Previous studies have argued that enhanced activity of the epidermal growth factor receptor (EGFR) and the mitogen-activated protein kinase (MAPK) pathway can promote tumor cell survival in response to cytotoxic insults. In this study, we examined the impact of MAPK signaling on the survival of primary hepatocytes exposed to low concentrations of deoxycholic acid (DCA, 50 microM). Treatment of hepatocytes with DCA caused MAPK activation, which was dependent upon ligand independent activation of EGFR, and downstream signaling through Ras and PI(3) kinase. Neither inhibition of MAPK signaling alone by MEK1/2 inhibitors, nor exposure to DCA alone, enhanced basal hepatocyte apoptosis, whereas inhibition of DCA-induced MAPK activation caused approximately 25% apoptosis within 6 h. Similar data were also obtained when either dominant negative EGFR-CD533 or dominant negative Ras N17 were used to block MAPK activation. DCA-induced apoptosis correlated with sequential cleavage of procaspase 8, BID, procaspase 9, and procaspase 3. Inhibition of MAPK potentiated bile acid-induced apoptosis in hepatocytes with mutant FAS-ligand, but did not enhance in hepatocytes that were null for FAS receptor expression. These data argues that DCA is causing ligand independent activation of the FAS receptor to stimulate an apoptotic response, which is counteracted by enhanced ligand-independent EGFR/MAPK signaling. In agreement with FAS-mediated cell killing, inhibition of caspase function with the use of dominant negative Fas-associated protein with death domain, a caspase 8 inhibitor (Ile-Glu-Thr-Asp-p-nitroanilide [IETD]) or dominant negative procaspase 8 blocked the potentiation of bile acid-induced apoptosis. Inhibition of bile acid-induced MAPK signaling enhanced the cleavage of BID and release of cytochrome c from mitochondria, which were all blocked by IETD. Despite activation of caspase 8, expression of dominant negative procaspase 9 blocked procaspase 3 cleavage and the potentiation of DCA-induced apoptosis. Treatment of hepatocytes with DCA transiently increased expression of the caspase 8 inhibitor proteins c-FLIP-(S) and c-FLIP-(L) that were reduced by inhibition of MAPK or PI(3) kinase. Constitutive overexpression of c-FLIP-(s) abolished the potentiation of bile acid-induced apoptosis. Collectively, our data argue that loss of DCA-induced EGFR/Ras/MAPK pathway function potentiates DCA-stimulated FAS-induced hepatocyte cell death via a reduction in the expression of c-FLIP isoforms.
Resistance to DNA-damaging agents is a significant cause of treatment failure and poor outcomes in oncology. To identify unrecognized regulators of cell survival we performed a whole-genome CRISPR-Cas9 screen using treatment with ionizing radiation as a selective pressure, and identified STING (stimulator of interferon genes) as an intrinsic regulator of tumor cell survival. We show that STING regulates a transcriptional program that controls the generation of reactive oxygen species (ROS), and that STING loss alters ROS homeostasis to reduce DNA damage and to cause therapeutic resistance. In agreement with these data, analysis of tumors from head and neck squamous cell carcinoma patient specimens show that low STING expression is associated with worse outcomes. We also demonstrate that pharmacologic activation of STING enhances the effects of ionizing radiation in vivo, providing a rationale for therapeutic combinations of STING agonists and DNA-damaging agents. These results highlight a role for STING that is beyond its canonical function in cyclic dinucleotide and DNA damage sensing, and identify STING as a regulator of cellular ROS homeostasis and tumor cell susceptibility to reactive oxygen dependent, DNA damaging agents.
TPS3162 Background: Activation of the Stimulator of Interferon Genes (STING) pathway in immune cells in the tumor microenvironment (TME) and tumor cells results in the induction of innate and adaptive immunity and subsequent activation of cytotoxic T cells and NK cells for durable anti-tumor responses. SB 11285 is a novel agonist of the STING pathway leading to the activation of tumor-resident APCs and priming of tumor antigen specific CD8+ T cells. In our preclinical studies using multiple tumor-derived cell lines, SB 11285 has been observed to cause the induction of cytokines, such as INF-b, INF- a, TNFa and others consistent with engagement of the STING target, as well as tumor cell death by STING-mediated apoptosis. SB 11285 reduced tumor volumes in multiple rodent tumor models when administered intravenously, intraperitoneally or intratumorally as monotherapy or in combination with checkpoint inhibitors such as anti-CTLA-4 or anti-PD-1 antibody. Systemic administration could additionally facilitate trafficking of newly activated CD8+T cells from periphery into the tumor site. Methods: This open-label, multicenter phase 1a/1b clinical trial (NCT04096638) aims to enroll approximately 110 patients in the dose escalation (Part 1) and expansion cohorts (Part 2). Part 1 of the trial is a dose escalation study with IV SB 11285 monotherapy followed by combination with the checkpoint inhibitor nivolumab. Part 1 Dose Escalation of the study will evaluate ascending doses of intravenously administered SB 11285 with respect to dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) and the pharmacokinetic (PK)/pharmacodynamic profile as monotherapy and in combination with nivolumab. SB 11285, with a starting dose of 0.3μg/kg, will be administered as monotherapy weekly on Days 1, 8, 15, and 22 of repeated 28-day cycles in escalating doses and in combination with nivolumab administered on Q4W schedule. Part 2 Expansion Cohorts of the study will explore initial signs of efficacy in pre-specified tumor types (such as Melanoma, Head and Neck squamous cell carcinoma) using the recommended phase 2 dose (RP2D) of SB 11285 in combination with nivolumab. In addition, the biological effects of SB 11285 will be evaluated by changes in immune cell types and activation state, serum cytokines, and gene expression patterns indicative of activation of the immune compartment. The trial is being conducted at multiple sites in the U.S . Clinical trial information: NCT04096638 .
Background: Activation of the Stimulator of Interferon Genes (STING) pathway within immune and tumor cells of the tumor microenvironment (TME) results in durable anti-tumor effects via induction of innate and adaptive immunity. SB 11285 is a nextgeneration immunotherapeutic cyclic dinucleotide that activates the STING pathway leading to stimulation of tumor-resident APCs, NK cells and priming of tumor antigen specific CD8+ T cells. In preclinical studies using multiple tumor-derived cell lines, SB 11285 induced cytokines, such as IFN-a and -b, TNF-a and others consistent with
BackgroundImmunotherapy has emerged as a transformative approach for the treatment of cancer. However, a significant percentage of patients are nonresponsive to these immunotherapies or experience disease relapse which highlights the need for new therapies. Recent work has highlighted a major role for Stimulator of Interferon Genes (STING) agonists in immunotherapy. Conceptually, the activation of the STING pathway in immune cells in the tumor microenvironment (TME) and tumor cells could result in the induction of innate and adaptive immunity and subsequent activation of cytotoxic T cells and NK cells for durable anti-tumor responses. SB 11285 is a novel agonist of STING pathway leading to the activation of tumor-resident APCs and priming of tumor antigen specific CD8+ T cells. In our preclinical studies using multiple tumor-derived cell lines, SB 11285 has been observed to cause the induction of cytokines, such as INF-b, INF-a, TNFa and others consistent with engagement of the STING target, as well as tumor cell death by STING-mediated apoptosis. SB 11285 reduced tumor volumes in multiple rodent tumor models when administered intravenously, intraperitoneally and intratumorally. Systemic administration could additionally facilitate trafficking of newly activated CD8+T cells from periphery into the tumor site. In addition, preclinical models indicate that survival and local tumor shrinkage were significantly enhanced when SB11285 was administered with anti-CTLA-4 or anti-PD-1 antibody, suggesting that SB 11285 can be administered with anti-PD-1 and anti-CTLA-4 antibody for synergistic activity. A multiple ascending dose, phase 1a/1b trial of SB11285 in multiple tumor types has been initiated and the objectives of this trial include determining a safe and efficacious dose of intravenous SB 11285 and a preliminary assessment of antitumor activity/efficacy as either monotherapy or in combination with nivolumab.Materials and MethodsThis open-label, multicenter phase 1a/1b clinical trial (NCT04096638) aims to enroll approximately 110 patients in the dose escalation (Part 1) and expansion cohorts (Part 2). Part 1 of the trial is a dose escalation study with IV SB11285 monotherapy followed by combination with the checkpoint inhibitor nivolumab. Part 1 Dose Escalation of the study will evaluate ascending doses of intravenously administered SB 11285 with respect to dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) and the pharmacokinetic (PK)/pharmacodynamic profile as monotherapy and in combination with nivolumab. SB 11285, with a starting dose of 0.3 μg/kg, will be administered as monotherapy weekly on Days 1, 8, 15, and 22 of repeated 28-day cycles in escalating doses and in combination with nivolumab administered on Q4W schedule. Part 2 Expansion Cohorts of the study will explore initial signs of efficacy in pre-specified tumor types (such as Melanoma, HNSCC) using the recommended phase 2 dose (RP2D) of SB 11285 in combination with nivolumab. In addition, the biological effects of SB 11285 will be evaluated by changes in immune cell types and activation state, serum cytokines, and gene expression patterns indicative of activation of the immune compartment. The trial is being conducted at multiple sites in the U.S.Disclosure InformationA. Abbas: A. Employment (full or part-time); Modest; Spring Bank Pharmaceutical Inc. J. Strauss: E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; Abbvie, Abbott Laboratories, Bristol-Myers Squibb, Intuitive Surgical, Johnson & Johnson, Merck. F. Consultant/Advisory Board; Modest; Tempus. Other; Modest; Dialectic Therapeutics. F. Janku: None. R. Karim: None. A. Olszanski: F. Consultant/Advisory Board; Modest; Bristol Myers Squibb. J.J. Luke: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; All to institution for clinical trials unless noted) Abbvie, Bristol Myers Squibb, Medimmune, Necktar, Novartis, Merck, Leap, Incyte, Immunocore, Compugen, Corvus, Evil, Five Prime, Genentech, Immatic. F. Consultant/Advisory Board; Modest; Consultant:Akrevia, Algios, Array, Astellas,AstraZeneca, Bayer, Bristol Myers Squibb/Advisory Board:7 Hills, Actym, Alphamab Oncology, Mavu (now part of Abbvie), Pyxis, Spring Bank Pharma, Tempest. Other; Modest; Travel: Akrevia, Bayer, Bristol Myers Squibb, Reflexion, EMD Serono, Incyte, Janssen, Merck, Mersana, Novartis. K. Leach: A. Employment (full or part-time); Modest; Spring Bank Pharmaceuticals Inc. R. Iyer: A. Employment (full or part-time); Modest; Spring Bank Pharmaceuticals Inc.
BackgroundActivation of the Stimulator of Interferon Genes (STING) pathway within immune and tumor cells of the tumor microenvironment (TME) results in durable anti-tumor effects via induction of innate and adaptive immunity. SB 11285 is a next-generation immunotherapeutic cyclic dinucleotide that activates the STING pathway leading to stimulation of tumor-resident APCs, NK cells and priming of tumor antigen specific CD8+ T cells. In preclinical studies using multiple tumor-derived cell lines, SB 11285 induced cytokines, such as IFN-α and -β, TNF- α and others consistent with engagement of TBK1 downstream of STING activation. Exposure of SB 11285 directly to tumor also induces cell death by STING-mediated apoptosis. SB 11285 reduced tumor volumes in multiple rodent tumor models when administered intravenously, intraperitoneally or intratumorally, as monotherapy and with amplified effect in combination with CTLA-4 or PD-1 antibodies. The novel properties of SB 11285 facilitate systemic administration which may facilitate trafficking of newly activated CD8+ T cells from the periphery into the TME.MethodsThis open-label, multicenter phase 1/1b clinical trial (NCT04096638) will enroll approximately 110 patients in the dose escalation (Part 1) and expansion cohorts (Part 2). Part 1 will includ parallel dose escalations evaluating ascending doses of intravenously administered SB 11285 via 3+3 design with respect to dose-limiting toxicities, maximum tolerated dose, recommended phase 2 dose (RP2D) and the pharmacokinetic/pharmacodynamic profile. Part 2 Expansion Cohorts of the study will explore initial efficacy via overall response rate in pre-specified tumor types (such as Melanoma, Head and Neck Squamous Cell Carcinoma) at the RP2D in combination with atezolizumab. SB 11285 will be administered as monotherapy weekly on Days 1, 8, 15, and 22 of repeated 28-day cycles in escalating doses and in combination with atezolizumab administered Q4W. Biological effects of SB 11285 will be evaluated via changes in immune cell types, serum cytokines, and gene expression patterns indicative of activation of the peripheral and TME immune compartments.Results‘N/A’Conclusions‘N/A’
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