Abstract: Recent clinical data support ideas of Programmed death receptor-ligand 1 (PD-L1; also called B7-H1, CD274) playing an important role in immune evasion of tumor cells. Expression of PD-L1 on tumors strongly correlates with the survival of cancer patients. PD-L1 on tumors interacts with the co-inhibitory molecule Programmed death receptor-1 (PD-1, CD279) on T cells mediating decreased TCR-mediated proliferation and cytokine production. In animal tumor models, blockade of PD-L1/PD-1 interactions resulted in an improved tumor control. In addition, exhausted T cells during chronic viral infections could be revived by PD-L1 blockade. Thus, targeting PD-L1/PD-1 interactions might improve the efficacy of adoptive cell therapies (ACT) of chronic infections as well as cancers. Obstacles for a general blockade of PD-L1 might be its role in mediating peripheral tolerance. This review discusses the currently available data concerning the role of PD-L1 in tumor immune evasion and envisions possibilities for implementation into ACT for cancer patients.

Abstract: Negative co-stimulatory signaling mediated via cell surface programmed death (PD)-1 expression modulates T and B cell activation and is involved in maintaining peripheral tolerance. In this study, we examined the effects of a fully human PD-1-abrogating antibody on the in vitro expansion and function of human vaccine-induced CD81 T cells (CTLs) specific for the melanoma-associated antigens glycoprotein 100 (gp100) and melanoma antigen recognized by T cells (MART)-1. PD-1 blockade during peptide stimulation augmented the absolute numbers of CD31, CD41, CD81 and gp100/MART-1 MHC:peptide tetramer1 CTLs. This correlated with increased frequencies of IFN-gsecreting antigen-specific cells and augmented lysis of gp1001/MART-11 melanoma targets. PD-1 blockade also increased the fraction of antigen-specific CTLs that recognized melanoma targets by degranulation, suggesting increased recognition efficiency for cognate peptide. The increased frequencies and absolute numbers of antigen-specific CTLs by PD-1 blockade resulted from augmented proliferation, not decreased apoptosis. Kinetic analysis of cytokine secretion demonstrated that PD-1 blockade increased both type-1 and type-2 cytokine accumulation in culture without any apparent skewing of the cytokine repertoire. These findings have implications for developing new cancer immunotherapy strategies.

Abstract: Toll-like receptors (TLRs) trigger the production of inflammatory cytokines and shape adaptive and innate immunity to pathogens. We report the identification of B cell leukemia (Bcl)–3 as an essential negative regulator of TLR signaling. By blocking ubiquitination of p50, a member of the nuclear factor (NF)-κB family, Bcl-3 stabilizes a p50 complex that inhibits gene transcription. As a consequence, Bcl-3–deficient mice and cells were found to be hypersensitive to TLR activation and unable to control responses to lipopolysaccharides. Thus, p50 ubiquitination blockade by Bcl-3 limits the strength of TLR responses and maintains innate immune homeostasis. These findings indicate that the p50 ubiquitination pathway can be selectively targeted to control deleterious inflammatory diseases.

Abstract: Rationale: Partial neuromuscular transmission failure by acetylcholine receptor blockade (neuromuscular blockade) or antibody-mediated functional loss (myasthenia gravis), even with a magnitude of muscle weakness that does not evoke respiratory symptoms, can evoke dysphagia and decreased inspiratory airflow, and increases the risk of susceptible patients to develop severe pulmonary complications.Objectives: To assess whether impaired neuromuscular transmission predisposes individuals to inspiratory upper airway collapse, we assessed supraglottic airway diameter and volume by respiratory-gated magnetic resonance imaging, upper airway dilator muscle function (genioglossus force and EMG), and changes in lung volume, respiratory timing, and peripheral muscle function before, during, and after partial neuromuscular blockade in healthy, awake volunteers.Measurements and Main Results: Partial neuromuscular blockade (train-of-four [TOF] ratio: 0.5 and 0.8) was associated with the following: (1) a decrease of insp...

Abstract: Angiotensin II (Ang II), the active principle of the renin-angiotensin system (RAS), was discovered as a vasoconstrictive, fluid retentive circulating hormone. It was revealed later that there are local RAS in many organs, including the brain. The physiological receptor for Ang II, the AT(1) receptor type, was found to be highly expressed in many tissues and brain areas involved in the hypothalamic-pituitary-adrenal axis response to stress and in the sympathoadrenal system. The production of circulating and local Ang II, and the expression of AT(1) receptors increase during stress. Blockade of peripheral and brain AT(1) receptors with receptor antagonists administered peripherally prevented the hormonal and sympathoadrenal response to isolation stress, the stress-related alterations in cortical CRF(1) and benzodiazepine receptors, part of the GABA(A) complex, and reduced anxiety in rodents. AT(1) receptor blockade prevented the ulcerations of the gastric mucosa produced by cold-restraint stress, by preservation of the gastric blood flow, prevention of the stress-induced inflammatory response of the gastric mucosa, and partial blockade of the sympathoadrenal response to the stress. Our observations demonstrate that Ang II is an important stress hormone, and that blockade of AT(1) receptors could be proposed as a potentially useful therapy for stress-induced disorders.

Abstract: Recent studies from our laboratory have shown that the mineralocorticoid receptor (MR) blockade with spironolactone (Sp) prevented renal dysfunction and reduced renal injury in both acute and chron...

Abstract: Signaling through the insulin-like growth factor-I receptor (IGF-IR) is implicated in cellular proliferation, apoptosis, carcinogenesis, metastasis, and resistance to cytotoxic cancer therapies. Targeted disruption of IGF-IR signaling combined with cytotoxic therapy may therefore yield improved anticancer efficacy over conventional treatments alone. In this study, a fully human anti-IGF-IR monoclonal antibody A12 (ImClone Systems, Inc., New York, NY) is examined as an adjunct to radiation therapy. IGF-IR expression is shown for a diverse cohort of cell lines, whereas targeted IGF-IR blockade by A12 inhibits IGF-IR phosphorylation and activation of the downstream effectors Akt and mitogen-activated protein kinase. Anchorage-dependent proliferation and xenograft growth is inhibited by A12 in a dose-dependent manner, particularly for non-small cell lung cancer lines. Clonogenic radiation survival of H226 and H460 cells grown under anchorage-dependent conditions is impaired by A12, demonstrating a radiation dose-enhancing effect for IGF-IR blockade. Postradiation anchorage-independent colony formation is inhibited by A12 in A549 and H460 cells. In the H460 xenograft model, combining A12 and radiation significantly enhances antitumor efficacy compared with either modality alone. These effects may be mediated by promotion of radiation-induced, double-stranded DNA damage and apoptosis as observed in cell culture. In summary, these results validate IGF-IR signal transduction blockade as a promising strategy to improve radiation therapy efficacy in human tumors, forming a basis for future clinical trials.

Abstract: BACKGROUND:The effect of clonidine on the duration of sensory blockade after peripheral nerve blockade is controversial. We evaluated the effects of clonidine on the duration of sensory and motor block and analgesia time in children who underwent a variety of peripheral nerve blocks.METHODS:We revie

Abstract: Removal of pathogenic B lymphocytes by depletion of monoclonal antibodies (mAbs) or deprivation of B-cell survival factors has demonstrated clinical benefit in both oncologic and immunologic diseases. Partial clinical responses and emerging data demonstrating incomplete B-cell depletion after immunotherapy fuels the need for improved therapeutic modalities. Lessons from the first generation of therapeutics directed against B-cell-specific antigens (CD20, CD22) are being applied to develop novel antibodies with additional functional attributes. We describe the generation of a novel class of B-cell-directed therapy (anti-BR3 mAbs) that combines the depleting capacity of a therapeutic mAb and blockade of B-cell-activating factor (BAFF)-BR3 B-cell survival. In mice, treatment with antagonistic anti-BR3 antibodies results in quantitatively greater reduction in some B-cell subsets and qualitatively different effects on bone marrow plasma cells compared with BR3-Fc BAFF blockade or with anti-CD20 treatment. Comparative analysis of BR3-Fc and anti-BR3 mAb reveals a lower B-cell dependence for BAFF-mediated survival in nonhuman primates than in mice. This novel class of B-cell-targeted therapies shows species characteristics in mice and primates that will guide translation to treatment of human disease.

Abstract: Although significant advances have been made in the therapeutic blockade of the renin-angiotensin-aldosterone system (RAAS) using angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers and non-selective aldosterone receptor antagonists, there is a clear need for both additional blocking strategies and enhancements of current therapeutic approaches. Vasopeptidase inhibition may still find a role despite the small incremental value of this approach and the obvious issue of kinin-mediated adverse effects still to be fully addressed. Blockade of the RAAS upstream using renin inhibitors as well as the greater selectivity of aldosterone blockade using selective aldosterone blockers such as eplerenone are also novel approaches. Not yet in clinical use but certainly an attractive therapeutic target is angiotensin II growth factor receptor transactivation, with selective inhibitors having been developed for various specific kinase pathways. Finally, ACE2 augmentation, antisense gene strategies, and vaccination against the renin-angiotensin system should still be considered experimental, but have significant appeal as additional approaches to the blockade of this system.

Abstract: We studied the effect of CTLA-4 blockade on graft-versus-leukemia and graft-versus-host responses in a mouse model of minor histocompatibility-mismatched bone marrow transplantation. Early CTLA-4 blockade induced acute graft-versus-host disease. Delayed CTLA-4 blockade resulted in a lethal condition with lymphosplenomegaly, but with stable mixed T-cell chimerism, unchanged alloreactive T-cell frequencies and absent anti-host reactivity in vitro. In contrast, multiorgan lymphoproliferative disease with autoimmune hepatitis and circulating anti-DNA auto-antibodies were documented. Splenic lymphocytes exhibited ex vivo spontaneous proliferation and a marked proliferative response against host-type dendritic cells pulsed with syngeneic (host-type) tissue-peptides. Both phenomena were exclusively mediated by host and not donor T cells, supporting an autoimmune pathogenesis. Selectively host-derived T-cell immune reactivity was equally documented against leukemia-peptide-pulsed dendritic cells, and this was paralleled by a strong in vivo antileukemic effect in anti-CTLA-4-treated and subsequently leukemia-challenged chimeras. In conclusion, delayed CTLA-4 blockade induced a host-derived antileukemic effect, occurring in the context of an autoimmune syndrome and strictly separated from graft-versus-host disease. Both antileukemic and autoimmune responses depended on the allogeneic component, as neither effect was seen after syngeneic bone marrow transplantation. Our findings reveal the potential of using CTLA-4 blockade to establish antileukemic effects after allogeneic hematopoietic stem cell transplantation, provided autoimmunity can be controlled.

Abstract: OBJECTIVES To review treatment results of intercostal nerve blockade at our centre and those reported in the literature, and to determine which patients benefit most from this procedure. DESIGN Retrospective study. SETTING Regional palliative care centre in a regional hospital in Hong Kong. PATIENTS Oncology patients who had intercostal nerve blockade at Tuen Mun Hospital from 1995 to 2005 were divided into three groups: (1) those who appeared not to tolerate opioids; (2) those deemed to have inadequate pain control, despite high doses of analgesics; and (3) those referred to avoid early use of high-dose opioids and tolerance. MAIN OUTCOME MEASURES The effectiveness and complications of intercostal nerve blockade, and the extent of benefit derived from intercostal nerve blockade in different patient groups. RESULTS This study found that 80% of the 25 patients noted optimal local pain control and 56% experienced reduction in analgesic use after intercostal nerve blockade. About 32% did not notice recurrence of the targeted pain till the end of their lives. None of the patients developed pneumothorax. Most benefit from intercostal nerve blocks were derived by group 2 patients, 90% of whom obtained optimal local pain control (P=0.23) and enjoyed a significant reduction in analgesics use (P=0.019), and in 40% their target pain was controlled till the end of life. Only about one third of group 3 patients had subsequent reduction in use of analgesics, mainly because they had co-existing pain other than at the target selected for treatment. Half (50%) of group 1 patients achieved optimal pain control. CONCLUSION Our treatment results from intercostal nerve blockade are comparable to those reported in the literature. The procedure is safe if closely monitored. Good selection of cases is important for optimising the therapeutic gain. The largest benefit is obtained in patients who have inadequate pain control after high-dose morphine.

Abstract: Modulation of the immune response with tumor necrosis factor (TNF) blockers is not a new treatment strategy for many inflammatory disorders; however, relatively little is known about their specific mechanism of action. Understanding the mode of action, pharmacology, and pharmacokinetics of the monoclonal TNF antibodies, infliximab and adalimumab, and the soluble TNF receptor, etanercept, may therefore enable us to account for their differing clinical profiles. The aim of this supplement is to explore the roles and mechanisms of TNF and TNF blockade using in vitro pharmacological and in vivo animal modeling experiments, and in vivo studies of the effects of etanercept on the inflammatory cascade in patients with psoriasis.

Abstract: Blockade of CTLA-4 by monoclonal antibodies (mAb) can mediate regression of tumors and increase the efficacy of tumor antigen specific vaccines. Blockade of CTLA-4 has also been shown to significantly increase the avidity of antigen-specific T cells after immunization with live recombinant viral vector based vaccine. Here, we demonstrate a biological synergy between CTLA-4 blockade and active vaccine therapy consisting of recombinant vaccinia and avipox viruses expressing carcinoembryonic antigen (CEA) and three T cell costimulatory molecules to enhance antitumor effects. However, this synergy was very much dependent on the temporal relationship of scheduling of the two agents. We evaluated the strategies in both a foreign antigen model using β-galactosidase as immunogen, and in a “self” antigen model using CEA as immunogen. For antitumor activity the model used consisted of mice transgenic for human CEA and a murine carcinoma cell line transfected with CEA. The enhanced antitumor activity after vaccine and CTLA-4 blockade did not result in any signs of autoimmunity. These studies form a rational basis for the use of vector-based vaccines with anti-CTLA-4 and demonstrate that both enhancement of positive costimulatory signals and inhibition of negative costimulatory signals can be simultaneously exploited. These studies also underscore the importance of “drug” scheduling in vaccine combination therapies.

Abstract: BACKGROUND. A prospective, double-blind, 3-arm, parallel group, randomized clinical trial was performed to compare 3 anesthetic techniques for preventing pain during prostate biopsy. METHODS. A total of 243 men undergoing a 12-core prostate biopsy were randomized to 1 of 3 anesthetic methods: 1) seminal vesical-prostatic base blockade, 2) intraprostatic blockade, and 3) apical-rectal blockade. Pain was estimated with the 10-point visual analog scale. Multivariate logistic regression evaluated factors predictive of pain. The Kruskal-Wallis test analyzed overall group comparisons and the Steel-Dwass test assessed between-group comparisons in pain scores. Proportional odds ordinal logistic regression quantified the ability of covariates and treatment arms to predict biopsy pain. These values are presented as odds ratios with confidence intervals (OR, 95% CI). RESULTS. From November 2005 to June 2006, 81 men were randomized to 3 study arms. Lidocaine administration was the most painful element of the procedure, while probe insertion was the least. Apical biopsies were routinely more painful than mid-gland biopsies, which were more painful than base biopsies. The apical-rectal blockade was the most painful to administer, but has lasting effects and led to better pain control than the prostatic base-seminal vesicle blockade. Similarly, the intraprostatic blockade was more effective than the prostatic base-seminal vesicle blockade. Besides pain reported at the time of anesthetic injection, no difference was identified between the intraprostatic and apical-rectal blockades. CONCLUSIONS. Mid and apical biopsies of the prostate are more painful than base biopsies. The seminal vesicle-prostatic base blockade is less effective than intraprostatic and apical-rectal blockade at controlling pain. Cancer 2007. © 2007 American Cancer Society.

Abstract: The finding that pyridoxalphosphate-6-azophenyl-2,4-disulfonic acid (PPADS), a P2 antagonist, attenuated the pressor response to calcaneal tendon stretch, a purely mechanical stimulus, raises the p...

Abstract: Patients with hypertension, particularly those with diabetes mellitus, are at heightened risk for cardiovascular and renal disease. Accumulated evidence indicates that the majority of hypertensive patients at high risk will require more than one antihypertensive agent to reach their blood pressure (BP) target. A reasonable strategy is to use agents with complementary mechanisms of action to enhance BP-lowering efficacy and prevent target organ damage. In experimental models, the combination of a calcium channel blocker (CCB) with an agent that blocks the renin-angiotensin system (RAS), an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker, improves measures of endothelial function, inflammation, ventricular remodelling and renal function to a greater degree than these classes given as monotherapy. In clinical trials, calcium channel/RAS blockade combination therapy has been shown to provide greater BP reductions and improve renal function in patients with diabetic and nondiabetic renal disease earlier and to a greater extent than monotherapy. In addition, dual calcium channel/RAS blockade increases arterial compliance, arterial distensibility and flow-mediated vasodilation. Expanding upon extensive research on the benefits of calcium channel blockade and RAS blockade for the prevention of vascular events and preclinical and clinical trial evidence suggests added effects of combination therapy by targeting the underlying mechanisms of hypertensive vascular disease.

Abstract: SIR, We read with interest the article by Roux et al. [1] regarding the use of tumour necrosis factor-a (TNF-a) blocking agents in patients with hepatitis B virus (HBV) and hepatitis C virus (HCV). The authors describe three patients with chronic HBV infection (all surface antigen positive) who were successfully treated with TNF-a blockade, in conjunction with lamivudine, with no evidence of HBV reactivation at follow-up of between 10 and 32 months. The article’s key message was ‘Anti-TNF-a appeared to be safe when administered to patients with HBV or HCV infection. However, concomitant treatment with lamivudine or adefovir is necessary in hepatitis B.’ We have previously described our initial successful experience of using anti-TNF-a therapy in two patients with HBV without the use of lamivudine or adefovir [2], and can now report on longterm follow-up of 2 and 3 yrs. These two cases were: a 50-yr-old woman with RA and resolved HBV infection [HBV surface antigen negative (HBsAg), HBV core antibody negative, HBV surface antibody positive] who had failed treatment with five disease-modifying anti-rheumatic drugs (DMARDs), and was commenced on etanercept without combination DMARD therapy. She did not receive any antiviral therapy prior to or during anti-TNF-a treatment, and has now completed 3 yrs of treatment and with no evidence of HBV reactivation—HBV surface antigen is negative, HBV DNA undetectable, and liver function tests are normal. Etanercept was switched to adalimumab due to concerns that this may have been causing diarrhoea, however, the patient has since been successfully switched back to etanercept due to a lack of efficacy of adalimumab. The second case is a 62-yr-old woman with RA and chronic HBV infection (HBsAg negative, HBV core antibody +positive, HBV surface antibody positive) who had failed treatment with three DMARDs. She was commenced on etanercept in combination with 15 mg methotrexate s.c. No antiviral therapy was given prior to or during treatment with etanercept, and we have seen no evidence of HBV reactivation to date—HBV surface antigen is negative and LFTs are normal. She has now had 2 yrs of treatment with etanercept with no complications. A recent review of HBV in rheumatic diseases by Calabrese et al. [3] summarized the published experience of patients with rheumatic disease and underlying HBV infection treated with biological agents and discussed strategies for screening and prophylaxis. The benefit vs risk of prophylactic antiviral therapy in patients receiving a prolonged course of immunosuppression is undetermined, and prolonged treatment with lamivudine may be linked with the development of lamivudine resistant strains of HBV [4]. Calabrese et al. [3] concluded that prophylactic antiviral therapy may not be necessary routinely, providing decisions are made on an individual patient basis and that regular follow-up takes place. The article by Roux et al. [1] helps to further clarify the risks of HBV reactivation in patients treated with anti-TNF-a therapy. However, our clinical experience is not in keeping with the article’s key message that ‘. . . concomitant treatment with lamivudine or adefovir is necessary in hepatitis B’. We believe that the currently available data suggest that TNF-a blockade is a therapeutic option in patients with RA and chronic HBV infection, though the risk/benefit ratio must be carefully assessed in each patient. Prophylactic antiviral therapy is indicated routinely in HBsAgpositive patients, but our experience is that anti-viral prophylaxis may not be necessary routinely in HBsAg-negative patients requiring an extended course of immunosuppressive therapy. As HBV is the commonest chronic viral infection in humans, this is scenario that many rheumatology centres are likely to encounter at some point. Further reporting of such cases is vital to further inform and clarify on an area where there is still a paucity of data.

Abstract: In the last decade the development of a number of biological therapies has revolutionised the treatment of rheumatic diseases. The first and most widely used of these approaches, tumour necrosis factor (TNF) blockade (infliximab, entanercept, adalimumab), has now been administered to over a million patients. However, the success of these biological therapies has also highlighted their limitations. None of these treatments has shown a 100% patient response; normally responses are in the 50-70% range. As proteins, these drugs cannot be given orally and they are expensive to produce, a cost ultimately borne by the patient/health provider that can seriously limit the availability of these drugs. Lastly, these treatments, whether involving the systemic neutralisation of a cytokine (eg, TNF or IL6 receptor blockade (tocilizumab)), the ablation of a B cell population (anti-CD20, rituximab), or the potential disruption of important cellular interactions as with CTLA4-Ig (abatacept), can cause major perturbations of the immune system, the long-term effects of which are still unclear. At present, treatments such as TNF blockade can result in an increased infectious risk and the reactivation of tuberculosis can be a major issue in certain populations. As with all therapies, there is an increasing large refractory population over time. Therefore, despite the undoubted success of these therapies, there is room for improvement. Although it might be too much to expect any new treatment to affect a "cure" (all the current biological therapies require repeated administrations), there are definite gains to be made in terms of cost, oral bioavailability and a more selective interference with the immune-inflammatory response.