A Phase I Trial of the Dual MET Kinase/OCT-2 Inhibitor OMO-1 in Metastatic Solid Malignancies Including MET Exon 14 Mutated Lung Cancer

Introduction: Targeted therapy in non-small cell lung cancer (NSCLC) patients with mesenchymal epithelial transition (MET) exon 14 skipping mutations (METex14) and MET amplifications has improved patients’ outcomes. The development of more potent MET kinase inhibitors could further benefit these patients. The aim of this trial is to determine the safety and recommended phase 2 dose (RP2D) of OMO-1 (an oral dual MET kinase/OCT-2 inhibitor) and to assess preliminary clinical efficacy in METex14-positive NSCLC and other MET-positive solid tumors.// Materials and Methods: This was a first-in-patient, open-label, multicenter study of OMO-1 in patients with locally advanced or metastatic solid malignancies. A standard 3 + 3 dose escalation design was utilized starting at a dose level of 100 mg BID continuously. Preliminary efficacy was investigated in patients with METex14-positive NSCLC, and MET amplified NSCLC and other solid tumors (MET basket).// Results: In the dose-escalation part, 24 patients were included in 5 dose levels ranging from 100 mg twice daily (BID) to 400 mg BID. Most common adverse events (≥ 20%) were nausea, fatigue, vomiting, increased blood creatinine, and headache. The RP2D was determined at 250 mg BID. In the expansion cohorts, 15 patients were included (10 in METex14-positive NSCLC cohort and 5 in MET basket cohort) and received either 200 or 250 mg BID. Eight out of the 10 patients with METex14 positive NSCLC had stable disease as the best response.// Conclusion: OMO-1 was tolerated at the dose of 250 mg BID and shows initial signs of MET inhibition and anti-tumor activity in METex14 mutated NSCLC patients

A Phase I Trial of the Dual MET Kinase/OCT-2 Inhibitor OMO-1 in Metastatic Solid Malignancies Including MET Exon 14 Mutated Lung Cancer

Introduction: Targeted therapy in non-small cell lung cancer (NSCLC) patients with mesenchymal epithelial transition (MET) exon 14 skipping mutations (METex14) and MET amplifications has improved patients' outcomes. The development of more potent MET kinase inhibitors could further benefit these patients. The aim of this trial is to determine the safety and recommended phase 2 dose (RP2D) of OMO-1 (an oral dual MET kinase/OCT-2 inhibitor) and to assess preliminary clinical efficacy in METex14-positive NSCLC and other MET-positive solid tumors. Materials and Methods: This was a first-in-patient, open-label, multicenter study of OMO-1 in patients with locally advanced or metastatic solid malignancies. A standard 3 + 3 dose escalation design was utilized starting at a dose level of 100 mg BID continuously. Preliminary efficacy was investigated in patients with METex14-positive NSCLC, and MET amplified NSCLC and other solid tumors (MET basket). Results: In the dose-escalation part, 24 patients were included in 5 dose levels ranging from 100 mg twice daily (BID) to 400 mg BID. Most common adverse events (≥ 20%) were nausea, fatigue, vomiting, increased blood creatinine, and headache. The RP2D was determined at 250 mg BID. In the expansion cohorts, 15 patients were included (10 in METex14-positive NSCLC cohort and 5 in MET basket cohort) and received either 200 or 250 mg BID. Eight out of the 10 patients with METex14 positive NSCLC had stable disease as the best response. Conclusion: OMO-1 was tolerated at the dose of 250 mg BID and shows initial signs of MET inhibition and anti-tumor activity in METex14 mutated NSCLC patients.</p

Rab7A Is Required for Efficient Production of Infectious HIV-1

Retroviruses take advantage of cellular trafficking machineries to assemble and release new infectious particles. Rab proteins regulate specific steps in intracellular membrane trafficking by recruiting tethering, docking and fusion factors, as well as the actin- and microtubule-based motor proteins that facilitate vesicle traffic. Using virological tests and RNA interference targeting Rab proteins, we demonstrate that the late endosome-associated Rab7A is required for HIV-1 propagation. Analysis of the late steps of the HIV infection cycle shows that Rab7A regulates Env processing, the incorporation of mature Env glycoproteins into viral particles and HIV-1 infectivity. We also show that siRNA-mediated Rab7A depletion induces a BST2/Tetherin phenotype on HIV-1 release. BST2/Tetherin is a restriction factor that impedes HIV-1 release by tethering mature virus particles to the plasma membrane. Our results suggest that Rab7A contributes to the mechanism by which Vpu counteracts the restriction factor BST2/Tetherin and rescues HIV-1 release. Altogether, our results highlight new roles for a major regulator of the late endocytic pathway, Rab7A, in the late stages of the HIV-1 replication cycle

CXCR4 as a novel target in immunology: moving away from typical antagonists

CXCR4 has been a target of interest in drug discovery for numerous years. However, so far, most if not all studies focused on finding antagonists of CXCR4 function. Recent studies demonstrate that targeting a minor allosteric pocket of CXCR4 induces an immunomodulating effect in immune cells expressing CXCR4, connected to the TLR pathway. Compounds binding in this minor pocket seem to be functionally selective with inverse agonistic properties in selected GPCR signaling pathways (Gi activation), but additional signaling pathways are likely to be involved in the immunomodulating effects. In depth research into these CXCR4-targeted immunomodulators could lead to novel treatment options for (auto)-immune diseases

Effect of filgotinib, a selective JAK 1 inhibitor, with and without methotrexate in patients with rheumatoid arthritis: patient-reported outcomes

Abstract Background The aim was to assess patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA) treated with filgotinib during two phase 2b, 24-week, randomized, placebo-controlled studies. Methods Patients with moderate-to-severe active RA and an inadequate response to methotrexate (MTX) were randomized to daily placebo or filgotinib 50 mg, 100 mg, or 200 mg as add-on therapy to MTX (NCT01888874) or as monotherapy (NCT01894516). At week 12, nonresponders receiving filgotinib 50 mg in both studies or placebo in the add-on study, and all patients receiving placebo as monotherapy, were re-assigned to filgotinib 100 mg. PROs were measured using the Health Assessment Questionnaire - Disability Index (HAQ-DI) including Patient Pain assessed by visual analog scale, and the Patient Global Assessment of Disease Activity (Patient Global), the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale (Version 4), and the 36-Item Short Form Health Survey (SF-36). Results At week 12, improvements in all PROs, apart from the SF-36 mental component in the add-on study, were statistically better with filgotinib than placebo; some improvements were noted as early as the first assessment time point (week 1 or week 4). Filgotinib improved HAQ-DI by 0.58–0.84 points, FACIT-Fatigue by 6.9–11.4 points, Patient Global by 25.2–35.6 mm, and Pain by 24.2–37.9 mm; scores were maintained or improved to week 24. Across all PROs, more patients achieved minimal clinically important differences and normative values with filgotinib 200 mg than placebo. Patients re-assigned to filgotinib 100 mg at week 12 experienced improvements in PROs between weeks 12 to 24. Conclusions Filgotinib as MTX add-on therapy or as monotherapy demonstrated rapid and sustained (to 24 weeks) improvements in health-related quality of life and functional status in patients with active RA. Trial registration MTX add-on study: ClinicalTrials.gov, NCT01888874. Registered on 28 June 2013. Monotherapy study: ClinicalTrials.gov, NCT01894516. Registered on 10 July 2013

Splenic immunomodulatory effects of cisplatin in an immunocompetent intraductal model for triple-negative breast cancer

Chemotherapy remains the mainstay treatment for aggressive breast cancer subtypes such as triple-negative breast cancer (TNBC). It has been recognized that some chemotherapeutics besides being cytotoxic to tumor cells, also induce immunomodulatory effects that can stimulate tumor cell killing. We aimed to in-depth investigate this presumed chemotherapy-induced immunomodulation in TNBC, focusing on the platinum-based agent cisplatin and using an in-house characterized immunocompetent intraductal mouse model. Our model relies on the injection of 4T1 triple-negative mammary tumor cells in syngeneic lactating mice, representing TNBC progression from early ductal carcinoma in situ/DCIS to late invasive carcinoma/IC stages. As soon as primary tumors transitioned from DCIS to IC, cisplatin treatment was provided and induced significant reduction in disease progression as corroborated by decreased serum levels of immune-related metastatic biomarkers chitinase 3-like 1 and lipocalin 2. After 3 weeks of treatment, primary tumors, metastases-bearing organs (i.e., axillary lymph nodes and lungs), spleen and blood were isolated for flow cytometric immunophenotyping and expression of immune checkpoint proteins programmed death (PD)-1 and PD-ligand (L)1. Immunosuppressive myeloid cells, most abundantly CD11b+Ly6C-Ly6G+ granulocytic myeloid-derived suppressor cells, accumulated in all investigated compartments and were significantly reduced by cisplatin treatment in axillary lymph nodes and spleen. In contrast to the axillary lymph nodes, cisplatin-treated spleens showed enhanced content of CD3ε+CD4+CD8α- helper T cells, CD3ε+CD4-CD8α+ cytotoxic T cells and CD19+ B cells. Cisplatin-treated spleens also showed significant increased PD-(L)1 expression. These results highlight spatial immunomodulatory differences and suggest significant splenic support of anti-tumor immunity upon cisplatin treatment in our TNBC model

Immunomodulation by cisplatin chemotherapy in an immunocompetent intraductal model for triple-negative breast cancer

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype showing limited immunotherapeutic efficacy due to a highly immunosuppressed tumor microenvironment. Some chemotherapeutics such as the platinum-based agent cisplatin have been reported to alleviate this immunosuppression. More recently, cisplatin was suggested to even synergize with the inhibition of immune checkpoint proteins programmed death (PD)-1 and PD-ligand (L) 1. Our goal was to investigate this immunomodulation by cisplatin at the local tumor and systemic level using an immunocompetent intraductal model that recapitulates the complete TNBC disease process. Lactating female BALB/c mice were inoculated with triple-negative, syngeneic and bioluminescent 4T1 mammary tumor cells through the mammary teat canal of the third mammary gland pair. At 3 weeks after the inoculations, tumor cells broke through the ductal epithelial barrier and invaded the mammary fat pad, providing a clinical indication for chemotherapy. The mice therefore received cisplatin intraperitoneally every 5 days for 3 weeks, after which primary tumors, axillary lymph nodes, lungs, spleen and blood were isolated and immune cell subtypes as well as PD-(L)1 expression were analyzed through flow cytometry. The immune-related biomarkers chitinase 3-like 1 (CHI3L1) and lipocalin 2 (LCN2) were analyzed locally and systemically to verify disease progression. Cisplatin treatment significantly reduced tumor and metastatic growth, corroborated by decreased CHI3L1 and LCN2 levels in primary tumors, spleen and serum. Immunosuppressive CD11b+ myeloid cells that accumulated in body fluids and tissues were not uniformly eliminated by cisplatin. CD11b+Ly6C-Ly6G+ granulocytic myeloid-derived suppressor cells, the most abundant myeloid subpopulation, were significantly reduced in spleen and axillary lymph nodes only, keeping primary tumors, lungs and blood immunosuppressed. Focusing on adaptive immune cell subtypes, axillary lymph nodes showed a significant decrease in CD3ε+CD4+CD8α- helper T cells and even complete absence of CD3ε+CD4-CD8α+ cytotoxic T cells following cisplatin treatment, representing a drawback for immunotherapeutic efficacy. In contrast, helper T cells, cytotoxic T cells and CD19+ B cells were enhanced in the spleen, creating an anti- tumorigenic niche. The expression of PD-(L)1 was also significantly increased in the cisplatin-exposed spleen. In conclusion, our study provides a unique detailed characterization of the modulation of TNBC progression by cisplatin treatment and associated immune cell and immune checkpoint content across multiple tissues, identifying the spleen as most positively affected and potential driver for synergy with immunotherapy

Unexpected effects of a selective and potent c-MET inhibitor in an immunocompetent intraductal model for triple-negative breast cancer

Tumor growth and dissemination are often driven by stimulatory signaling pathways that can be targeted to reduce disease progression. The c-MET pathway represents such a typical treatment candidate, but till date most c-MET inhibitors are either not effective and/or selective against aggressive cancers such as triple-negative breast cancer (TNBC). A novel selective and potent c-MET inhibitor OMO-1 was preclinically evaluated for its efficacy in combination with and without cisplatin chemotherapy in an innovative mouse model for TNBC. After 4T1 triple-negative mammary tumor cells were injected intraductally in lactating mammary glands of syngeneic BALB/c mice, they recapitulated the complete TNBC process from ductal carcinoma in situ (DCIS) to invasive carcinoma (IC) and subsequent metastasis. Systemic treatment was started once tumor cells underwent ductal epithelial breakthrough (i.e. DCIS to IC transition), mirroring clinical indications in TNBC patients. Although 4T1 primary tumor growth did not rely on c-MET signaling, the daily oral administration of OMO-1 resulted in decreased tumor growth and provided additional tumor and metastasis reduction in combination with cisplatin. At the stromal level, OMO-1 stimulated an anti-tumorigenic microenvironment by increasing immune activation in primary tumors. Importantly, OMO-1 treatment reduced tumor hypoxia by stimulating vessel normalization as indicated by the increased expression of pericyte markers (alpha-smooth muscle actin, platelet-derived growth factor receptor-β and angiopoietin-1). In turn, these matured vessels facilitated enhanced delivery of cisplatin to the primary tumors and subsequent tumor cell death. Our partially unexpected data now warrant translation of this candidate OMO-1 therapy from a preclinical setting to TNBC patients

Oral administration of GLPG0259, an inhibitor of MAPKAPK5, a new target for the treatment of rheumatoid arthritis: a phase II, randomised, double-blind, placebo-controlled, multicentre trial.

Background: Mitogen-activated protein (MAP) kinases are key regulators of cytokine production, and are therefore potential targets for treatment of rheumatoid arthritis (RA). Objective: This two-part phase II study investigated the efficacy and safety of a once-daily 50 mg GLPG0259 (an inhibitor of MAP kinase-activated protein kinase 5) dose vs placebo ( part A). An interim analysis after part A would determine whether the dose-finding part ( part B) would be performed. Methods: In part A, eligible methotrexate (MTX)- refractory patients with RA were randomised to receive either a once-daily 50 mg dose of GLPG0259 or placebo, in addition to a stable dose of MTX, for 12 weeks. The primary efficacy end point was the percentage of patients achieving an American College of Rheumatology 20% improvement (ACR20) response after 12 weeks. Results: The interim analysis showed no difference between the percentage of subjects achieving the primary efficacy variable of ACR20 or the secondary efficacy variables (ACR50, ACR70 and Disease Activity Score 28) at week 12 in the GLPG0259-treated (n=19) and placebo-treated (n=11) groups. Owing to lack of efficacy, the study was terminated, and part B was not initiated. Conclusions: This innovative study design quickly provided conclusive results on the lack of efficacy of GLPG0259 in patients with RA