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Integrative Development of a TLR8 Agonist for Ovarian Cancer Chemoimmunotherapy.

ABSTRACT: Purpose: Immunotherapy is an emerging paradigm for the treatment of cancer, but the potential efficacy of many drugs cannot be sufficiently tested in the mouse. We sought to develop a rational combination of motolimod-a novel Toll-like receptor 8 (TLR8) agonist that stimulates robust innate immune responses in humans but diminished responses in mice-with pegylated liposomal doxorubicin (PLD), a chemotherapeutic that induces immunogenic cell death.Experimental Design: We followed an integrative pharmacologic approach including healthy human volunteers, non-human primates, NSG-HIS ("humanized immune system") mice reconstituted with human CD34+ cells, and patients with cancer to test the effects of motolimod and to assess the combination of motolimod with PLD for the treatment of ovarian cancer.Results: The pharmacodynamic effects of motolimod monotherapy in NSG-HIS mice closely mimicked those in non-human primates and healthy human subjects, whereas the effects of the motolimod/PLD combination in tumor-bearing NSG-HIS mice closely mimicked those in patients with ovarian cancer treated in a phase Ib trial (NCT01294293). The NSG-HIS mouse helped elucidate the mechanism of action of the combination and revealed a positive interaction between the two drugs in vivo The combination produced no dose-limiting toxicities in patients with ovarian cancer. Two subjects (15%) had complete responses and 7 subjects (53%) had disease stabilization. A phase II study was consequently initiated.Conclusions: These results are the first to demonstrate the value of pharmacologic approaches integrating the NSG-HIS mouse, non-human primates, and patients with cancer for the development of novel immunomodulatory anticancer agents with human specificity. Clin Cancer Res; 23(8); 1955-66. ©2016 AACR.

SUBMITTER: Monk BJ

PROVIDER: S-EPMC5437973 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Integrative Development of a TLR8 Agonist for Ovarian Cancer Chemoimmunotherapy.

Monk Bradley J BJ Facciabene Andrea A Brady William E WE Aghajanian Carol A CA Fracasso Paula M PM Walker Joan L JL Lankes Heather A HA Manjarrez Kristi L KL Danet-Desnoyers Gwenn-Äel H GH Bell-McGuinn Katherine M KM McCourt Carolyn K CK Malykhin Alexander A Hershberg Robert M RM Coukos George G

Clinical cancer research : an official journal of the American Association for Cancer Research 20161004 8

<b>Purpose:</b> Immunotherapy is an emerging paradigm for the treatment of cancer, but the potential efficacy of many drugs cannot be sufficiently tested in the mouse. We sought to develop a rational combination of motolimod-a novel Toll-like receptor 8 (TLR8) agonist that stimulates robust innate immune responses in humans but diminished responses in mice-with pegylated liposomal doxorubicin (PLD), a chemotherapeutic that induces immunogenic cell death.<b>Experimental Design:</b> We followed an ...[more]

PMID: 27702821

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Project description:BackgroundOvarian cancer is the most lethal gynecologic disease and is one of the most commonly diagnosed cancers among women worldwide. The phosphatidylinositol 3-kinase (PI3K) family plays an important regulatory role in various cancer signaling pathways, including those involved in ovarian cancer development; however, its exact function remains to be fully understood. We conducted this study to understand the role of P13K in the molecular mechanisms underlying ovarian cancer development.MethodsTo determine the differential gene expression of phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3), a regulatory subunit of PI3K, in normal, tumor, and metastatic ovary tissues, TNM plotter analysis was performed. The microarray dataset GSE53759 was downloaded from Gene Expression Omnibus. ROC plotter analysis was conducted to understand the potential of PIK3R3 as a predictive marker for effectiveness of therapy in ovarian cancer. muTarget was used to identify mutations that alter PIK3R3 expression in ovarian cancer. To determine the interacting partners for PIK3R3 in ovarian tissues, the interactome-atlas tool was used. The Kyoto encyclopedia of genes and genomes (KEGG) analysis was conducted to identify the pathways in which these interacting partners were primarily enriched.ResultsPIK3R3 was overexpressed in ovarian and metastatic tumors. Elevated PIK3R3 levels were observed in ovarian cancer stem cells, wherein inhibiting PIK3R3 expression significantly reduced the size of ovarian cancer spheroids. Treatment of ovarian cancer stem cells with PF-04691502 (10 μM), an inhibitor of both PI3K and mTOR kinases, also reduced the size of spheroids and the level of OCT4. PIK3R3 was highly expressed in ovarian cancer with several somatic mutations and was predicted better outcomes in patients undergoing Avastin® chemotherapy using bioinformatic tool. Protein interaction analysis showed that PIK3R3 interacts with 157 genes, including GRB2, EGFR, ERBB3, PTK2, HCK, IGF1R, YES1, and PIK3CA, in the ovary. KEGG enrichment analysis revealed that the interacting partners of PIK3R3 are involved in the ErbB signaling pathway, proteoglycans in cancer, FoxO, prolactin, chemokine, and insulin signaling pathways.ConclusionsPIK3R3 plays a pivotal role in ovarian cancer development and is therefore a potential candidate for developing novel therapeutic approaches.

Project description:UNLABELLED:VTX-2337 (USAN: motolimod) is a selective toll-like receptor 8 (TLR8) agonist, which is in clinical development as an immunotherapy for multiple oncology indications, including squamous cell carcinoma of the head and neck (SCCHN). Activation of TLR8 enhances natural killer cell activation, increases antibody-dependent cell-mediated cytotoxicity, and induces Th1 polarizing cytokines. Here, we show that VTX-2337 stimulates the release of mature IL-1? and IL-18 from monocytic cells through coordinated actions on both TLR8 and the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome complex. In vitro, VTX-2337 primed monocytic cells to produce pro-IL-1?, pro-IL-18, and caspase-1, and also activated the NLRP3 inflammasome, thereby mediating the release of mature IL-1? family cytokines. Inhibition of caspase-1 blocked VTX-2337-mediated NLRP3 inflammasome activation, but had little impact on production of other TLR8-induced mediators such as TNF?. IL-18 activated natural killer cells and complemented other stimulatory pathways, including Fc?RIII and NKG2D, resulting in IFN? production and expression of CD107a. NLRP3 activation in vivo was confirmed by a dose-related increase in plasma IL-1? and IL-18 levels in cynomolgus monkeys administered VTX-2337. These results are highly relevant to clinical studies of combination VTX-2337/cetuximab treatment. Cetuximab, a clinically approved, epidermal growth factor receptor-specific monoclonal antibody, activates NK cells through interactions with Fc?RIII and facilitates ADCC of tumor cells. Our preliminary findings from a Phase I open-label, dose-escalation, trial that enrolled 13 patients with recurrent or metastatic SCCHN show that patient NK cells become more responsive to stimulation by NKG2D or Fc?RIII following VTX-2337 treatment. Together, these results indicate that TLR8 stimulation and inflammasome activation by VTX-2337 can complement Fc?RIII engagement and may augment clinical responses in SCCHN patients treated with cetuximab. TRIAL REGISTRATION:ClinicalTrials.gov NCT01334177.

Project description:BackgroundNewborns display distinct immune responses that contribute to susceptibility to infection and reduced vaccine responses. Toll-like receptor (TLR) agonists may serve as vaccine adjuvants, when given individually or in combination, but responses of neonatal leukocytes to many TLR agonists are diminished. TLR8 agonists are more effective than other TLR agonists in activating human neonatal leukocytes in vitro, but little is known about whether different TLR8 agonists may distinctly activate neonatal leukocytes. We characterized the in vitro immuno-stimulatory activities of a novel benzazepine TLR8 agonist, VTX-294, in comparison to imidazoquinolines that activate TLR8 (R-848; (TLR7/8) CL075; (TLR8/7)), with respect to activation of human newborn and adult leukocytes. Effects of VTX-294 and R-848 in combination with monophosphoryl lipid A (MPLA; TLR4) were also assessed.MethodsTLR agonist specificity was assessed using TLR-transfected HEK293 cells expressing a NF-?B reporter gene. TLR agonist-induced cytokine production was measured in human newborn cord and adult peripheral blood using ELISA and multiplex assays. Newborn and adult monocytes were differentiated into monocyte-derived dendritic cells (MoDCs) and TLR agonist-induced activation assessed by cytokine production (ELISA) and co-stimulatory molecule expression (flow cytometry).ResultsVTX-294 was ? 100x more active on TLR8- than TLR7-transfected HEK cells (EC50, ? 50 nM vs. ? 5700 nM). VTX-294-induced TNF and IL-1? production were comparable in newborn cord and adult peripheral blood, while VTX-294 was 1 log more potent in inducing TNF and IL-1? production than MPLA, R848 or CL075. Combination of VTX-294 and MPLA induced greater blood TNF and IL-1? responses than combination of R-848 and MPLA. VTX-294 also potently induced expression of cytokines and co-stimulatory molecules HLA-DR and CD86 in human newborn MoDCs.ConclusionsVTX-294 is a novel ultra-potent TLR8 agonist that activates newborn and adult leukocytes and is a candidate vaccine adjuvant in both early life and adulthood.

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Integrative Development of a TLR8 Agonist for Ovarian Cancer Chemoimmunotherapy.

Publications

Integrative Development of a TLR8 Agonist for Ovarian Cancer Chemoimmunotherapy.

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