Inhibitor Of Apoptosis Proteins Antagonism Research Articles

Xevinapant Combined with Pembrolizumab in Patients with Advanced, Pretreated, Colorectal and Pancreatic Cancer: Results of the Phase Ib/II CATRIPCA Trial.

Xevinapant is an orally available inhibitor of apoptosis proteins (IAP) inhibitor. Preclinical data suggest that IAP antagonism may synergize with immune checkpoint blockers by modulating the NFκB pathway in immune cells. Adult patients with non-high microsatellite instability advanced/metastatic pancreatic ductal adenocarcinoma (PDAC) or colorectal cancer were enrolled in this phase Ib/II study and received pembrolizumab 200 mg every 3 weeks intravenously, and ascending doses of oral xevinapant (100, 150, and 200 mg daily for 14 days on/7 days off). Dose escalation followed a 3+3 design with a 21-day dose-limiting toxicity (DLT) evaluation period. Following the determination of the recommended phase II dose (RP2D), 14 patients with PDAC and 14 patients with colorectal cancer were enrolled in expansion cohorts to assess preliminary efficacy. Forty-one patients (26 males) with a median age of 64 years were enrolled: 13 in the dose escalation and 28 in the two expansion cohorts. No DLT was observed during dose escalation. The RP2D was identified as xevinapant 200 mg/day + pembrolizumab 200 mg every 3 weeks. The most common adverse events (AE) were fatigue (37%), gastrointestinal AE (decreased appetite in 37%, nausea in 24%, stomatitis in 12%, and diarrhea and vomiting in 10% each), and cutaneous AE (pruritus, dry skin, and rash seen in 20%, 15%, and 15% of patients, respectively). The best overall response according to RECIST1.1 was partial response (confirmed) in 1 (3%), stable disease in 4 (10%), and progressive disease in 35 (88%). Xevinapant combined with pembrolizumab was well tolerated with no unexpected AEs. However, antitumor activity was low.

The Immuno-Modulatory Effects of Inhibitor of Apoptosis Protein Antagonists in Cancer Immunotherapy.

One of the hallmarks of cancer cells is their ability to evade cell death via apoptosis. The inhibitor of apoptosis proteins (IAPs) are a family of proteins that act to promote cell survival. For this reason, upregulation of IAPs is associated with a number of cancer types as a mechanism of resistance to cell death and chemotherapy. As such, IAPs are considered a promising therapeutic target for cancer treatment, based on the role of IAPs in resistance to apoptosis, tumour progression and poor patient prognosis. The mitochondrial protein smac (second mitochondrial activator of caspases), is an endogenous inhibitor of IAPs, and several small molecule mimetics of smac (smac-mimetics) have been developed in order to antagonise IAPs in cancer cells and restore sensitivity to apoptotic stimuli. However, recent studies have revealed that smac-mimetics have broader effects than was first attributed. It is now understood that they are key regulators of innate immune signalling and have wide reaching immuno-modulatory properties. As such, they are ideal candidates for immunotherapy combinations. Pre-clinically, successful combination therapies incorporating smac-mimetics and oncolytic viruses, as with chimeric antigen receptor (CAR) T cell therapy, have been reported, and clinical trials incorporating smac-mimetics and immune checkpoint blockade are ongoing. Here, the potential of IAP antagonism to enhance immunotherapy strategies for the treatment of cancer will be discussed.

SMAC mimetics as potential cancer therapeutics in myeloid malignancies.

Evasion of apoptosis has been identified as one of the essential hallmarks of cancer. Inhibitor of apoptosis proteins (IAPs) are implicated in a host of myeloid malignancies, providing the rationale for strategies aimed at neutralizing IAPs to lower the cancer cell apoptosis threshold. Modes of IAP antagonism may include down-regulating IAP expression, up-regulating endogenous pro-apoptotic proteins, such as tumour necrosis factor-α or Fas ligand, or directly antagonizing IAP activity against caspases. Direct targeting of IAPs using mimetics of the second mitochondria-derived activator of caspase (SMAC) protein has shown therapeutic promise by sensitizing the effect of chemotherapy on malignant cells. In pre-clinical studies, SMAC mimetics have demonstrated broad synergistic activity with a wide range of therapeutics, including cytotoxic chemotherapy, receptor tyrosine kinase inhibitors, agents targeting death receptors and alternative mechanisms of cell death, such as necroptosis or autophagy and immune check point blockade. SMAC mimetics represent a novel approach for further investigation in patients with high-risk, chemo-refractory blood cancers, as single agents or in thoughtfully selected combinations. In this review, we discuss the development and therapeutic rationale of small molecule SMAC mimetics, with an emphasis on agents in clinical development for myeloid malignancies.

IAP Antagonists Enhance Cytokine Production from Mouse and Human iNKT Cells.

Inhibitor of apoptosis protein (IAP) antagonists are in clinical trials for a variety of cancers, and mouse models show synergism between IAP antagonists and anti-PD-1 immunotherapy. Although IAP antagonists affect the intrinsic signaling of tumor cells, their most pronounced effects are on immune cells and the generation of antitumor immunity. Here, we examined the effects of IAP antagonism on T-cell development using mouse fetal thymic organ culture and observed a selective loss of iNKT cells, an effector cell type of potential importance for cancer immunotherapy. Thymic iNKT-cell development probably failed due to increased strength of TCR signal leading to negative selection, given that mature iNKT cells treated with IAP antagonists were not depleted, but had enhanced cytokine production in both mouse and human ex vivo cultures. Consistent with this, mature mouse primary iNKT cells and iNKT hybridomas increased production of effector cytokines in the presence of IAP antagonists. In vivo administration of IAP antagonists and α-GalCer resulted in increased IFNγ and IL-2 production from iNKT cells and decreased tumor burden in a mouse model of melanoma lung metastasis. Human iNKT cells also proliferated and increased IFNγ production dramatically in the presence of IAP antagonists, demonstrating the utility of these compounds in adoptive therapy of iNKT cells. Cancer Immunol Res; 6(1); 25-35. ©2017 AACR.

Abstract C2: Clinical safety, pharmacokinetics and early evidence of activity of the oral IAPs inhibitor Debio 1143 in combination with carboplatin and paclitaxel: a phase Ib study

Abstract Background: Resistance to apoptosis is a typical hallmark of cancer. Inhibitor of Apoptosis Proteins (IAPs) block caspase activation, modulate NF-kB signaling pathways, and are involved in resistance to standard chemo and radiation therapies. As such, IAPs antagonism represents an attractive target for therapeutic intervention. Debio 1143 is a potent orally-available monovalent SMAC mimetic antagonist of IAPs currently in clinical development. A previous phase I study showed Debio 1143 was well tolerated up to 900 mg QD as a single agent, with strong evidence of pharmacodynamic (PD) activity and appropriate pharmacokinetic (PK) disposition at doses ≥ 120 mg. [1] This Phase I study defined the dose limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, PK, and PD of Debio 1143 in combination with carboplatin and paclitaxel. Methods: Treatment-naïve and previously treated patients with squamous non-small cell lung cancer (NSCLC), and previously treated patients with triple negative breast cancer (TNBC) and platinum-resistant epithelial ovarian cancer (EOC) were treated with carboplatin (AUC 6) and paclitaxel 175 mg/m2 on day 1 of every 21-day-cycle up to a maximum of 6 cycles, combined with escalating doses of Debio 1143, administered once daily on days 1-5 of every 21-day cycle. The starting dose of Debio 1143 was 200 mg QD. Results: Thirty-one patients were included in the study. Four patients are still on treatment. Hematological DLTs were observed in 2/4 patients in the first two dose levels despite the reduction of Debio 1143 dose to 100 mg. PK data suggested a PK interaction between Debio 1143 and paclitaxel. The study protocol was amended to reduce the doses of carboplatin to AUC 5 and paclitaxel to 135 mg/m2. Afterwards, patients received Debio 1143 doses of 100 mg (n = 2), 125 mg (n = 2), 175 mg (n = 2), 200 mg (n = 7), 225 mg (n = 5), 250 mg (n = 9). DLTs were febrile neutropenia (n = 2) and G3 ALT increase (n = 1). The MTD of Debio 1143 to be combined with carboplatin (AUC 5) and paclitaxel (135 mg/m2) is 250 mg QD. Most common treatment-related AEs reported in ≥ 15% of patients were asthenia (n = 13), decreased appetite (n = 11), diarrhea (n = 9), neutropenia (n = 9), thrombocytopenia (n = 8), anemia (n = 8), nausea (n = 7), fatigue (n = 7), vomiting (n = 4), AST increase (n = 4), hypomagnesaemia (n = 4), myalgia (n = 4),and epistaxis (n = 4). Paclitaxel exposure in patients dosed at 135 mg/m2 in combination with Debio 1143 was similar to historical control dosed at 175 mg/m2 due to a 25 to 40% reduction in clearance. Preliminary evaluation of PD endpoints confirmed Debio 1143-induced cIAP1 degradation in PBMCs at doses starting from 100mg. In line with the expected mechanism of action, modulation of serum PD markers of NF-kB signaling pathways and epithelial apoptosis was also observed during treatment. Twenty-three patients were evaluable for response. Partial responses by RECIST have been observed in 7 patients with EOC (6/17) and TNBC (1/5). Conclusions: The combination of Debio 1143 with carboplatin and paclitaxel is well tolerated, with significant PD activity and hints of activity. The clinical PK interaction between Debio 1143 and paclitaxel is well-controlled and managed in the patients. These findings support a further Phase II program. [1] HI Hurwitz et al., Cancer Chemother Pharmacol (2015) 75:851 Citation Format: Isabelle Ray-Coquard, Christophe Le Tourneau, Nicolas Isambert, Carlos A. Gomez-Roca, Philippe Cassier, Marie Paule Sablin, Bruno Gavillet, Daniela Purcea, Elisabeth Rouits, Claudia Schusterbauer, Claudio Zanna, Pierre Fumoleau, Jean-Pierre Delord. Clinical safety, pharmacokinetics and early evidence of activity of the oral IAPs inhibitor Debio 1143 in combination with carboplatin and paclitaxel: a phase Ib study. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C2.

Inhibitor of Apoptosis Proteins (IAPs) and Their Antagonists Regulate Spontaneous and Tumor Necrosis Factor (TNF)-induced Proinflammatory Cytokine and Chemokine Production

Inhibitor of apoptosis proteins (IAPs) play a major role in determining whether cells undergo apoptosis in response to TNF as well as other stimuli. However, TNF is also highly proinflammatory through its ability to trigger the secretion of multiple inflammatory cytokines and chemokines, which is arguably the most important role of TNF in vivo. Indeed, deregulated production of TNF-induced cytokines is a major driver of inflammation in several autoimmune conditions such as rheumatoid arthritis. Here, we show that IAPs are required for the production of multiple TNF-induced proinflammatory mediators. Ablation or antagonism of IAPs potently suppressed TNF- or RIPK1-induced proinflammatory cytokine and chemokine production. Surprisingly, IAP antagonism also led to spontaneous production of chemokines, particularly RANTES, in vitro and in vivo. Thus, IAPs play a major role in influencing the production of multiple inflammatory mediators, arguing that these proteins are important regulators of inflammation in addition to apoptosis. Furthermore, small molecule IAP antagonists can modulate spontaneous as well as TNF-induced inflammatory responses, which may have implications for use of these agents in therapeutic settings.

Inhibitor of apoptosis protein (IAP) antagonists demonstrate divergent immunomodulatory properties in human immune subsets with implications for combination therapy.

Inhibitor of apoptosis proteins (IAPs) are critical in regulating apoptosis resistance in cancer. Antagonists of IAPs, such as LCL161, are in clinical development and show promise as anti-cancer agents for solid and hematological cancers, with preliminary data suggesting they may act as immunomodulators. IAP antagonists hypersensitize tumor cells to TNF-α-mediated apoptosis, an effect that may work in synergy with that of cancer vaccines. This study aimed to further investigate the immunomodulatory properties of LCL161 on human immune subsets. T lymphocytes treated with LCL161 demonstrated significantly enhanced cytokine secretion upon activation, with little effect on CD4 and CD8 T-cell survival or proliferation. LCL161 treatment of peripheral blood mononuclear cells significantly enhanced priming of naïve T cells with synthetic peptides in vitro. Myeloid dendritic cells underwent phenotypic maturation upon IAP antagonism and demonstrated a reduced capacity to cross-present a tumor antigen-based vaccine. These effects are potentially mediated through an observed activation of the canonical and non-canonical NF-κB pathways, following IAP antagonism with a resulting upregulation of anti-apoptotic molecules. In conclusion, this study demonstrated the immunomodulatory properties of antagonists at physiologically relevant concentrations and indicates their combination with immunotherapy requires further investigation.

Inhibitor of Apoptosis Proteins as Novel Targets in Inflammatory Processes

Inhibitor of apoptosis proteins (IAPs), such as X-linked or cellular IAP 1/2 (XIAP, cIAP1/2), are important regulators of apoptosis. IAP antagonists are currently under clinical investigation as anticancer agents. Interestingly, IAPs participate in the inflammation-associated TNF receptor signaling complex and regulate NFκB signaling. This raises the question about the role of IAPs in inflammation. Here, we investigated the anti-inflammatory potential of IAP inhibitors and the role of IAPs in inflammatory processes of endothelial cells. In mice, the small molecule IAP antagonist A-4.10099.1 (ABT) suppressed antigen-induced arthritis, leukocyte infiltration in concanavalin A-evoked liver injury, and leukocyte transmigration in the TNFα-activated cremaster muscle. In vitro, we observed an attenuation of leukocyte-endothelial cell interaction by downregulation of the intercellular adhesion molecule-1. ABT did not impair NFκB signaling but decreased the TNFα-induced activation of the TGF-β-activated kinase 1, p38, and c-Jun N-terminal kinase. These effects are based on the proteasomal degradation of cIAP1/2 accompanied by an altered ratio of the levels of membrane-localized TNF receptor-associated factors 2 and 5. Our results reveal IAP antagonism as a profound anti-inflammatory principle in vivo and highlight IAPs as important regulators of inflammatory processes in endothelial cells.

IAP inhibitors enhance co-stimulation to promote tumor immunity

The inhibitor of apoptosis proteins (IAPs) have recently been shown to modulate nuclear factor κB (NF-κB) signaling downstream of tumor necrosis factor (TNF) family receptors, positioning them as essential survival factors in several cancer cell lines, as indicated by the cytotoxic activity of several novel small molecule IAP antagonists. In addition to roles in cancer, increasing evidence suggests that IAPs have an important function in immunity; however, the impact of IAP antagonists on antitumor immune responses is unknown. In this study, we examine the consequences of IAP antagonism on T cell function in vitro and in the context of a tumor vaccine in vivo. We find that IAP antagonists can augment human and mouse T cell responses to physiologically relevant stimuli. The activity of IAP antagonists depends on the activation of NF-κB2 signaling, a mechanism paralleling that responsible for the cytotoxic activity in cancer cells. We further show that IAP antagonists can augment both prophylactic and therapeutic antitumor vaccines in vivo. These findings indicate an important role for the IAPs in regulating T cell–dependent responses and suggest that targeting IAPs using small molecule antagonists may be a strategy for developing novel immunomodulating therapies against cancer.