Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): a novel strategy for the treatment of melanoma and other malignancies.
Cancer immunotherapy centers on modulating the host's tumor-directed immune response. One promising approach involves augmentation of cell-mediated immunity by interrupting T-cell pathways responsible for immune down-regulation or tolerance. The discovery of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and its role as a key negative regulator for T cells has prompted efforts to target this signaling molecule to improve cancer therapy. Activation, or 'priming', of naive T cells in response to tumor-cell invasion comprises a dual-signaling mechanism. Signal 1 requires tumor-associated antigen recognition by the T-cell receptor, while signal 2 occurs through binding of CD80 or CD86 (B7.1 of 2) on the antigen presenting cell (APC) with CD28 on the T cell. Importantly, there is a final step responsible for naturally occurring immune regulation; this occurs in response to competitive binding of CD80/CD86 on the APC by CTLA-4 on the T cell. This 'immune checkpoint' interrupts signal 2 and inhibits the activated T cell. Targeting CTLA-4 as an anticancer strategy: Following proof-of-concept studies in animals, fully human anti-CTLA-4 antibodies were developed and 2 are undergoing clinical evaluation. Ipilimumab and tremelimumab have shown promising antitumor activity, initially in patients with advanced melanoma. Class-specific immune-related adverse events (irAEs) were common and mostly transient and/or manageable. These events are thought to be mechanism-of-action-related, indicating immune tolerance is broken; this relation may also explain the association between irAEs and response seen in several trials. Interruption of immune inhibitory pathways via CTLA-4 blockade appears to be a promising strategy for cancer immunotherapy.
O'Day
Steven J
SJ
Medical Oncology, The Angeles Clinic and Research Institute, Santa Monica, California, USA. soday@theangelesclinic.org
Hamid
Omid
O
Urba
Walter J
WJ
D000465:Algorithms; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000276:immunology*; D000943:Antigens, Differentiation / Q000276:immunology*; D060908:CTLA-4 Antigen; D002986:Clinical Trials as Topic; D016503:Drug Delivery Systems; D006801:Humans; D007108:Immune Tolerance; D000074324:Ipilimumab; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D051379:Mice; D012878:Skin Neoplasms / Q000276:immunology / Q000628:therapy*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D000074324:Ipilimumab; C520704:tremelimumab