Enhancing the in vivo expansion of adoptively transferred EBV-specific CTL with lymphodepleting CD45 monoclonal antibodies in NPC patients.
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 antitumor activity. Lymphodepleting patients with chemotherapy before 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) before 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 interleukin-15 (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 benefits 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.clinialtrials.gov) as NCT00608257.
Louis
Chrystal U
CU
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA.
Straathof
Karin
K
Bollard
Catherine M
CM
Gerken
Claudia
C
Huls
M Helen
MH
Gresik
M Victoria
MV
Wu
Meng-Fen
MF
Weiss
Heidi L
HL
Gee
Adrian P
AP
Brenner
Malcolm K
MK
Rooney
Cliona M
CM
Heslop
Helen E
HE
Gottschalk
Stephen
S
D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D002277:Carcinoma / Q000150:complications / Q000276:immunology / Q000628:therapy*; D020031:Epstein-Barr Virus Infections / Q000150:complications; D005260:Female; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D016219:Immunotherapy, Adoptive / Q000379:methods*; D017493:Leukocyte Common Antigens / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009303:Nasopharyngeal Neoplasms / Q000150:complications / Q000276:immunology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000637:transplantation*; D013997:Time Factors; D019172:Transplantation Conditioning / Q000379:methods
D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D017493:Leukocyte Common Antigens