Monoclonal antibodies (mAbs) targeting coinhibitory molecules such as PD-1, PD-L1 and CTLA-4 are increasingly used as targets of therapeutic intervention against cancer. While these targets have led to a critical paradigm shift in treatments for cancer, these approaches are also plagued with limitations owing to cancer immune evasion mechanisms and adverse toxicities associated with continuous treatment. It has been difficult to reproduce and develop interventions to these limitations preclinically due to poor reagent efficacy and reagent xenogenecity not seen in human trials. In this study, we investigated adverse effects of repeated administration of PD-1 and PD-L1 mAbs in the murine 4T1 mammary carcinoma model. We observed rapid and fatal hypersensitivity reactions in tumor bearing mice within 30-60 min after 4-5 administrations of PD-L1 or PD-1 mAb but not CTLA-4 antibody treatment. These events occurred only in mice bearing the highly inflammatory 4T1 tumor and did not occur in mice bearing non-inflammatory tumors. We observed that mortality was associated with systemic accumulation of IgG1 antibodies, antibodies specific to the PD-1 mAb, and accumulation of Gr-1(high) neutrophils in lungs which have been implicated in the IgG mediated pathway of anaphylaxis. Anti-PD-1 associated toxicities were alleviated when PD-1 blockade was combined with the therapeutic HSP90 inhibitor, ganetespib, which impaired immune responses toward the xenogeneic PD-1 mAb. This study highlights a previously uncharacterized fatal hypersensitivity exacerbated by the PD-1/PD-L1 axis in the broadly used 4T1 tumor model as well as an interesting relationship between this particular class of checkpoint blockade and tumor-dependent immunomodulation.

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In recent years, heparanase has attracted considerable attention as a promising target for innovative pharmacological applications. Heparanase is a multifaceted protein endowed with enzymatic activity, as an endo-β-D-glucuronidase, and nonenzymatic functions. It is responsible for the cleavage of heparan sulfate side chains of proteoglycans, resulting in structural alterations of the extracellular matrix. Heparanase appears to be involved in major human diseases, from the most studied tumors to chronic inflammation, diabetic nephropathy, bone osteolysis, thrombosis and atherosclerosis, in addition to more recent investigation in various rare diseases. The present review provides an overview on heparanase, its biological role, inhibitors and possible clinical applications, covering the latest findings in these areas.

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Very late antigen-4 (VLA-4), which is concerned with cell-cell adhesion, plays important roles in development of the heart, and some VLA-4 antagonists cause cardiac anomalies. In this study, we evaluated the teratogenic potential of VLA-4 antagonist derivatives as screening, and investigated the conditions that induce cardiac anomalies. Seventeen compounds were orally administered to pregnant rats throughout the organogenesis period, and fetal examinations were performed. In addition, drug concentrations in the embryos were assayed. As a result, the incidence of ventricular septal defect (VSD) ranged from 0 to 100% depending on the compound. Plasma drug concentrations in the dams were related to increased incidence of VSD; however, these incidences were not increased when the concentration of the compound in the embryos at 24h after dosing was low. It is considered that continuous pharmacological activity in the embryo for more than 24h might disrupt closure of the ventricular septum.
Copyright © 2014. Published by Elsevier Inc.

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To evaluate gynecologic safety of conjugated estrogens/bazedoxifene treatment for menopausal symptoms and osteoporosis prevention in nonhysterectomized women.
We pooled data from five randomized, placebo-controlled trials of conjugated estrogens 0.625 mg/bazedoxifene 20 mg (n = 1583), conjugated estrogens 0.45 mg/bazedoxifene 20 mg (n = 1585), and placebo (n = 1241). Gynecologic safety was evaluated by pelvic examination, Papanicolaou smear, endometrial biopsy, transvaginal ultrasound, mammogram, adverse events, and diary records of vaginal bleeding and breast pain/tenderness. Incidence rates and relative risks (RR) versus placebo were calculated with inverse variance weighting. Data for conjugated estrogens 0.45 mg/medroxyprogesterone acetate 1.5 mg, an active comparator in two trials (n = 399), are included for comparison.
Endometrial hyperplasia occurred in <1% (n = 4 [0.3%], 2 [0.2%], 1 [0.5%], and 2 [0.2%] for conjugated estrogens 0.625 mg/bazedoxifene 20 mg, conjugated estrogens 0.45 mg/bazedoxifene 20 mg, conjugated estrogens/medroxyprogesterone acetate, and placebo). There was one endometrial cancer, which occurred with conjugated estrogens 0.45 mg/bazedoxifene 20 mg (0.44/1000 woman-years [95% confidence interval (CI), 0.00-2.37]; RR versus placebo 0.91 [95% CI, 0.17-4.82]). There were seven cases of breast cancer: four with conjugated estrogens 0.45 mg/bazedoxifene 20 mg (1.00/1000 woman-years [95% CI, 0.00-3.21] RR 1.11 [95% CI, 0.33-3.78]), two with placebo, and one with conjugated estrogens/medroxyprogesterone acetate. Unlike conjugated estrogens/medroxyprogesterone acetate, conjugated estrogens/bazedoxifene did not increase breast density, breast pain/tenderness, or vaginal bleeding versus placebo. No active treatment increased ovarian cysts.
Conjugated estrogens/bazedoxifene provides endometrial protection without increasing breast pain/density, vaginal bleeding, or ovarian cysts in nonhysterectomized postmenopausal women studied up to 2 years.

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Adjuvants are a key component in enhancing immunogenicity of vaccines and play a vital role in facilitating the induction of the correct type of immunity required for each vaccine to be optimally efficacious. Several different adjuvants are found in licensed vaccines, and many others are in pre-clinical or clinical testing. Agonists for Toll-like receptors (TLR) are potent activators of the innate immune system and some, such as CpG (TLR9 agonist) are particularly good for promoting cellular immunity due to the induction of Th1 cytokines. Emulsions, which have both delivery and adjuvant properties, are classified as water-in-oil (W/O) or oil-in-water (O/W) formulations. The W/O emulsion Montanide ISA-51, often combined with CpG, has been widely tested in cancer vaccine clinical trials. Squalene-based O/W emulsions are in licensed influenza vaccines and T cell responses have been assessed pre-clinically. No clinical study has compared the two types of emulsions and the continued use of W/O with CpG in cancer vaccines may be because the lack of single adjuvant controls has masked the interference issue. These findings may have important implications for development of vaccines where T cell immunity is considered essential, such as those for cancer and chronic infections. Using particulate (HBsAg) and soluble protein (ovalbumin) antigen, we show in mice that a W/O emulsion (ISA-51) abrogates CpG-mediated augmentation of CD8+ T cell responses, whereas a squalene-based O/W emulsion significantly enhanced them.
© The Japanese Society for Immunology. 2016. All rights reserved. For permissions, please e-mail: [email protected].

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