Agonist antibodies to TNFR molecules that costimulate T and NK cells Journal Article
| Authors: | Melero, I.; Hirschhorn-Cymerman, D.; Morales-Kastresana, A.; Sanmamed, M. F.; Wolchok, J. D. |
| Article Title: | Agonist antibodies to TNFR molecules that costimulate T and NK cells |
| Abstract: | 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 additionalimmunotherapeutic 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-CD137mAbshave been shownto enhanceNK-mediated cytotoxicity elicited by rituximab and trastuzumab. Combinations with other immunomodulatorymAbthat block T-cell checkpoint blockade receptors such as CTLA-4 and PD-1 are also promising. © 2012 American Association for Cancer Research. |
| Keywords: | controlled study; protein expression; protein phosphorylation; unclassified drug; nonhuman; solid tumor; rituximab; antineoplastic agent; protein domain; neoplasms; transcription factor foxp3; t lymphocyte; animal cell; mouse; animals; cell death; ipilimumab; cancer immunotherapy; melanoma; apoptosis; dendritic cell; animal experiment; animal model; cyclophosphamide; cell differentiation; monoclonal antibody; drug dose escalation; prostate cancer; t lymphocyte receptor; lymphocyte activation; antibodies, monoclonal; hematologic malignancy; ubiquitination; immunotherapy; cd4+ t lymphocyte; cytotoxic t lymphocyte; natural killer cell; killer cells, natural; malignant neoplastic disease; tumor necrosis factor receptor; immunostimulation; negative feedback; trastuzumab; cytotoxic t lymphocyte antigen 4; cytokine release; ubiquitin protein ligase e3; cd134 antigen; immunocompetent cell; tetanus toxoid; receptors, tumor necrosis factor; memory t lymphocyte; metastatic melanoma; cd137 antigen; ox 40; tumor necrosis factor receptor associated factor; cdx 1127; pf 05082566; pfz 05082566; trx 518; tumor necrosis factor receptor associated factor 2; tumor necrosis factor receptor associated factor 3; tumor necrosis factor receptor associated factor 5; urelumab |
| Journal Title: | Clinical Cancer Research |
| Volume: | 19 |
| Issue: | 5 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2013-01-01 |
| Start Page: | 1044 |
| End Page: | 1053 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-12-2065 |
| PROVIDER: | scopus |
| PUBMED: | 23460535 |
| PMCID: | PMC4397897 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 4" - "Export Date: 1 April 2013" - "CODEN: CCREF" - "Source: Scopus" |
