houston, TX, United States
Department of Immunology, Baylor College of Medicine, Texas Children's Hospital, The Methodist Hospital, Houston, TX, United States
* Corresponding author; email: smg{at}bcm.edu.
Treatment of Epstein Barr virus (EBV)-positive nasopharyngeal carcinoma (NPC) with EBV-specific cytotoxic T cells (EBV-specific CTL) has been promising, producing clinical responses. However, infused EBV-specific CTL did not expand in vivo, likely limiting their anti-tumor activity. Lymphodepleting patients with chemotherapy prior to T-cell transfer enhances in vivo T-cell expansion, but results in nonspecific destruction of the resident immune system and can have significant toxicity. To evaluate if monoclonal antibodies (MAbs) can produce a more selective lymphodepletion, we conducted a clinical study in which NPC patients received a pair of lymphodepleting MAbs targeted to the CD45 antigen (CD45 MAbs) prior to EBV-specific CTL infusion. Eight patients with recurrent NPC received CD45 MAbs followed by escalating doses of autologous EBV-specific CTL. Infusion of CD45 MAbs resulted in transient lymphopenia in all patients and an increase in IL-15 levels in 6 out 8 patients. All patients had an increase in their peripheral blood frequency of EBV-specific T cells after CTL infusion. Three patients with a persistent increase had clinical responses including 1 complete response (>24 months) and 2 with stable disease (for 12 and 15 months). Lymphodepleting MAbs prior CTL transfer may represent an alternative to chemotherapy to enhance expansion of infused CTL. This study is registered at http://www.clinicaltrials.gov as NCT00608257.
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