Complete responses of relapsed lymphoma following genetic modification of tumor-antigen presenting cells and T-lymphocyte transfer.
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 (CTLs) reactivated using EBV-transformed B-lymphoblastoid cells lines (LCLs) 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 (APCs) to augment the expression and immunogenicity of LMP2. These modified APCs increased the frequency of LMP2-specific CTLs by up to 100-fold compared with unmodified LCL-APCs. The LMP2-specific population expanded and persisted in vivo without adverse effects. Nine of 10 patients treated in remission of high-risk disease remain in remission, and 5 of 6 patients with active relapsed disease had a tumor response, which was complete in 4 and sustained for more than 9 months. It is therefore possible to generate immune responses to weak tumor antigens by ex vivo genetic modification of APCs and the CTLs so produced can have substantial antitumor activity. This study is registered at http://www.cancer.gov/clinicaltrials (protocol IDs: BCM-H-9936, NCT00062868, NCT00070226).
Bollard
Catherine M
CM
Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX 77030, USA. cmbollar@txccc.org
Gottschalk
Stephen
S
Leen
Ann M
AM
Weiss
Heidi
H
Straathof
Karin C
KC
Carrum
George
G
Khalil
Mariam
M
Wu
Meng-fen
MF
Huls
M Helen
MH
Chang
Chung-Che
CC
Gresik
M Victoria
MV
Gee
Adrian P
AP
Brenner
Malcolm K
MK
Rooney
Cliona M
CM
Heslop
Helen E
HE
D000293:Adolescent; D000328:Adult; D000368:Aged; D000938:Antigen-Presenting Cells / Q000276:immunology*; D002648:Child; D020031:Epstein-Barr Virus Infections / Q000150:complications; D005260:Female; D018014:Gene Transfer Techniques; D004854:Herpesvirus 4, Human; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008223:Lymphoma / Q000473:pathology / Q000628:therapy* / Q000821:virology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000637:transplantation*; D016896:Treatment Outcome; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins