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Given its ability to induce both humoral and cellular immune responses, NY-ESO-1 has been considered a suitable antigen for a cancer vaccine. Despite promising results from early-phase clinical studies in patients with melanoma, NY-ESO-1 vaccine immunotherapy has not been widely investigated in larger trials; consequently, many questions remain as to the optimal vaccine formulation, predictive biomarkers, and sequencing and timing of vaccines in melanoma treatment. We conducted an adjuvant phase I/II clinical trial in high-risk resected melanoma to optimize the delivery of poly-ICLC, a TLR-3/MDA-5 agonist, as a component of vaccine formulation. A phase I dose-escalation part was undertaken to identify the MTD of poly-ICLC administered in combination with NY-ESO-1 and montanide. This was followed by a randomized phase II part investigating the MTD of poly-ICLC with NY-ESO-1 with or without montanide. The vaccine regimens were generally well tolerated, with no treatment-related grade 3/4 adverse events. Both regimens induced integrated NY-ESO-1-specific CD4 + T-cell and humoral responses. CD8 + T-cell responses were mainly detected in patients receiving montanide. T-cell avidity toward NY-ESO-1 peptides was higher in patients vaccinated with montanide. In conclusion, NY-ESO-1 protein in combination with poly-ICLC is safe, well tolerated, and capable of inducing integrated antibody and CD4 + T-cell responses in most patients. Combination with montanide enhances antigen-specific T-cell avidity and CD8 + T-cell cross-priming in a fraction of patients, indicating that montanide contributes to the induction of specific CD8 + T-cell responses to NY-ESO-1., (©2019 American Association for Cancer Research.)

The Toll-like receptor (TLR) 7/8 agonist resiquimod has been used as an immune adjuvant in cancer vaccines. We evaluated the safety and immunogenicity of the cancer testis antigen NY-ESO-1 given in combination with Montanide (Seppic) with or without resiquimod in patients with high-risk melanoma. In part I of the study, patients received 100 μg of full-length NY-ESO-1 protein emulsified in 1.25 mL of Montanide (day 1) followed by topical application of 1,000 mg of 0.2% resiquimod gel on days 1 and 3 (cohort 1) versus days 1, 3, and 5 (cohort 2) of a 21-day cycle. In part II, patients were randomized to receive 100-μg NY-ESO-1 protein plus Montanide (day 1) followed by topical application of placebo gel [(arm A; n = 8) or 1,000 mg of 0.2% resiquimod gel (arm B; n = 12)] using the dosing regimen established in part I. The vaccine regimens were generally well tolerated. NY-ESO-1-specific humoral responses were induced or boosted in all patients, many of whom had high titer antibodies. In part II, 16 of 20 patients in both arms had NY-ESO-1-specific CD4⁺ T-cell responses. CD8⁺ T-cell responses were only seen in 3 of 12 patients in arm B. Patients with TLR7 SNP rs179008 had a greater likelihood of developing NY-ESO-1-specific CD8⁺ responses. In conclusion, NY-ESO-1 protein in combination with Montanide with or without topical resiquimod is safe and induces both antibody and CD4⁺ T-cell responses in the majority of patients; the small proportion of CD8⁺ T-cell responses suggests that the addition of topical resiquimod to Montanide is not sufficient to induce consistent NY-ESO-1-specific CD8⁺ T-cell responses., (©2015 American Association for Cancer Research.)

Therapeutic interventions for HIV-1 that successfully augment adaptive immunity to promote killing of infected cells may be a requisite component of strategies to reduce latent cellular reservoirs. Adoptive immunotherapies utilizing autologous monocyte-derived dendritic cells (DCs) that have been activated and antigen loaded ex vivo may serve to circumvent defects in DC function that are present during HIV infection in order to enhance adaptive immune responses. Here we detail the clinical preparation of DCs loaded with autologous aldrithiol-2 (AT-2)-inactivated HIV that have been potently activated with the viral mimic, Polyinosinic-polycytidylic acid-poly-l-lysine carboxymethylcellulose (Poly-ICLC). HIV is first propagated from CD4+ T cells from HIV-infected donors and then rendered non-replicative by chemical inactivation with aldrithiol-2 (AT-2), purified, and quantified. Viral inactivation is confirmed through measurement of Tat-regulated β-galactosidase reporter gene expression following infection of TZM-bl cells. In-process testing for sterility, mycoplasma, LPS, adventitious agents, and removal of AT-2 is performed on viral preparations. Autologous DCs are generated and pulsed with autologous AT-2-inactivated virus and simultaneously stimulated with Poly-ICLC to constitute the final DC vaccine product. Phenotypic identity, maturation, and induction of HIV-specific adaptive immune responses are confirmed via flow cytometric analysis of DCs and cocultured autologous CD4+ and CD8+ T cells. Lot release criteria for the DC vaccine have been defined in accordance with Good Manufacturing Practice (GMP) guidelines. The demonstrated feasibility of this approach has resulted in approval by the FDA for investigational use in antiretroviral (ART) suppressed individuals. We discuss how this optimized DC formulation may enhance the quality of anti-HIV adaptive responses beyond what has been previously observed during DC immunotherapy trials for HIV infection., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: Children and youth accumulate their daily moderate-to-vigorous physical activity (MVPA) in bouts (i.e., ≥ 5 consecutive minutes) and in a sporadic manner (i.e., <5 consecutive minutes). The study objective was to determine, within children and youth, whether MVPA accumulated in bouts is more strongly associated with cardiometabolic risk factors than an equivalent volume of MVPA accumulated sporadically., Methods: Participants consisted of 2754 children and youth aged 6-19 years from the 2003-2006 National Health and Nutrition Examination Survey, a representative cross-sectional study. Bouts and sporadic MVPA were measured objectively over 7 days using Actigraph accelerometers. Thresholds of 5 and 10 consecutive minutes were used to differentiate between bouts and sporadic MVPA. A high cardiometabolic risk factor score (CRS) was created based on measures of waist circumference, non-high-density lipoprotein cholesterol, C-reactive protein, and systolic blood pressure. Associations were examined using logistic regression and controlled for covariates (sex, age, ethnicity, socioeconomic status, dietary fat and sodium, smoking, and accelerometry wear time)., Results: The odds of a high CRS decreased in a dose-response for both the sporadic and bout MVPA measures. Relative to quartile 1, the odds ratio (95% confidence interval) for a high CRS in quartile 4 was 0.25 (0.10-0.60) for sporadic MVPA, 0.17 (0.09-0.34) for ≥ 5 minute bouts of MVPA, and 0.19 (0.11-0.34) for ≥ 10 minute bouts of MVPA. The sporadic and bout MVPA measures had a similar ability to distinguish between participants with high and normal CRS. Relative to 0 minutes of MVPA, an equivalent number of minutes of sporadic MVPA and bouts of MVPA had an almost identical odds ratio for a high CRS. The findings were consistent for 5 and 10 minute bout thresholds., Conclusions: The relations between sporadic MVPA and bouts of MVPA with cardiometabolic risk factors were remarkably similar in children and youth.

T cell-mediated immunity to microbes and to cancer can be enhanced by the activation of dendritic cells (DCs) via TLRs. In this study, we evaluated the safety and feasibility of topical imiquimod, a TLR7 agonist, in a series of vaccinations against the cancer/testis Ag NY-ESO-1 in patients with malignant melanoma. Recombinant, full-length NY-ESO-1 protein was administered intradermally into imiquimod preconditioned sites followed by additional topical applications of imiquimod. The regimen was very well tolerated with only mild and transient local reactions and constitutional symptoms. Secondarily, we examined the systemic immune response induced by the imiquimod/NY-ESO-1 combination, and show that it elicited both humoral and cellular responses in a significant fraction of patients. Skin biopsies were assessed for imiquimod's in situ immunomodulatory effects. Compared with untreated skin, topical imiquimod induced dermal mononuclear cell infiltrates in all patients composed primarily of T cells, monocytes, macrophages, myeloid DCs, NK cells, and, to a lesser extent, plasmacytoid DCs. DC activation was evident. This study demonstrates the feasibility and excellent safety profile of a topically applied TLR7 agonist used as a vaccine adjuvant in cancer patients. Imiquimod's adjuvant effects require further evaluation and likely need optimization of parameters such as formulation, dose, and timing relative to Ag exposure for maximal immunogenicity.

An open study is reported in which 35 general practitioners treated 128 patients suffering from 'Red Eye' with a new eye ointment containing 10% Tanderil(oxyphenbutazone) and 1% chloramphenicol. One hundred and seventeen patients completed the seven day treatment period, in which time 99 had completed resolution of the symptoms and were discharged, the remaining 18 patients needed a longer period of treatment. Eleven patients failed to complete the study period, of whom 5 patients were subsequently referred to a specialist and 6 had their treatment changed by the general practitioner. Six patients showed signs of allergy to the ointment, all of whom were being treated for allergic conjunctivitis. Seventeen per cent of patients had some difficulty in applying the eye ointment or complained of subsequent blurring of vision.