Pembrolizumab: a novel antiprogrammed death 1 (PD-1) monoclonal antibody for treatment of metastatic melanoma.

WHAT IS KNOWN AND OBJECTIVE: To review the pharmacology, efficacy, safety, formulary and economic considerations of pembrolizumab, a novel, first-in-class, anti-PD-1 monoclonal antibody for treatment of advanced melanoma. METHODS: A literature search was conducted using PubMed (July 2013-December 2014) with search terms: pembrolizumab, MK-3475 and lambrolizumab. Additional sources were identified through a subsequent review of all relevant papers, clinicaltrials.gov, product labelling and media releases. All English-language studies conducted in humans with clinical data were included. Review papers were excluded from analysis. RESULTS AND DISCUSSION: Patients with advanced melanoma have limited options available. Immune therapies have shown promise in treating advanced melanoma, but can have significant toxicities. Identification of the role of PD-1 in tumour immune evasion and the subsequent development of pembrolizumab, a novel agent that inhibits PD-1, has led to the availability of an additional treatment option for patients who have progressive disease despite treatment with currently approved agents. Phase I cohort studies have demonstrated promising overall response rates and an estimated progression-free survival of approximately 5·5 months. Minimal toxicity has been observed in patients receiving pembrolizumab, although significant severe immune-mediated reactions have been reported. WHAT IS NEW AND CONCLUSION: Pembrolizumab is a novel anti-PD-1 monoclonal antibody that is an effective option for advanced melanoma previously treated with agents such as ipilimumab and BRAF inhibitors. Additional studies will provide the necessary data for determining its true place in therapy for advanced melanoma and exploring its efficacy in additional malignant indications.

Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production.

Interferon-gamma-inducing factor (IGIF, interleukin-18) is a recently described cytokine that shares structural features with the interleukin-1 (IL-1) family of proteins and functional properties with IL-12. Like IL-12, IGIF is a potent inducer of interferon (IFN)-gamma from T cells and natural killer cells. IGIF is synthesized as a biologically inactive precursor molecule (proIGIF). The cellular production of IL-1beta, a cytokine implicated in a variety of inflammatory diseases, requires cleavage of its precursor (proIL-1beta) at an Asp-X site by interleukin-1beta-converting enzyme (ICE, recently termed caspase-1). The Asp-X sequence at the putative processing site in proIGIF suggests that a protease such as caspase-1 might be involved in the maturation of IGIF. Here we demonstrate that caspase-1 processes proIGIF and proIL-1beta with equivalent efficiencies in vitro. A selective caspase-1 inhibitor blocks both lipopolysaccharide-induced IL-1beta and IFN-gamma production from human mononuclear cells. Furthermore, caspase-1-deficient mice are defective in lipopolysaccharide-induced IFN-gamma production. Our results thus implicate caspase-1 in the physiological production of IGIF and demonstrate that it plays a critical role in the regulation of multiple proinflammatory cytokines. Specific caspase-1 inhibitors would provide a new class of anti-inflammatory drugs with multipotent action.

Protease activity of in vitro transcribed and translated Caenorhabditis elegans cell death gene (ced-3) product.

The Caenorhabditis elegans cell death gene, ced-3, encodes one of the two proteins required for apoptosis in this organism. The primary sequence similarities between Ced-3 and the mammalian interleukin-1beta converting enzyme (ICE) suggest that these two proteins may have functionally similar active sites and that Ced-3 may function as a cysteine protease. Here we report that in vitro transcribed and translated Ced-3 protein (p56) underwent rapid processing to smaller fragments. Replacement of the predicted active site cysteine of Ced-3 with serine (C364S) prevented the generation of smaller proteolytic fragments, suggesting that the processing might be an autocatalytic process. Peptide aldehydes with aspartic acid at the P1 position blocked Ced-3 autocatalysis. Furthermore, the protease inhibition profile of Ced-3 was similar to the profile reported for ICE. These functional data demonstrate that Ced-3 is an Asp-dependent cysteine protease with substrate specificity similar to that of ICE. Aurintricarboxylic acid, an inhibitor of apoptosis in mammalian cells, blocked Ced-3 autocatalytic activity, suggesting that an aurintricarboxylic acid-sensitive Ced-3/ICE-related protease might be involved in the apoptosis pathway(s) in mammalian cells.

IL-1 beta converting enzyme (ICE) is not required for apoptosis induced by lymphokine deprivation in an IL-2-dependent T cell line.

Clonal T cells undergo programmed cell death (PCD) or apoptosis when cultured without the appropriate cytokines. The cysteine protease, IL-1 beta converting enzyme (ICE), is implicated in apoptosis based on its structural similarity to the PCD gene, ced-3, in Caenorhabditis elegans and the induction of PCD in fibroblasts transfected with recombinant ICE. We show that the murine IL-2-dependent CTLL T cell line expresses ICE but not IL-1 beta. Interestingly, ICE mRNA and protein levels increase during apoptosis. Yet inhibition of ICE enzymatic activity (> 90%) with either of two cell-permeable ICE inhibitors does not abrogate or delay apoptosis following IL-2 deprivation, as measured by DNA fragmentation and viability. Our results suggest that ICE is not required for apoptosis in lymphokine-deprived T cells.