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  • 1
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    Phase Ib Trial of the Toll-like Receptor 8 Agonist, Motolimod (VTX-2337), Combined with Cetuximab in Patients with Recurrent or Metastatic SCCHN
    American Association for Cancer Research (AACR) ; 2017
    In:  Clinical Cancer Research Vol. 23, No. 10 ( 2017-05-15), p. 2442-2450
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 23, No. 10 ( 2017-05-15), p. 2442-2450
    Abstract: Purpose: As Toll-like receptors (TLR) are key mediators of immune responses, TLR agonists may be important for augmenting the efficacy of therapies for squamous cell carcinoma of the head and neck (SCCHN). Motolimod (VTX-2337), a selective small-molecule agonist of TLR8, stimulates natural killer (NK) cells, dendritic cells, and monocytes. A phase Ib clinical trial assessed the safety and antitumor activity of motolimod in combination with cetuximab in patients with SCCHN. Correlative biomarkers of immune activity were explored. Experimental Design: Thirteen patients with recurrent or metastatic SCCHN were enrolled in this open-label, dose–escalation study using a standard 3 + 3 design. Doses of motolimod (2.5, 3.0, or 3.5 mg/m2) were given on days 1, 8, and 15, in combination with fixed weekly doses of cetuximab in 28-day cycles. Results: There were no protocol-defined dose-limiting toxicities, drug-related deaths, or evidence of synergistic toxicities between motolimod and cetuximab. Clinical tolerability at the 3.5 mg/m2 dose level was not optimal for repeated dosing and 3.0 mg/m2 was identified as the MTD. Two patients achieved partial responses for an overall response rate of 15%. Five patients had disease stabilization equating to a disease control rate of 54%. Statistically significant increases in plasma cytokines and in the frequency and activation of circulating NK cells were observed. Conclusions: Motolimod can be safely administered in combination with cetuximab with an acceptable toxicity profile. Encouraging antitumor activity and robust pharmacodynamic responses were observed. Motolimod is being further investigated in a phase II trial in patients with SCCHN (ClinicalTrials.gov ID: NCT01836029). Clin Cancer Res; 23(10); 2442–50. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-16-1934
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 2
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    Late-Stage Cancer Patients Remain Highly Responsive to Immune Activation by the Selective TLR8 Agonist Motolimod (VTX-2337)
    American Association for Cancer Research (AACR) ; 2015
    In:  Clinical Cancer Research Vol. 21, No. 24 ( 2015-12-15), p. 5445-5452
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 21, No. 24 ( 2015-12-15), p. 5445-5452
    Abstract: Purpose: Immunotherapy as a treatment for cancer holds the promise of complete and durable tumor remission, yet the immunosuppressive environment created by many tumors, advanced patient age, and previous treatments with cytotoxic agents may limit the approach. The activity of motolimod (VTX-2337), a potent and selective Toll-like receptor 8 (TLR8) agonist, was therefore assessed in the context of advanced, late-stage cancer patients. Experimental Design: The repertoire of mediators induced from human peripheral blood mononuclear cells in response to motolimod was characterized. Translational studies in cynomolgus monkeys elucidated the activity of motolimod on an intact immune system, identified biomarkers of TLR8 activation, and defined the relationship between the pharmacokinetic and pharmacodynamic (PK/PD) response. The PK/PD relationship for motolimod in cancer patients was assessed, compared with preclinical findings, and contrasted with activity in healthy volunteers. Results: In late-stage cancer patients, plasma levels of multiple biomarkers, including IL6, G-CSF, MCP-1, and MIP1-β, increased with increasing motolimod dose. The magnitude and breadth of the biomarker response closely aligned with the response seen in preclinical studies, demonstrating that advanced cancer patients remained responsive to TLR8 activation. In addition, the PK/PD response in cancer patients closely aligned with the activity of motolimod seen in healthy volunteers. Conclusions: Late-stage cancer patients are highly sensitive to TLR8 activation by motolimod. Tumor burden, advanced age, and prior treatment history with cytotoxic agents did not moderate or modify the response predicted by nonclinical studies and confirmed in healthy volunteers. Clin Cancer Res; 21(24); 5445–52. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-15-0578
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 3
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    Coordinated Activation of Toll-Like Receptor8 (TLR8) and NLRP3 by the TLR8 Agonist, VTX-2337, Ignites Tumoricidal Natural Killer Cell Activity
    Public Library of Science (PLoS) ; 2016
    In:  PLOS ONE Vol. 11, No. 2 ( 2016-2-29), p. e0148764-
    Details
    In: PLOS ONE, Public Library of Science (PLoS), Vol. 11, No. 2 ( 2016-2-29), p. e0148764-
    Type of Medium: Online Resource
    ISSN: 1932-6203
    URL: Article
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    DOI: 10.1371/journal.pone.0148764
    DOI: 10.1371/journal.pone.0148764.g001
    DOI: 10.1371/journal.pone.0148764.g002
    DOI: 10.1371/journal.pone.0148764.g003
    DOI: 10.1371/journal.pone.0148764.g004
    DOI: 10.1371/journal.pone.0148764.g005
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    DOI: 10.1371/journal.pone.0148764.g007
    DOI: 10.1371/journal.pone.0148764.s001
    DOI: 10.1371/journal.pone.0148764.s002
    DOI: 10.1371/journal.pone.0148764.s003
    DOI: 10.1371/journal.pone.0148764.s004
    Language: English
    Publisher: Public Library of Science (PLoS)
    Publication Date: 2016
    detail.hit.zdb_id: 2267670-3
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  • 4
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    A Phase I Dose-Finding Study of the Novel Toll-like Receptor 8 Agonist VTX-2337 in Adult Subjects with Advanced Solid Tumors or Lymphoma
    American Association for Cancer Research (AACR) ; 2014
    In:  Clinical Cancer Research Vol. 20, No. 14 ( 2014-07-15), p. 3683-3691
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 20, No. 14 ( 2014-07-15), p. 3683-3691
    Abstract: Purpose: This phase I, open-label, uncontrolled, ascending-dose study explored the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacology of the TLR8 agonist VTX-2337 in subjects with advanced solid tumors or lymphoma. Experimental Design: VTX-2337 doses (0.1–3.9 mg/m2) were administered subcutaneously on days 1, 8, and 15 of each 28-day cycle. Safety/tolerability assessments included adverse events (AE); physical, ophthalmologic, and laboratory evaluations; and electrocardiograms. Dose-limiting toxicities (DLT) were evaluated during the first cycle. Pharmacokinetics were evaluated after the first dose. Plasma samples were quantitatively assessed for chemokines, cytokines, and other inflammatory mediators. Antitumor activity was assessed. Results: Thirty-three subjects were enrolled in 8 cohorts and received an average of 2 treatment cycles (range, 1–8 cycles). Most AEs were grades 1 to 2; the most common drug-related AEs were injection site reactions, chills, pyrexia, and influenza-like illness. One DLT was reported: grade 3 hypotension (3.9 mg/m2). The MTD was considered the highest dose administered. Peak drug plasma levels and total systemic exposure were generally dose proportional. At doses ≥0.4 mg/m2, increases above baseline levels were observed for plasma levels of G-CSF, monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and TNFα. Eight subjects (24.2%) had a best response of stable disease (median duration, 54.5 days). Conclusions: VTX-2337 is clinically well tolerated and biologically active with a predictable pharmacokinetic profile. Suitable doses for testing in combination studies were identified. Phase II placebo-controlled studies of VTX-2337 in combination with doxorubicin in ovarian cancer, and in combination with platinum chemotherapy, 5 FU, and cetuximab in head and neck cancer have been initiated (NCT #01666444 and NCT#01836029). Clin Cancer Res; 20(14); 3683–91. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-14-0392
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 5
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    Requirements for αd in IgG Immune Complex-Induced Rat Lung Injury 
    The American Association of Immunologists ; 1998
    In:  The Journal of Immunology Vol. 160, No. 2 ( 1998-01-15), p. 1014-1020
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 160, No. 2 ( 1998-01-15), p. 1014-1020
    Abstract: αd is a newly cloned adhesion molecule that forms a heterodimer with CD18. The requirement for αd in IgG immune complex-induced lung injury in rats has been evaluated by the use of blocking polyclonal and monoclonal antibodies to rat αd. Using whole lung extracts, Northern and Western blot analyses have revealed up-regulation of mRNA and αd protein in inflamed lungs. Immunostaining has revealed the presence of αd in lung tissue and in alveolar macrophages as early as 1 h after initiation of the inflammatory reaction. When polyclonal rabbit Ab to rat αd was coinstilled into lung together with Ab to BSA, lung injury (as determined by leakage of [125I]albumin into lung parenchyma) was significantly diminished. In parallel, there was reduced accumulation of neutrophils recoverable in bronchoalveolar lavage (BAL) fluids. These findings were associated with reduced levels of TNF-α as well as NO2−/NO3− in BAL fluids. A hamster mAb to rat αd was also protective in this lung injury model. Anti-αd inhibited in vitro production of NO2−/NO3− by rat alveolar macrophages (stimulated with LPS and IFN-γ) by approximately 60%. These data suggest that, in the lung inflammatory model employed, αd up-regulation occurs in lung macrophages and is necessary for expression of TNF-α, recruitment of neutrophils, and full development of lung injury.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.160.2.1014
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 1998
    detail.hit.zdb_id: 1475085-5
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  • 6
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    Granzyme B Expression Is Enhanced in Human Monocytes by TLR8 Agonists and Contributes to Antibody-Dependent Cellular Cytotoxicity
    The American Association of Immunologists ; 2015
    In:  The Journal of Immunology Vol. 194, No. 6 ( 2015-03-15), p. 2786-2795
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 194, No. 6 ( 2015-03-15), p. 2786-2795
    Abstract: FcγRs are critical mediators of mAb cancer therapies, because they drive cytotoxic processes upon binding of effector cells to opsonized targets. Along with NK cells, monocytes are also known to destroy Ab-coated targets via Ab-dependent cellular cytotoxicity (ADCC). However, the precise mechanisms by which monocytes carry out this function have remained elusive. In this article, we show that human monocytes produce the protease granzyme B upon both FcγR and TLR8 activation. Treatment with TLR8 agonists elicited granzyme B and also enhanced FcγR-mediated granzyme B production in an additive fashion. Furthermore, monocyte-mediated ADCC against cetuximab-coated tumor targets was enhanced by TLR8 agonist treatment, and this enhancement of ADCC required granzyme B. Hence we have identified granzyme B as an important mediator of FcγR function in human monocytes and have uncovered another mechanism by which TLR8 agonists may enhance FcγR-based therapies.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1402316
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2015
    detail.hit.zdb_id: 1475085-5
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  • 7
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    Prevention of cerebral vasospasm by a humanized anti-CD11/CD18 monoclonal antibody administered after experimental subarachnoid hemorrhage in nonhuman primates
    Journal of Neurosurgery Publishing Group (JNSPG) ; 2003
    In:  Journal of Neurosurgery Vol. 99, No. 2 ( 2003-08), p. 376-382
    Details
    In: Journal of Neurosurgery, Journal of Neurosurgery Publishing Group (JNSPG), Vol. 99, No. 2 ( 2003-08), p. 376-382
    Abstract: Object. Leukocyte—endothelial cell interactions occurring in the first hours after subarachnoid hemorrhage (SAH) initiate changes in the endothelium and vessel wall that lead to an influx of leukocytes and the development of chronic vasospasm days later. Upregulation of intercellular adhesion molecule—1 (ICAM-1), also called CD54, appears to be a crucial step in this process. There is increasing experimental evidence that blocking the interaction between ICAM-1, which is expressed on endothelium, and integrins such as lymphocyte function—associated antigen—1 (CD11a/CD18) and macrophage antigen—1 (complement receptor 3, CD11b/CD18), which are expressed on the surface of leukocytes, prevents not only inflammation of vessel walls but also chronic vasospasm. The authors extend their previous work with monoclonal antibody (mAb) blockade of leukocyte migration to a nonhuman primate model of chronic, posthemorrhagic cerebral vasospasm. Methods. Before surgery was performed, six young adult male cynomolgus monkeys underwent baseline selective biplane common carotid and vertebrobasilar artery cerebral angiography via a transfemoral route. On Day 0, a right frontosphenotemporal craniectomy was performed with arachnoid microdissection and placement of 2 to 3 ml of clotted autologous blood in the ipsilateral basal cisterns. The animals were given daily intravenous infusions of 2 mg/kg of either a humanized anti-CD11/CD18 or a placebo mAb beginning 30 to 60 minutes postoperatively. The monkeys were killed on Day 7 after a repeated selective cerebral angiogram was obtained. The area of contrast-containing vessels observed in each hemisphere on anteroposterior angiographic views was calculated for the angiograms obtained on Day 7 and expressed as a percentage of the area on baseline angiograms (percent control areal fraction). Review of flow cytometry and enzyme immunoassay data confirmed the presence of the anti-CD11/CD18 antibody in the serum and bound to leukocytes in the peripheral blood of treated animals. Comparisons of the groups revealed 53 ± 4.8% control vascular areal fraction in the placebo group (two animals) and 95.8 ± 9.4% in the anti-CD11/CD18—treated group (three animals), a statistically significant difference (p = 0.043, t-test). Conclusions. These results show that blockade of leukocyte migration into the subarachnoid space by an anti-CD11/CD18 mAb is effective in preventing experimental cerebral vasospasm in nonhuman primates, despite the unaltered presence of hemoglobin in the subarachnoid space. These experimental data support the hypothesis that inflammation plays a role in cerebral vasospasm after SAH.
    Type of Medium: Online Resource
    ISSN: 0022-3085
    URL: Article
    DOI: 10.3171/jns.2003.99.2.0376
    RVK:
    XA 10000
    RVK:
    XA 55270
    Language: Unknown
    Publisher: Journal of Neurosurgery Publishing Group (JNSPG)
    Publication Date: 2003
    detail.hit.zdb_id: 2026156-1
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  • 8
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    Characterization of the Inflammatory Response to a Highly Selective PDE4 Inhibitor in the Rat and the Identification of Biomarkers that Correlate with Toxicity
    SAGE Publications ; 2006
    In:  Toxicologic Pathology Vol. 34, No. 1 ( 2006-01), p. 39-51
    Details
    In: Toxicologic Pathology, SAGE Publications, Vol. 34, No. 1 ( 2006-01), p. 39-51
    Abstract: The primary toxicity associated with repeated oral administration of the PDE4 inhibitor IC542 to the rat is an inflammatory response leading to tissue damage primarily in the gastrointestinal tract and mesentery. Although necrotizing vasculitis is frequently seen with other PDE4 inhibitors, blood vessel injury was rare following IC542 administration and was always associated with inflammation in the surrounding tissue. The incidence and severity of the histologic changes in these studies correlated with elevated peripheral blood leukocytes, serum IL-6, haptoglobin, and fibrinogen, and with decreased serum albumin. By monitoring haptoglobin, fibrinogen and serum albumin changes in IC542-treated rats, it was possible to identify rats with early histologic changes that were reversible. Since PDE4 inhibition is generally associated with anti-inflammatory activity, extensive inflammation in multiple tissues was unexpected with IC542. Co-administration of dexamethasone completely blocked IC542-induced clinical and histologic changes in the rat, confirming the toxicity resulted from inflammatory response. In addition, IC542 augmented release of the proinflammatory cytokine IL-6 in LPS-activated whole blood from rats but not monkeys or humans. The effect of IC542 on IL-6 release from rat leukocytes in vitro is consistent with the proinflammatory response observed in vivo and demonstrates species differences to PDE4 inhibition.
    Type of Medium: Online Resource
    ISSN: 0192-6233 , 1533-1601
    URL: Article
    DOI: 10.1080/01926230500385549
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2006
    detail.hit.zdb_id: 2056753-4
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  • 9
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    Inhibition of Experimental Vasospasm With Anti–Intercellular Adhesion Molecule-1 Monoclonal Antibody in Rats
    Ovid Technologies (Wolters Kluwer Health) ; 1997
    In:  Stroke Vol. 28, No. 10 ( 1997-10), p. 2031-2038
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 28, No. 10 ( 1997-10), p. 2031-2038
    Abstract: Background and Purpose Inflammation may play a role in delayed chronic vasospasm after aneurysmal subarachnoid hemorrhage. We investigated the role of intercellular adhesion molecule-1 (ICAM-1) and macrophage/granulocyte infiltration in the rat femoral artery model of vasospasm using systemic administration of a murine anti–ICAM-1 monoclonal antibody (MAb). Methods The femoral arteries (n=72) in Sprague-Dawley rats (n=36) were enclosed in latex pouches bilaterally. Autologous blood was injected into the pouch on one side, and saline was injected on the contralateral side. Chronic vessel narrowing was evaluated with the use of 29 rats, which were randomized into one of three groups for intraperitoneal injections: (1) anti–ICAM-1 MAb (2 mg/kg per dose, n=10), (2) isotype-matched MAb (2 mg/kg per dose, n=9), or (3) saline (n=10), given at 3 hours and 3, 6, and 9 days after blood exposure. These rats were killed 12 days after blood exposure, and femoral artery lumen cross-sectional areas were determined by computerized image analysis. Saturation of ICAM-1 binding sites with this dosing schedule was evaluated by fluorescence-activated cell sorter (FACS) analysis of splenocytes. Immunohistochemical studies with objective cell counts were performed to evaluate macrophage/granulocyte infiltration at 24 hours in 7 rats, comparing anti–ICAM-1 MAb treatment (n=4) with isotype-matched control MAb (n=3). Results Animals treated with anti–ICAM-1 MAb showed a significant inhibition of arterial narrowing at 12 days ( P =.0081), with lumen patency of 96.5±5.3% (mean±SEM), compared with 77.3±5.6% for isotype-matched MAb and 72.2±5.3% for saline-treated controls. FACS analysis of splenocytes from animals treated with anti–ICAM-1 MAb confirmed saturation of ICAM-1 binding sites. Vessels treated with anti–ICAM-1 MAb showed a significant decrease in inflammatory cell infiltrates, with objective macrophage/granulocyte counts of 31.3±26.6 (mean±SEM) per high-powered field, compared with 171.4±30.7 for isotype-matched control MAb ( P =.0027). Conclusions Anti–ICAM-1 MAb administered systemically starting 3 hours after blood exposure results in significant inhibition of chronic vasospasm in the rat femoral artery model and is correlated with a reduction in the number of infiltrating macrophages and granulocytes in the periadventitial region of blood-exposed arteries. We conclude that inflammatory changes associated with ICAM-1–mediated macrophage and granulocyte migration play an important role in the development of posthemorrhagic chronic vasospasm in this model.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/01.STR.28.10.2031
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 1997
    detail.hit.zdb_id: 1467823-8
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  • 10
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    The Role of Recombinant Platelet-Activating Factor Acetylhydrolase in a Neonatal Rat Model of Necrotizing Enterocolitis
    Springer Science and Business Media LLC ; 1997
    In:  Pediatric Research Vol. 42, No. 6 ( 1997-12), p. 779-783
    Details
    In: Pediatric Research, Springer Science and Business Media LLC, Vol. 42, No. 6 ( 1997-12), p. 779-783
    Type of Medium: Online Resource
    ISSN: 0031-3998 , 1530-0447
    URL: Article
    DOI: 10.1203/00006450-199712000-00010
    Language: Unknown
    Publisher: Springer Science and Business Media LLC
    Publication Date: 1997
    detail.hit.zdb_id: 2031217-9
    SSG: 12
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