Immune correlates of talactoferrin alfa in biopsied tumor of relapsed/refractory metastatic non-small cell lung cancer patients

Context: Talactoferrin alfa (TLF) is a unique recombinant form of human lactoferrin. The hypothesized mechanism of action involves TLF binding to the intestinal endothelium inducing dendritic cell maturation and cytokine release leading to infiltration of tumor with monocytes and T-lymphocytes and inhibition of tumor growth.

Objective: Based on promising phase II trial results, this correlative study was undertaken to examine immune mechanism of action of TLF in metastatic non-small cell lung cancer (NSCLC) patients.

Methods: Talactoferrin was administered orally at 1.5?g bid weeks 1–12 with 2 weeks off on a 14-week cycle. Enrolled patients had a pathologic diagnosis of NSCLC previously treated with at least two lines of systemic treatment. Patients had core biopsy of tumor before initiation of talactoferrin and at week 7 on TLF. Flow cytometry and quantitative immunohistochemistry for immune correlates were performed on the biopsied specimens.

Results: Four patients with metastatic NSCLC were enrolled. The trial was halted pre-maturely in light of negative phase III trial results. For the two patients who had repeat on-treatment tumor biopsies, a consistent increase in monocytes as a percentage of total immune cells was observed. Otherwise, no clear trend of increase or decrease was observed in any other immune cell parameters compared to matched patient pre-treatment biopsies.

Conclusion: Repeat biopsies for immune correlates by flow cytometry and quantitative immunohistochemistry in NSCLC patients are feasible. In the few patients sampled before trial closure, increased monocytes as a total percentage of the immune cell population within tumor was observed in response to TLF.     

Managing pasireotide-associated hyperglycemia: a randomized,open-label,Phase IV study

Purpose

Pasireotide is an effective treatment for acromegaly and Cushing’s disease, although treatment-emergent hyperglycemia can occur. The objective of this study was to assess incretin-based therapy versus insulin for managing pasireotide-associated hyperglycemia uncontrolled by metformin/other permitted oral antidiabetic drugs.

Methods

Multicenter, randomized, open-label, Phase IV study comprising a core phase (≤?16-week pre-randomization period followed by 16-week randomized treatment period) and optional extension (ClinicalTrials.gov ID: NCT02060383). Adults with acromegaly (n?=?190) or Cushing’s disease (n?=?59) received long-acting (starting 40 mg IM/28 days) or subcutaneous pasireotide (starting 600 µg bid), respectively. Patients with increased fasting plasma glucose (≥?126 mg/dL on three consecutive days) during the 16-week pre-randomization period despite metformin/other oral antidiabetic drugs were randomized 1:1 to open-label incretin-based therapy (sitagliptin followed by liraglutide) or insulin for another 16 weeks. The primary objective was to evaluate the difference in mean change in HbA_1c from randomization to end of core phase between incretin-based therapy and insulin treatment arms.

Results

Eighty-one (32.5%) patients were randomized to incretin-based therapy (n?=?38 received sitagliptin, n?=?28 subsequently switched to liraglutide; n?=?12 received insulin as rescue therapy) or insulin (n?=?43). Adjusted mean change in HbA_1c between treatment arms was – 0.28% (95% CI – 0.63, 0.08) in favor of incretin-based therapy. The most common AE other than hyperglycemia was diarrhea (incretin-based therapy, 28.9%; insulin, 30.2%). Forty-six (18.5%) patients were managed on metformin (n?=?43)/other OAD (n?=?3), 103 (41.4%) patients did not require any oral antidiabetic drugs and 19 patients (7.6%) were receiving insulin at baseline and were not randomized.

Conclusion

Many patients receiving pasireotide do not develop hyperglycemia requiring oral antidiabetic drugs. Metformin is an effective initial treatment, followed by incretin-based therapy if needed.

ClinicalTrials.gov ID: NCT02060383.

     

Polymerase chain reaction assay for Cydia pomonella granulovirus detection in Cydia pomonella population

The polymerase chain reaction (PCR) assay was successfully used to identify Cydia pomonella granulovirus (CpGV) in larvae of Cydia pomonella L. (codling moth). PCR with the primers CpGV-2A/CpGV-2B and CpGV-3A/CpGV-3B was found suitable for detection of CpGV. The primers Cp-I/Cp-II and Cp-III/Cp-IV were able to identify the transposable element TCp3.2 in C. pomonella larvae. The presence of CpGV in the larvae from orchards,which had been infected with CpGV was tested during 2 years post infection. (p.i.). CpGV was found in as many as 15% of the surviving larvae 1 year p.i. in one location. The virus was not detected in CpGV-infected orchards 2 years p.i. or in natural C. pomonella populations. This result suggests a poor persistence of CpGV in surviving C. pomonella individuals and its slow spread in a natural host population. One the other hand, the presence of a transposable element, transposon TCp3.2 may correlate with virus redistribution in this insect population.     

Disaggregation Following Agonist-Induced Platelet Activation in Patients on Dual Antiplatelet Therapy

Disaggregation as the difference between maximal and final platelet aggregation by light transmission aggregometry indicates the stability of platelet aggregates. We evaluated the extent of disaggregation after platelet stimulation with adenosine diphosphate (ADP), arachidonic acid (AA), collagen, epinephrine, and thrombin receptor-activating peptide (TRAP)-6 in 323 patients on dual antiplatelet therapy with daily aspirin and clopidogrel (group 1), prasugrel (group 2), or ticagrelor (group 3) therapy. All patients in group 1 underwent elective angioplasty and stenting, whereas all patients included in groups 2 and 3 suffered from acute coronary syndromes (STEMI or NSTEMI) and underwent urgent PCI. Significant differences between maximal and final platelet aggregation were observed with all agonists throughout the groups (all p<0.001). Disaggregation was highest using AA (clopidogrel 36.5%; prasugrel/ticagrelor 100%) and ADP (clopidogrel 21.7%; prasugrel/ticagrelor 100%). In contrast, low disaggregation was observed after platelet stimulation with collagen and TRAP-6 in clopidogrel-treated patients, and after platelet stimulation with collagen and epinephrine in prasugrel- and ticagrelor-treated patients. In conclusion, pathways of platelet activation that are not inhibited by standard antiplatelet therapy allow persisting platelet aggregation and may at least in part be responsible for adverse ischemic events.     

Decreased platelet inhibition by P2Y12 receptor blockers in anaemia

Background

Anaemic patients undergoing angioplasty and stenting are at an increased risk of ischaemic events, which may be caused by an inadequate response to antiplatelet therapy with adenosine diphosphate (ADP) P2Y₁₂ inhibitors. In the current study, we investigated the associations between anaemia and on‐treatment platelet reactivity in clopidogrel‐treated (group 1, n = 306) and prasugrel‐/ticagrelor‐treated (group 2, n = 109) patients undergoing elective and acute angioplasty with stent implantation, respectively.

Materials and methods

Monocyte‐platelet aggregate (MPA) formation was determined by flow cytometry in both groups. On‐treatment residual platelet reactivity in response to ADP was assessed by light transmission aggregometry (LTA) in both groups, and by the VerifyNow P2Y₁₂ assay and the Impact‐R in group 1. P‐selectin expression was measured by flow cytometry in group 2.

Results

In both groups, anaemia was associated with significantly higher MPA formation in response to ADP (both P ≤ .02). Moreover, by LTA maximal aggregation in response to ADP was significantly higher in patients with anaemia in both groups (both P < .05), and anaemic patients in group 1 had a significantly higher on‐treatment platelet reactivity by the VerifyNow P2Y₁₂ assay and the Impact‐R than those without anaemia (both P < .001). In group 2, significantly higher platelet surface expression of P‐selectin was seen in anaemia after stimulation with ADP (P = .02).

Conclusion

Anaemia is associated with decreased platelet inhibition by ADP P2Y₁₂ receptor antagonists after elective and acute percutaneous interventions with stent implantation. However, due to inconsistencies between different platelet function tests additional data are needed to clarify the role of anaemia for platelet inhibition.     

Blockade of insulin-like growth factor type-1 receptor with cixutumumab (IMC-A12): a novel approach to treatment for multiple cancers

Insulin-like growth factor type-1 receptor (IGF-1R) plays a central role in cell proliferation and survival and is overexpressed in many tumor types. Notably, IGF-1R-mediated signaling confers resistance to diverse cytotoxic, hormonal, and biologic agents, suggesting that therapies targeting IGF-1R may be effective against a broad range of human malignancies. Cixutumumab (IMC-A12; ImClone Systems) is a fully human immunoglobulin G1 (IgG1) monoclonal antibody that specifically inhibits IGF-1R signaling. Binding of cixutumumab to IGF-1R results in receptor internalization and degradation. Because cixutumumab is an IgG1 monoclonal antibody, it may induce additional cytotoxicity via immune effector mechanisms such as antibody-dependent cellular cytotoxicity. In preclinical studies, cixutumumab monotherapy resulted in growth inhibition of multiple experimental cancers. Moreover, cixutumumab safely enhanced the tumor growth inhibitory and cytotoxic effects of a broad range of chemotherapeutics, and modulated the action of agents that target hormone receptors and signal transduction, which may have implications for cancer therapy. Herein, we review published preclinical and clinical data for cixutumumab and provide a comprehensive overview of selected clinical studies.     

Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Acute Coronary Syndrome: Implications for Platelet Reactivity?

Cardiovascular Drugs and Therapy - In patients with acute coronary syndrome (ACS), angiotensin-converting enzyme (ACE) inhibitors are preferred over angiotensin receptor blockers (ARBs). However,...     

Critical role of the sample matrix in a point-of-care protein chip for sepsis

Both highly specific antibodies and appropriate assay buffers are key elements in the development of sensitive multi-analyte diagnostic tests and essential assay components to minimize interferences from the sample matrix. Herein, we investigate the influence of 0.1 M Tris (pH 7.4)/0.1 M NaCl/10 mM CaCl(2)/0.1% Tween-20 used as assay buffer and diluent for serum, plasma and saliva samples in a protein biomarker chip for the diagnosis of sepsis. In detail, on-chip sandwich assays for detection of IL-6 and PCT are established using pure assay buffer and serum, plasma, and saliva, each diluted by a factor of 10 and 100 with assay buffer. The dilution linearity as well as the cross-reactivity to immobilized IL-8, IL-10 and TNF-α antibodies (<1.8% in plasma and serum) is investigated; furthermore the influence of immunoglobulin G, fibrinogen and lysozyme, highly abundant proteins in serum, plasma and saliva. This effect is two times more pronounced in serum than in plasma and saliva and strongly decreases with increasing analyte concentration. Though the matrix proteins bind unspecifically to the immobilized receptors, they do not prevent the analyte binding; on the contrary, the analyte is reliably detected with high sensitivity, featuring limits of detection of 16 ng/L and 0.31 μg/L, and coefficients of variation of 18% and 29% for IL-6 and PCT in 10% serum.