Anti-tumor activity of patient-derived NK cells after cell-based immunotherapy--a case report.
BACKGROUND
Membrane-bound heat shock protein 70 (Hsp70) serves as a tumor-specific recognition structure for Hsp70-peptide (TKD) plus IL-2 activated NK cells. A phase I clinical trial has shown that repeated re-infusions of ex vivo TKD/IL-2-activated, autologous leukapheresis product is safe. This study investigated the maintenance of the cytolytic activity of NK cells against K562 cells and autologous tumor after 6 plus 3 infusions of TKD/IL-2-activated effector cells.


METHODS
A stable tumor cell line was generated from the resected anastomotic relapse of a patient with colon carcinoma (pT3, N2, M0, G2). Two months after surgery, the patient received the first monthly i.v. infusion of his ex vivo TKD/IL-2-activated peripheral blood mononuclear cells (PBMNC). After 6 infusions and a pause of 3 months, the patient received another 3 cell infusions. The phenotypic characteristics and activation status of tumor and effector cells were determined immediately before and at times after each infusion.


RESULTS
The NK cell ligands Hsp70, MICA/B, and ULBP-1,2,3 were expressed on the patient's anastomotic relapse. An increased density of activatory NK cell receptors following ex vivo stimulation correlated with an enhanced anti-tumoricidal activity. After 4 re-infusion cycles, the intrinsic cytolytic activity of non-stimulated PBMNC was significantly elevated and this heightened responsiveness persisted for up to 3 months after the last infusion. Another 2 re-stimulations with TKD/IL-2 restored the cytolytic activity after the therapeutic pause.


CONCLUSIONS
In a patient with colon carcinoma, repeated infusions of ex vivo TKD/IL-2-activated PBMNC initiate an intrinsic NK cell-mediated cytolytic activity against autologous tumor cells.
Milani
Valeria
V
Department of Internal Medicine, University Medical Center Grosshadern, Ludwig-Maximilians-Universität München, Germany. valeria.bruehl-milani@med.uni-muenchen.de
Stangl
Stefan
S
Issels
Rolf
R
Gehrmann
Mathias
M
Wagner
Beate
B
Hube
Kathrin
K
Mayr
Doris
D
Hiddemann
Wolfgang
W
Molls
Michael
M
Multhoff
Gabriele
G
D000230:Adenocarcinoma / Q000628:therapy; D019264:Adoptive Transfer / Q000009:adverse effects; D000368:Aged; D019002:CD56 Antigen / Q000378:metabolism; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D003110:Colonic Neoplasms / Q000628:therapy*; D017809:Fatal Outcome; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy; D007262:Infusions, Intravenous / Q000009:adverse effects; D007376:Interleukin-2 / Q000276:immunology*; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology*; D007937:Leukapheresis; D008297:Male; D051920:NK Cell Lectin-Like Receptor Subfamily D / Q000378:metabolism
D019002:CD56 Antigen; D018840:HSP70 Heat-Shock Proteins; D007376:Interleukin-2; D051920:NK Cell Lectin-Like Receptor Subfamily D