Small-molecule inhibitor of apoptosis (IAP) antagonists, called Smac mimetic compounds (SMCs), sensitize tumours to TNF-α-induced killing while simultaneously blocking TNF-α growth-promoting ...activities. SMCs also regulate several immunomodulatory properties within immune cells. We report that SMCs synergize with innate immune stimulants and immune checkpoint inhibitor biologics to produce durable cures in mouse models of glioblastoma in which single agent therapy is ineffective. The complementation of activities between these classes of therapeutics is dependent on cytotoxic T-cell activity and is associated with a reduction in immunosuppressive T-cells. Notably, the synergistic effect is dependent on type I IFN and TNF-α signalling. Furthermore, our results implicate an important role for TNF-α-producing cytotoxic T-cells in mediating the anti-cancer effects of immune checkpoint inhibitors when combined with SMCs. Overall, this combinatorial approach could be highly effective in clinical application as it allows for cooperative and complimentary mechanisms in the immune cell-mediated death of cancer cells.
The controlled production and downstream signaling of the inflammatory cytokine tumor necrosis factor-α (TNF-α) are important for immunity and its anticancer effects. Although chronic stimulation ...with TNF-α is detrimental to the health of the host in several autoimmune and inflammatory disorders, TNF-α-contrary to what its name implies-leads to cancer formation by promoting cell proliferation and survival. Smac mimetic compounds (SMCs), small-molecule antagonists of inhibitor of apoptosis proteins (IAPs), switch the TNF-α signal from promoting survival to promoting death in cancer cells. Using a genome-wide siRNA screen to identify factors required for SMC-to-TNF-α-mediated cancer cell death, we identified the transcription factor SP3 as a critical molecule in both basal and SMC-induced production of TNF-α by engaging the nuclear factor κB (NF-κB) transcriptional pathway. Moreover, the promotion of TNF-α expression by SP3 activity confers differential sensitivity of cancer versus normal cells to SMC treatment. The key role of SP3 in TNF-α production and signaling will help us further understand TNF-α biology and provide insight into mechanisms relevant to cancer and inflammatory disease.
Nature Communications 8: Article number: 14278 (2017); Published 15 February 2017, Updated 18 July 2018 The original HTML version of this Article omitted the article number; it should have been ...‘14278’. This has now been corrected in the HTML version of the Article. The PDF version was correct from the time of publication.
Abstract
Aim: To demonstrate the immune potentiating effects of small-molecule inhibitor-of-apoptosis (IAP) antagonists, known as Smac mimetics, with current standard-of-care cancer immunotherapies.
...Background: Smac mimetic compounds (SMCs) are synthetic small-molecule antagonists of the cellular inhibitor of apoptosis, cIAP1 and cIAP2, proteins. The IAPs act at a critical nexus in the cancer cell, capable of suppressing intrinsic cell death and avoiding immune-mediated killing of the target cancer cell. The cIAPs are essential mediators of TNF cytokine superfamily signaling which is responsible for the activation of classical and alternative NF-κB survival pathways. SMCs cause the rapid loss of cIAP1/2 proteins by ubiquitin-induced and proteasomal-mediated degradation. SMCs sensitize tumor cells to TNFα-mediated killing by blocking the formation of the RIP1 signalosome and by generating RIP1 death-inducing complexes, the ripoptosome and the necrosome. In addition, SMCs by depleting cIAPs in immune cells promote anti-tumor immunity by inducing T-cell co-stimulation, resulting in a multi-pronged cytolytic attack against tumor cells. SMCs are in early stage clinical trials for cancer and have proven safe as single agents or in combination with chemotherapy.
Methodology: We tested various combination immunotherapies in vitro and in vivo in multiple different orthotopic models of cancer, including glioblastoma, in immunocompetent mice to ascertain tumor responses. In addition, we elucidated the role of cytokines and immune cells in the efficacy observed.
Results: SMCs dramatically enhanced the anti-tumor effects of Toll-like receptor agonists, recombinant type-1 interferon, BCG vaccine or oncolytic rhabdoviruses in models of cancer. Importantly, we observed for the first time remarkable synergy between SMCs and immune checkpoint inhibitor biologics (e.g. anti-PD1, anti-CTLA-4 monoclonal antibodies) in brain tumor models for which neither single agent had any significant activity. We now demonstrate that SMCs induce long-term cancer immunity that is dependent on cytotoxic T-cell activity. Furthermore, SMCs cooperate with anti-PD1 immune checkpoint inhibitors to induce durable cures in aggressive tumor. We demonstrate that both the innate and adaptive immune response are responsible for the anti-tumor responses and the generation of durable cures in these models. Cytokine neutralization and immune-cell depletion experiments point to key roles for TNFα, interferons, macrophages and CD8-positive killer T-cells in the combination immunotherapy effects observed.
Conclusions: SMCs can make use of both innate and adaptive immunity to eradicate cancers in mice. Smac mimetic small-molecules represent a novel and universal form of cancer immunotherapy that greatly compliments immune checkpoint blockade. This highly effective combination approach is readily translatable to the clinic.
(Acknowledgements: This project was supported by an Impact grant co-funded by CCSRI and Brain Canada, and by operating grants from CIHR).
Citation Format: Eric LaCasse, Shawn Beug, Cristin Healey, Caroline Beauregard, Tarun Sanda, Tommy Alain, Robert Korneluk. Smac mimetics synergistically improve the efficacy of cancer immunotherapies including immune checkpoint blockade in preclinical models abstract. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B034.
The inhibitors of apoptosis (IAP) proteins regulate cell death signaling cascades. Smac mimetic (SM) compounds are antagonists of these proteins and are being evaluated for their anti-cancer efficacy ...and immunomodulatory effects. Here, I adopted an orthotopic murine model of urothelial carcinoma (MB49) resistant to prominent immune-stimulating therapies BCG mycobacterium and PD-1/PD-L1 checkpoint blockade. I found treatment with a monovalent SM, LCL161, generated T lymphocyte-dependent cures of MB49, retaining potent anti-tumour immune memory and significantly improving overall survival benefit. Separately, I report SM treatment modulates multiple components comprising the cellular adaptive immune response. Specifically, I found SM promoting the expansion of antigen-presenting cells (APCs) in vitro and enabling T lymphocyte priming in vivo. I evaluated SM in combination with concurrent immune checkpoint blockade. The combination of SM with a monoclonal antibody targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4, 9h10 clone) potentiated anticancer immunity, curing all tested subjects of MB49. I verified Fc receptor-dependent intratumoural regulatory T cell depletion as a required mechanism for enhancing survival probability with the combination of SM and anti-CTLA-4. The further evaluation of mechanisms responsible for SMs stimulating immunity will promote their clinical application for cancer therapy.
The aim of this study was to compare, in a large all-comers registry, major adverse cardiac and cerebrovascular events (MACCE) after percutaneous coronary intervention (PCI) with first-generation ...drug-eluting stents (DES) versus coronary artery bypass grafting (CABG) in unprotected left main coronary artery (ULMCA) stenosis.
Percutaneous coronary intervention with DES implantation in ULMCA has been shown to be a feasible and safe approach at midterm clinical follow-up.
All consecutive patients with ULMCA stenosis treated by PCI with DES versus CABG were analyzed in this multinational registry. A propensity score analysis was performed to adjust for baseline differences in the overall cohort.
In total 2,775 patients were included: 1,874 were treated with PCI versus 901 with CABG. At 1,295 (interquartile range: 928 to 1,713) days, there were no differences, at the adjusted analysis, in the primary composite endpoint of death, cerebrovascular accidents, and myocardial infarction (MI) (adjusted hazard ratio HR: 1.11; 95% confidence interval CI: 0.85 to 1.42; p = 0.47), mortality (adjusted HR: 1.16; 95% CI: 0.87 to 1.55; p = 0.32), or composite endpoint of death and MI (adjusted HR: 1.25; 95% CI: 0.95 to 1.64; p = 0.11). An advantage of CABG over PCI was observed in the composite secondary endpoint of MACCE (adjusted HR: 1.64; 95% CI: 1.33 to 2.03; p < 0.0001), driven exclusively by the higher incidence of target vessel revascularization with PCI.
In our multinational all-comers registry, no difference was observed in the occurrence of death, cerebrovascular accidents, and MI between PCI and CABG. An advantage of CABG over PCI was observed in the incidence of MACCE, driven by the higher incidence of target vessel revascularization with PCI.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The aim of this study was to compare, in a large all-comer registry, the long-term clinical outcomes after percutaneous coronary intervention (PCI) with drug-eluting stents (DES) for ostial/mid-shaft ...lesions versus distal bifurcation lesions in unprotected left main coronary artery (ULMCA) stenosis.
Limited data are available regarding clinical outcomes following DES implantation at the different ULMCA sites.
Patients with ULMCA stenosis treated by PCI with DES were analyzed in this multinational registry.
A total of 1,612 patients were included: 482 were treated for ostial/mid-shaft lesions versus 1,130 for distal bifurcation lesions. At a median follow-up period of 1,250 (interquartile range: 987 to 1,564) days, PCI for distal bifurcation lesions was associated with a higher incidence of major adverse cardiac events (propensity-score adjusted hazard ratio HR: 1.48, 95% confidence interval CI: 1.16 to 1.89; p = 0.001), largely because of the higher target vessel revascularization rate observed in this group as compared to the ostial/mid-shaft lesions group (propensity-score adjusted HR: 1.68, 95% CI: 1.19 to 2.38; p = 0.003). These results were sustained following propensity-score matched analysis. With regard to all-cause death and the composite endpoint of all-cause death and myocardial infarction, propensity-score adjusted analysis suggested a trend toward higher rates of these in the distal ULMCA PCI group, although this was not observed in the propensity-score matched analysis.
This study demonstrates that PCI for ostial/mid-shaft lesions is associated with better clinical outcomes than are distal bifurcation lesions in ULMCA, largely because there is a lower need for repeat revascularization in ostial/mid-shaft lesions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objectives The aim of this study was to report the long-term clinical outcomes after percutaneous coronary intervention (PCI) with drug-eluting stents (DES) versus coronary artery bypass grafting ...(CABG) for ostial/midshaft lesions in an unprotected left main coronary artery (ULMCA). Background Data regarding outcomes in these patients are limited. Methods Of a total of 2,775 patients enrolled in the DELTA multinational registry, 856 patients with isolated ostial/midshaft lesions in an ULMCA treated by PCI with DES (n = 482) or CABG (n = 374) were analyzed. Results At a median follow-up period of 1,293 days, there were no significant differences in the propensity score–adjusted analyses for the composite endpoint of all-cause death, myocardial infarction (MI), and cerebrovascular accident (hazard ratio HR: 1.21, 95% confidence interval CI: 0.79 to 1.86; p = 0.372), all-cause death (HR: 1.35, 95% CI: 0.80 to 2.27; p = 0.255), the composite endpoint of all-cause death and MI (HR: 1.33, 95% CI: 0.83 to 2.12; p = 0.235) and major adverse cardiac and cerebrovascular events (HR: 1.34, 95% CI: 0.93 to 1.93; p = 0.113). These results were sustained after propensity-score matching. However, a higher incidence of target vessel revascularization (HR: 1.94, 95% CI: 1.03 to 3.64; p = 0.039) was observed in the PCI compared with the CABG group, with a trend toward higher target lesion revascularization (HR: 2.00, 95% CI: 0.90 to 4.45; p = 0.090). Conclusions This study demonstrates that PCI for ostial/midshaft lesions in an ULMCA is associated with clinical outcomes comparable to those observed with CABG at long-term follow-up, despite the use of older first-generation DES.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Percutaneous coronary intervention (PCI) with drug-eluting stents is an accepted alternative to surgery for the treatment of unprotected left main coronary artery (ULMCA) disease, but the long-term ...outcome in elderly patients is unclear. Aim of our study was to compare the clinical outcomes of octogenarians with ULMCA disease treated either with PCI with drug-eluting stents or coronary artery bypass grafting (CABG). The primary study end point was the composite of death, cerebrovascular accident, and myocardial infarction at follow-up. A total of 304 consecutive patients with ULMCA stenosis treated with PCI or CABG and aged ≥80 years were selected and analyzed in a large multinational registry. Two hundred eighteen were treated with PCI and 86 with CABG. During the hospitalization, a trend toward a higher mortality rate was reported in PCI-treated patients (3.5% vs 7.3%, p = 0.32). At a median follow-up of 1,088 days, the incidence of the primary end point was similar in the 2 groups (32.6% vs 30.2%, p = 0.69). Incidence of target vessel revascularization at follow-up was higher in PCI-treated patients (10% vs 4.2%, p = 0.05). At multivariate analysis, left ventricular ejection fraction was the only independent predictor of the primary end point (hazard ratio 0.95, 95% confidence interval 0.91 to 0.98, p = 0.001). After adjustment with propensity score, the revascularization strategy was not significantly correlated to the incidence of the primary end point (hazard ratio 0.98, 95% confidence interval 0.57 to 1.71, p = 0.95). In octogenarians, no difference was observed in the occurrence of the primary end point after PCI or CABG for the treatment of ULMCA disease. However, the rate of target vessel revascularization was higher in the PCI group.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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