The apoptotic and proliferative fate of cytokine-induced killer cells after redirection to tumor cells with bispecific Ab.
BACKGROUND
Cytokine-induced killer (CIK) cells are ex vivo expanded T cells with co-expression of CD3 and CD56 and NK activity. They have recently been evaluated in a phase I/II clinical trial against malignant lymphoma. Bispecific Ab (bsAb) redirect CIK cells to tumor targets, thus enhancing their cytotoxicity. While bsAb may improve T-cell mediated anti-tumor activity, little is known about the fate of effector cells upon redirection to tumor targets using a bsAb.


METHODS
Using ex vivo-activated CIK cells, Her2/neu expressing breast and ovarian cell lines and a F(ab')2 Her2/neu x CD3 bsAb, we investigated the anti-tumor activity and the proliferative and apoptotic outcome of CIK cells.


RESULTS
When redirected to tumor targets with bsAb, there was a significant increase in anti-tumor activity as well as an increase in both CIK cell proliferation and apoptosis. The addition of agonistic Ab against CD28 did not significantly increase proliferation or apoptosis of CIK cells redirected to CD80- and CD86- tumor targets. To attempt to reduce T-cell apoptosis, we incubated CIK cells in the presence of the pan-caspase inhibitor z-VAD-fmk, which led to a partial reduction in T-cell apoptosis without increasing cellular cytotoxicity.


CONCLUSIONS
bsAb are effective in redirecting activated T cells to tumor targets and such redirection leads to both T-cell proliferation and apoptosis that are not altered by co-stimulation through CD28. Effector cell apoptosis can be reduced by using a caspase inhibitor but this does not increase CIK cell cytotoxicity.
Kornacker
M
M
Department of Internal Medicine V, University Hospital Heidelberg, Heidelberg, Germany.
Verneris
Mr
M
Kornacker
B
B
Ganten
Tm
T
Scheffold
C
C
Negrin
Rs
R
D018033:Antibodies, Bispecific / Q000276:immunology / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects*; D001666:Binding Sites, Antibody; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000276:immunology*; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018033:Antibodies, Bispecific; D016207:Cytokines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011956:Receptors, Cell Surface