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Efficacy of Local versus Systemic Application of Antibody-Cytokine Fusion Proteins in Tumor Therapy
Ist Teil von
Clinical cancer research, 2001-04, Vol.7 (4), p.985-998
Ort / Verlag
Philadelphia, PA: American Association for Cancer Research
Erscheinungsjahr
2001
Link zum Volltext
Quelle
EZB Electronic Journals Library
Beschreibungen/Notizen
Application of immunocytokines [fusion proteins (FuPs)] where the cytokine has been coupled to an antibody may not produce
the severe side effects frequently observed during systemic application of cytokines in cancer therapy. However, it has not
been explored whether FuPs are sufficient for intratumoral activation of leukocytes or whether intratumoral versus systemic application may be of greater efficacy. Interleukin 2 (IL2) or tumor necrosis factor (TNF) coupled to an anti-epidermal
growth factor receptor monoclonal antibody (IL2-FuP or TNF-FuP) were tested in SCID mice bearing a human epidermal growth
factor receptor-positive melanoma transplant and being reconstituted with human HLA-matched peripheral blood leukocytes. Whole-body
autoradiography revealed larger accumulation and prolonged retention of i.v. or intratumorally applied IL2-FuP or TNF-FuP
compared with the antibody. Even with low doses of FuP, tumor growth was significantly retarded, with the survival time being
further prolonged by the intratumoral application. Furthermore, outgrowth of the tumor was prevented in ∼50% of mice as long
as they received weekly injections of peripheral blood leukocytes concomitantly with the FuPs, which confirmed that it was
the donor leukocytes activated in vivo that retarded tumor growth. An in vitro analysis revealed that the IL2-FuP supported mainly proliferation and lymphokine-activated killer cell activity, whereas
TNF-FuP stimulated cytokine production and cytotoxic activity of monocytes and, to a low degree, of T cells. Both TNF-FuP
and IL2-FuP significantly accumulated in the tumor, which led to retardation of tumor growth. The therapeutic effect was improved
by intratumoral application. Importantly, the efficacy of both IL2-FuP and TNF-FuP depended on the induction of an immune
response in vivo .