title: Targeted treatment for metastatic renal cell carcinoma and immune regulation.
abstract: New targeted agents have become the mainstream of treatment in metastatic renal cell carcinoma (mRCC) and substituted the previous cytokine-based therapies. Vascular endothelial growth factor (VEGF) pathway is the principle target for drugs like sunitinib, sorafenib and bevacizumab. As VEGF is regulating dendritic cell (DC) function, inhibition of VEGF results in activation of DCs and a shift towards cellular (type 1) immunity, which is believed to favor cancer rejection. Recent studies have established the immune-stimulating effects of sunitinib that may as well be a marker for effectiveness. On the other hand, sorafenib not only inhibits VEGF receptor (VEGFR) but is also a B-Raf inhibitor (a component of the ras - MAPK pathway) and this leads to downregulation of immune responses. Sorafenib has not yet shown benefit in first-line treatment of mRCC when compared to interferon (IFN)-alpha and sorafenib-mediated immunosuppression may partially account for that. Mammalian target of rapamycin (mTOR), the target of temsirolimus, is an element of the DC activation pathway. There are no data for in vivo effects of temsirolimus in the immune system. The addition of IFN-alpha to temsirolimus resulted in inferior outcomes than temsirolimus alone. IFN-alpha has however still a place in mRCC treatment, as bevacizumab has been approved in combination with IFN-alpha. New clinical trials address the effects of the combination of cytokines with targeted agents. The immune-modulating effects of targeted treatments may be important in pharmacodynamic outcomes, effectiveness or the development of adverse events.
authors.affiliation: Applied Molecular Oncology Laboratory, Theagenion Cancer Hospital, 2, Alexandrou Simeonidi Str, 540 07 Thessaloniki, Greece. konstantinos.laschos@gmail.com
authors.forename: K A
authors.initials: KA
authors.lastname: Laschos
authors.forename: K T
authors.initials: KT
authors.lastname: Papazisis
authors.forename: L F
authors.initials: LF
authors.lastname: Kontovinis
authors.forename: C
authors.initials: C
authors.lastname: Kalaitzis
authors.forename: S
authors.initials: S
authors.lastname: Gianakopoulos
authors.forename: A H
authors.initials: AH
authors.lastname: Kortsaris
authors.forename: S
authors.initials: S
authors.lastname: Touloupidis
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000627:therapeutic use; D000068258:Bevacizumab; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000453:epidemiology / Q000276:immunology / Q000473:pathology*; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007211:Indoles / Q000627:therapeutic use; D016898:Interferon-alpha / Q000627:therapeutic use; D007376:Interleukin-2 / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000453:epidemiology / Q000276:immunology / Q000473:pathology*; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D000077157:Sorafenib; D000077210:Sunitinib; D013601:T-Lymphocytes / Q000276:immunology; D014481:United States / Q000453:epidemiology; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D007211:Indoles; D016898:Interferon-alpha; D007376:Interleukin-2; D010671:Phenylurea Compounds; D011725:Pyridines; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000068258:Bevacizumab; D000077157:Sorafenib; D000077210:Sunitinib