期刊
IMMUNOTHERAPY
卷 10, 期 9, 页码 787-796出版社
FUTURE MEDICINE LTD
DOI: 10.2217/imt-2017-0185
关键词
c-IAP1/c-IAP2; IAP antagonists; inhibitor of apoptosis proteins; SMAC mimetics; tumor immunotherapy
类别
资金
- Novartis
- Dana-Farber Cancer Institute/Novartis Program in Drug Discovery
- Melanoma Research Alliance
- Pew Foundation
- AGA Research Scholars Award
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Mentored Clinical Scientist Development Award [1K08DK114563-01]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [K08DK114563] Funding Source: NIH RePORTER
Inhibition of the T-cell co-inhibitory checkpoint receptors or their ligands CTLA-4, PD-1 and PD-L1 using monoclonal antibodies has proven to be highly effective against many cancers. Yet many cancers remain resistant to checkpoint blockade, and durable remissions occur in only a minority of patients. Novel approaches to enhancing antitumor responses are thus necessary in order to expand the reach of these treatments. The inhibitor of apoptosis (IAP) protein family comprises a diverse group of proteins, many of which have immunoregulatory roles. Small molecule IAP antagonists have been developed and are undergoing early phase clinical testing. These drugs were initially developed to promote tumor cell apoptosis; however, a considerable body of work now indicates that IAP antagonists induce antitumor activity through modulation of innate and adaptive immunity. Primarily through inhibition of cellular (c)-IAP1 and c-IAP2, IAP antagonists can activate alternative NF-kappa B signaling, promoting B-cell survival, activation of dendritic cells and delivering a broad co-stimulatory signal to T cells. At the same time, IAP antagonists can promote tumor cell intrinsic sensitization to innate immune signals, and enhance tumor cell killing by inflammatory cytokines and phagocytic macrophages. These drugs thus represent an attractive investigational approach to immunotherapy, providing a positive signaling counterpart to the relief of signal inhibition conferred by checkpoint blockade.
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