Induction of tumor-specific cytotoxic T lymphocytes by immunization with autologous tumor cells and interleukin-2 gene transfected fibroblasts.
In a phase I trial designed to study a vaccine composed of autologous tumor cells and interleukin-2 gene transfected fibroblasts we analyzed lymphocytes infiltrating the vaccination site (VIL) in two melanoma patients. Functional studies demonstrated that numbers of MHC class I restricted cytotoxic T cells directed against the autologous tumor had increased at the immunization site in both cases. Analysis of the variability of T cell receptors (TCR) in the VIL of one patient revealed that the cytotoxic T lymphocytes consisted of a predominant population of TCRBV21S3+ T cells. Enrichment of this subpopulation to more than 99% by specific anti-TCRBV21S3 monoclonal antibody linked immunomagnetic beads and sequencing of the TCR-beta chain disclosed exactly the same V-D-J junctional sequence in all eight TCRBV21 transcripts from these VIL. The identical sequence was also detected in all eight TCRBV21 transcripts from the patient's tumor-infiltrating lymphocytes, indicating that the same CTL clone had infiltrated the tumor, circulated in the peripheral blood, and was amplified at the vaccination site. The TCRBV21S3+ T cells were also found to display an MHC class I restricted cytotoxic activity specifically directed against the autologous tumor cells. At the beginning of treatment these cells were undetectable at the vaccination site and delayed-type hypersensitivity testing was negative, contrasting with the positive results after therapy. Thus it is likely that vaccination with autologous tumor cells plus interleukin-2 gene transfected allogeneic fibroblasts had induced not only local accumulation but also an increase in the frequency of circulating tumor specific CTL.
Mackensen
A
A
Department of Hematology/Oncology, University of Freiburg Medical Center, Germany.
Veelken
H
H
Lahn
M
M
Wittnebel
S
S
Becker
D
D
Köhler
G
G
Kulmburg
P
P
Brennscheidt
U
U
Rosenthal
F
F
Franke
B
B
Mertelsmann
R
R
Lindemann
A
A
D000595:Amino Acid Sequence; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D005260:Female; D005347:Fibroblasts / Q000637:transplantation; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D007376:Interleukin-2 / Q000235:genetics*; D016246:Lymphocytes, Tumor-Infiltrating; D008545:Melanoma / Q000628:therapy*; D008875:Middle Aged; D009368:Neoplasm Transplantation; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000097:blood / Q000235:genetics; D012867:Skin / Q000276:immunology; D013601:T-Lymphocytes; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014611:Vaccination
D019496:Cancer Vaccines; D007376:Interleukin-2; D016693:Receptors, Antigen, T-Cell, alpha-beta