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Background D2C7-IT is a novel immunotoxin (IT) targeting wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFR variant III (EGFRvIII) proteins in glioblastoma. In addition to inherent tumoricidal activity, immunotoxins induce secondary immune responses through the activation of T cells. However, glioblastoma-induced immune suppression is a major obstacle to an effective and durable immunotoxin-mediated antitumor response. We hypothesized that D2C7-IT-induced immune response could be effectively augmented in combination with αCTLA-4/αPD-1/αPD-L1 therapies in murine models of glioma. Methods To study this, we overexpressed the D2C7-IT antigen, murine EGFRvIII (dmEGFRvIII), in established glioma lines, CT-2A and SMA560. The reactivity and therapeutic efficacy of D2C7-IT against CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII cells was determined by flow cytometry and in vitro cytotoxicity assays, respectively. Antitumor efficacy of D2C7-IT was examined in immunocompetent, intracranial murine glioma models and the role of T cells was assessed by CD4+ and CD8+ T cell depletion. In vivo efficacy of D2C7-IT/αCTLA-4/αPD-1 monotherapy or D2C7-IT+αCTLA-4/αPD-1 combination therapy was evaluated in subcutaneous unilateral and bilateral CT-2A-dmEGFRvIII glioma-bearing immunocompetent mice. Further, antitumor efficacy of D2C7-IT+αCTLA-4/αPD-1/αPD-L1/αTim-3/αLag-3/αCD73 combination therapy was evaluated in intracranial CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII glioma-bearing mice. Pairwise differences in survival curves were assessed using the generalized Wilcoxon test. Results D2C7-IT effectively killed CT-2A-dmEGFRvIII (IC 50 = 0.47 ng/mL) and SMA560-dmEGFRvIII (IC 50 = 1.05 ng/mL) cells in vitro. Treatment of intracranial CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII tumors with D2C7-IT prolonged survival ( P = 0.0188 and P = 0.0057, respectively), which was significantly reduced by the depletion of CD4+ and CD8+ T cells. To augment antitumor immune responses, we combined D2C7-IT with αCTLA-4/αPD-1 in an in vivo subcutaneous CT-2A-dmEGFRvIII model. Tumor-bearing mice exhibited complete tumor regressions (4/10 in D2C7-IT+αCTLA-4 and 5/10 in D2C7-IT+αPD-1 treatment groups), and combination therapy-induced systemic antitumor response was effective against both dmEGFRvIII-positive and dmEGFRvIII-negative CT-2A tumors. In a subcutaneous bilateral CT-2A-dmEGFRvIII model, D2C7-IT+αCTLA-4/αPD-1 combination therapies showed dramatic regression of the treated tumors and measurable regression of untreated tumors. Notably, in CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII intracranial glioma models, D2C7-IT+αPD-1/αPD-L1 combinations improved survival, and in selected cases generated cures and protection against tumor re-challenge. Conclusions These data support the development of D2C7-IT and immune checkpoint blockade combinations for patie...

Bioadhesives have been widely used in healthcare and biomedical applications due to their ease‐of‐operation for wound closure and repair compared to conventional suturing and stapling. However, several challenges remain for developing ideal bioadhesives, such as unsatisfied mechanical properties, non‐tunable biodegradability, and limited biological functions. Considering these concerns, naturally derived biopolymers have been considered good candidates for making bioadhesives owing to their ready availability, facile modification, tunable mechanical properties, and desired biocompatibility and biodegradability. Over the past several years, remarkable progress has been made on biopolymer‐based adhesives, covering topics from novel materials designs and advanced processing to clinical translation. The developed bioadhesives have been applied for diverse applications, including tissue adhesion, hemostasis, antimicrobial, wound repair/tissue regeneration, and skin‐interfaced bioelectronics. Here in this comprehensive review, recent progress on biopolymer‐based bioadhesives is summarized with focuses on clinical translations and multifunctional bioadhesives. Furthermore, challenges and opportunities such as weak adhesion strength at the hydrated state, mechanical mismatch with tissues, and unfavorable immune responses are discussed with an aim to facilitate the future development of high‐performance biopolymer‐based bioadhesives.

Four different finishing techniques were used in a dentin bonding agent/composite resin restoration to evaluate the possible influence of finishing technique on microleakage. Results indicated that finishing technique affects the ability of the restorative system to resist microleakage. Under the conditions of this study, best results were achieved with a 30‐fluted bur followed by a short wet polish. Samples finished dry with polishing disks demonstrated considerable microleakage. This study also suggests that homogeneous nonagglomerated microfilled composite resin does not require disk finishing.