期刊
CLINICAL CANCER RESEARCH
卷 19, 期 5, 页码 1044-1053出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-12-2065
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类别
资金
- Novartis
- Bristol-Myers Squibb
- National Cancer Institute [R01 CA56821, P01 CA33049, P01 CA59350]
- Swim Across America
- Lita Annenberg Hazen Foundation
- T.J. Martell Foundation
- Commonwealth Cancer Foundation
- Ludwig Trust
- Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center
- Ministerio de Economia y Competitividad [SAF2011-22831]
- UTE for project CIMA
- A. Morales-Kastresana a FPI scholarship
- Ministerio de Economia y Competitividad
Therapy for cancer can be achieved by artificially stimulating antitumor T and natural killer (NK) lymphocytes with agonist monoclonal antibodies (mAb). T and NK cells express several members of the TNF receptor (TNFR) family specialized in delivering a costimulatory signal on their surface. Engagement of these receptors is typically associated with proliferation, elevated effector functions, resistance to apoptosis, and differentiation into memory cells. These receptors lack any intrinsic enzymatic activity and their signal transduction relies on associations with TNFR-associated factor (TRAF) adaptor proteins. Stimulation of CD137 (4-1BB), CD134 (OX40), and glucocorticoid-induced TNFR (GITR; CD357) promotes impressive tumor-rejecting immunity in a variety of murine tumor models. The mechanisms of action depend on a complex interplay of CTL, T-helper cells, regulatory T cells, dendritic cells, and vascular endothelium in tumors. Agonist mAbs specific for CD137 have shown signs of objective clinical activity in patients with metastatic melanoma, whereas anti-OX40 and anti-GITR mAbs have entered clinical trials. Preclinical evidence suggests that engaging TNFR members would be particularly active with conventional cancer therapies and additional immunotherapeutic approaches. Indeed, T-cell responses elicited to tumor antigens by means of immunogenic tumor cell death are amplified by these immunostimulatory agonist mAbs. Furthermore, anti-CD137 mAbs have been shown to enhance NK-mediated cytotoxicity elicited by rituximab and trastuzumab. Combinations with other immunomodulatory mAb that block T-cell checkpoint blockade receptors such as CTLA-4 and PD-1 are also promising. Clin Cancer Res; 19(5); 1044-53. (C) 2013 AACR.
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