Prednisolone reduces TNF-alpha release by PBMCs activated with a trifunctional bispecific antibody but not their anti-tumor activity.
BACKGROUND
New adjuvant immunological therapies, that selectively redirect effector cells towards tumors, are currently under development. These strategies include trifunctional bispecific antibodies (trAb) as promising tools for the elimination of disseminated tumor cells and micrometastases. To date, these chimeric molecules have demonstrated their antitumor potential mainly in vitro. Here, trAb-activated peripheral blood mononuclear cells (PBMCs) displayed considerable antitumor activity, accompanied by the release of cytokines, which contributed to the antitumor activity but, on the other hand, may evoke serious limiting side-effects in vivo, demanding therapeutic interventions.


METHODS
The antitumor activity and cytokine release by trAb-activated PBMCs were studied in co-cultures with multicellular tumor spheroids (MTS), which represent a three-dimensional in vitro model for solid tumors, especially non-vascularized micrometastases. The glucocorticoid prednisolone was tested for its influence on the release of TNF-alpha and the activity of PBMCs.


RESULTS
It was shown that PBMCs, which were stimulated with a trifunctional bispecific antibody, BiUII, displayed an excellent antitumor activity, resulting in complete disintegration of the MTS. Also, it was demonstrated that prednisolone significantly reduced the release of TNF-alpha, without impairing the antitumor activity of BiUII-activated PBMCs. In contrast, unspecific killing was reduced, as demonstrated with an identical trAb (Bi48), which recognizes an antigen absent from the target cells.


CONCLUSIONS
The in vivo application of bispecific antibodies for adjuvant tumor therapies may be limited by the manifest activation of immune effectors, accompanied by overwhelming cytokine release. Glucocorticoids, like prednisolone, may effectively reduce cytokine release without impairing the antitumor activity of trAb-activated immune cells.
Walz
Annette
A
Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Schleswig-Holstein, Campus Luebeck, Ratzeburgerallee 160, 23538 Luebeck, Germany.
Andratschke
Michaela
M
Wollenberg
Barbara
B
Lindhofer
Horst
H
Zeidler
Reinhard
R
D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D011239:Prednisolone / Q000494:pharmacology*; D051381:Rats; D018874:Spheroids, Cellular; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*
D018033:Antibodies, Bispecific; D014409:Tumor Necrosis Factor-alpha; D011239:Prednisolone