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The tumour microenvironment (TME) plays a pivotal role in tumour fate determination. The TME acts together with the genetic material of tumour cells to determine their initiation, metastasis and drug resistance. Stromal cells in the TME promote the growth and metastasis of tumour cells by secreting soluble molecules or exosomes. The abnormal microenvironment reduces immune surveillance and tumour killing. The TME causes low anti‐tumour drug penetration and reactivity and high drug resistance. Tumour angiogenesis and microenvironmental hypoxia limit the drug concentration within the TME and enhance the stemness of tumour cells. Therefore, modifying the TME to effectively attack tumour cells could represent a comprehensive and effective anti‐tumour strategy. Normal cells, such as stem cells and immune cells, can penetrate and disrupt the abnormal TME. Reconstruction of the TME with healthy cells is an exciting new direction for tumour treatment. We will elaborate on the mechanism of the TME to support tumours and the current cell therapies for targeting tumours and the TME—such as immune cell therapies, haematopoietic stem cell (HSC) transplantation therapies, mesenchymal stem cell (MSC) transfer and embryonic stem cell‐based microenvironment therapies—to provide novel ideas for producing breakthroughs in tumour therapy strategies. [ABSTRACT FROM AUTHOR]

The therapeutic potential of plumbagin, a naphthoquinone extracted from the officinal leadwort with anticancer properties, is hampered by its failure to specifically reach tumours at a therapeutic concentration after intravenous administration, without secondary effects on normal tissues. Its use in clinic is further limited by its poor aqueous solubility, its spontaneous sublimation, and its rapid elimination in vivo. We hypothesize that the entrapment of plumbagin within liposomes grafted with transferrin, whose receptors are overexpressed on many cancer cells, could result in a selective delivery to tumours after intravenous administration. The objectives of this study were therefore to prepare and characterize transferrin‐targeted liposomes entrapping plumbagin and to evaluate their therapeutic efficacy in vitro and in vivo. The entrapment of plumbagin in transferrin‐bearing liposomes led to an increase in plumbagin uptake by cancer cells and improved antiproliferative efficacy and apoptosis activity in B16‐F10, A431, and T98G cell lines compared with that observed with the drug solution. In vivo, the intravenous injection of transferrin‐bearing liposomes entrapping plumbagin led to tumour suppression for 10% of B16‐F10 tumours and tumour regression for a further 10% of the tumours. By contrast, all the tumours treated with plumbagin solution or left untreated were progressive. The animals did not show any signs of toxicity. Transferrin‐bearing liposomes entrapping plumbagin are therefore highly promising therapeutic systems that should be further optimized as a therapeutic tool for cancer treatment. [ABSTRACT FROM AUTHOR]

Polymer nanoparticles (nps) have gained growing interest as carriers for anticancer drugs as they can target tumour tissues by both passive and active pathways. While the passive targeting mechanisms mainly rely on the small size of the carriers, active targeting requires surface modifications of the polymer core in order to introduce specific functionalities to actively recognize cancer cells. The present work proposes an innovative method for the preparation of surface-functionalized nps based on the use of biodegradable polyester- and polyester/ether-urethanes ( PURs) embedding amino functionalities. Two polyurethanes were prepared, one based on just poly(ϵ-caprolactone) diol ( PCL-PUR) and the other based on both PCL diol and poly(ethylene glycol) ( PEG) (70/30 ratio, PCL-PEG-PUR). Nanoparticles of small size ranging between 150 and 200 nm and negative ζ potential (ranging from −18 mV to −27 mV) were obtained. Functional groups were exposed post nps preparation as confirmed by X-ray photoelectron spectroscopy, ninhydrin assay and 1H NMR, which evidenced a 24% tert-butyloxycarbonyl cleavage for PCL-PUR-NH2 nps and 29% for PCL-PEG-PUR-NH2 nps. The monoclonal antibody Herceptin ( HER), which targets HER-2 receptors, was coupled through ethyl(dimethylaminopropyl) carbodiimide/ N-hydroxysuccinimide (EDC/NHS) mediated chemistry. The optimal HER: NH2 ratio was determined to be 1:16 for the PEG-containing PUR and 1:8 for PCL-PUR. HER-nps maintained the intrinsic cytotoxicity of the antibody, as shown by the ca 50% decrease of HER-2-expressing HeLa cell viability. The results indicate that our protocol for surface functionalization of PUR nps, based on surface exposure of previously inserted functional groups followed by covalent coupling of biomolecules, is suitable for the preparation of nps for active recognition of target cells. © 2016 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

In this study, we describe the synthesis of novel functional non-nucleoside adenylyl cyclase inhibitors, which can be easily modified with thiol containing biomolecules such as tumour targeting structures. The linkage between inhibitor and biomolecule contains cleavable bonds to enable efficient intracellular delivery in the reductive milieu of the cytosol as well as in the acidic environment within endosomes and lysosomes. The suitability of this synthetic approach was shown by the successful bioconjugation of a poor cell-permeable inhibitor with a cell-penetrating peptide. Additionally, we have demonstrated the excellent inhibitory effect of the compounds presented here in a live-cell Förster resonance energy transfer-based assay in human embryonic kidney cells. [ABSTRACT FROM AUTHOR]

Anti-tumour therapies based on the use pro-apoptotic receptor agonists, including TNF-related apoptosis-inducing ligand ( TRAIL) or monoclonal antibodies targeting TRAIL-R1 or TRAIL- R2, have been disappointing so far, despite clear evidence of clinical activity and lack of adverse events for the vast majority of these compounds, whether combined or not with conventional or targeted anti-cancer therapies. This brief review aims at discussing the possible reasons for the lack of apparent success of these therapeutic approaches and at providing hints in order to rationally design optimal protocols based on our current understanding of TRAIL signalling regulation or resistance for future clinical trials. Linked Articles This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-8 [ABSTRACT FROM AUTHOR]

The function of T lymphocytes as orchestrators and effectors of the adaptive immune response is directed by the specificity of their T cell receptors (TCRs). By transferring into T cells the genes encoding antigen-specific receptors, the functional activity of large populations of T cells can be redirected against defined targets including virally infected or cancer cells. The potential of therapeutic T cells to traffic to sites of disease, to expand and to persist after a single treatment remains a major advantage over the currently available immunotherapies that use monoclonal antibodies. Here we review recent progress in the field of TCR gene therapy, outlining challenges to its successful implementation and the strategies being used to overcome them. We detail strategies used in the optimization of affinity and surface expression of the introduced TCR, the choice of T cell subpopulations for gene transfer, and the promotion of persistence of gene-modified T cells in vivo. We review the safety concerns surrounding the use of gene-modified T cells in patients, discussing emerging solutions to these problems, and describe the increasingly positive results from the use of gene-modified T cells in recent clinical trials of adoptive cellular immunotherapy. The increasing sophistication of measures to ensure the safety of engineered T cells is accompanied by an increasing number of clinical trials: these will be essential to guide the effective translation of cellular immunotherapy from the laboratory to the bedside. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

OBJECTIVE To investigate the effect of three different tyrosine kinase inhibitors (TKIs) on the biodistribution of chimeric monoclonal antibody (mAb) cG250, which identifies carbonic anhydrase IX (CAIX), in nude mice bearing human renal cell carcinoma (RCC) xenografts. TKIs represent the best, but still suboptimal treatment for metastatic RCC (mRCC) and combined therapy or sequential therapy might be beneficial. CAIX is abundantly over expressed in RCC and clinical trials have shown abundant and specific tumour accumulation of cG250. Combining a TKI with mAb cG250, involved in a different effector mechanism, might lead to improved tumour responses and survival in patients with mRCC. MATERIALS AND METHODS Nude mice bearing human RCC xenografts were treated orally with 0.75 mg/day sunitinib, 1 mg/day vandetanib, 1 mg/day sorafenib or vehicle control for 7 or 14 days. At 7 days, mice were injected i.v. with 185 kBq/5 μg 125I-cG250. Mice were killed at predetermined days and cG250 biodistribution was determined. Tumours were analysed by immunohistochemistry for the presence of endothelial cells, laminin, smooth muscle actin, CAIX expression and uptake of mAb cG250. RESULTS While on TKI treatment, tumour uptake of cG250 decreased dramatically, tumour growth was slightly inhibited and vascular density decreased considerably as judged by various markers. When treatment was stopped at 7 days, there was robust neovascularization, mainly at the tumour periphery. Consequently, cG250 uptake also recovered, albeit cG250 uptake appeared to be restricted to the tumour periphery where vigorous neovascularization was visible. CONCLUSIONS Simultaneous administration of a TKI and mAb cG250 severely compromised mAb accumulation. However, shortly after discontinuation of TKI treatment mAb accumulation was restored. Combined treatment strategies with TKI and mAb should be carefully designed. [ABSTRACT FROM AUTHOR]

The aims of this work were to obtain a human antibody against the tumour-associated antigen tenascin-C (TNC) and to compare the yield and quality of plant-produced antibody in either stable transgenics or using a transient expression system. To this end, the characterization of a full-sized human immunoglobulin G (IgG) [monoclonal antibody H10 (mAb H10)], derived from a selected single-chain variable fragment (scFv) and produced in plants, is presented. The human mAb gene was engineered for plant expression, and Nicotiana tabacum transgenic lines expressing both heavy (HC) and light (LC) chain were obtained and evaluated for antibody expression levels, in vivo assembly and functionality. Affinity-purified H10 from transgenics (yield, 0.6–1.1 mg/kg fresh weight) revealed that more than 90% of HC was specifically degraded, leading to the formation of functional antigen-binding fragments (Fab). Consequently, H10 was transiently expressed in Nicotiana benthamiana plants through an Agrobacterium-mediated gene-transfer system. Moreover, the use of the p19 silencing suppressor gene from artichoke mottled crinkle virus raised antibody expression levels by an order of magnitude (yields of purified H10, 50–100 mg/kg fresh weight). Approximately 75% of purified protein consisted of full-sized antibody functionally binding to TNC ( KD = 14 nm), and immunohistochemical analysis on tumour tissues revealed specific accumulation around tumour blood vessels. The data indicate that the purification yields of mAb H10, using a transient expression system boosted by the p19 silencing suppressor, are exceptionally high when compared with the results reported previously, providing a technique for the over-expression of anticancer mAbs by a rapid, cost-effective, molecular farming approach. [ABSTRACT FROM AUTHOR]

Summary Lewis system carbohydrate antigens have been shown to be expressed at high levels in many cancers of epithelial cell origin, including those of colon, breast, lung, prostate and ovary. The type 1 (Lea and Leb) antigens are important histo-blood groups, while type 2 (Lex and Ley) antigens in healthy individuals are only expressed, at relatively low levels, by a few tissues, including some epithelial cells. Thus, the type 2 antigens are considered to be tumour-associated antigens and are promising targets for cancer treatment, including antibody-based immunotherapy. In this review, we discuss the conformational characteristics of the free and bound forms of Lewis oligosaccharides and the 3D structures of antibodies in complex with Ley and Lex antigens. Collectively, the structural studies have demonstrated that the Lewis determinants are rigid structures, which generally maintain the same conformation in the free and bound states. The rigid nature and similarities in shape of type 1 and 2 Lewis oligosaccharides appear to make them perfectly suited to driving a structurally convergent immune response (at least in the case of Ley specific antibodies) toward a highly specific recognition of individual carbohydrate determinants, which is a goal in the development of effective antibody-based cancer treatments. [ABSTRACT FROM AUTHOR]