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Adjuvants are essential components of subunit vaccines added to enhance immune responses to antigens through immunomodulation. Very few adjuvants have been approved for human use by regulatory agencies due to safety concerns. Current subunit vaccine adjuvants approved for human use are very effective in promoting humoral immune responses but are less effective at promoting T-cell immunity. In this study, we evaluated a novel pure enantio-specific cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (R-DOTAP) as an immunomodulator for subunit vaccines capable of inducing both humoral- and cellular-mediated immunity. Using recombinant protein antigens derived from SARS-CoV2 spike or novel computationally optimized broadly reactive influenza antigen (COBRA) proteins, we demonstrated that R-DOTAP nanoparticles promoted strong cellular- and antibody-mediated immune responses in both monovalent and bivalent vaccines. R-DOTAP-based vaccines induced antigen-specific and polyfunctional CD8+ and CD4+ effector T cells and memory T cells, respectively. Antibody responses induced by R-DOTAP showed a balanced Th1/Th2 type immunity, neutralizing activity and protection of mice from challenge with live SARS-CoV2 or influenza viruses. R-DOTAP also facilitated significant dose sparing of the vaccine antigens. These studies demonstrate that R-DOTAP is an excellent immune stimulator for the production of next-generation subunit vaccines containing multiple recombinant proteins.
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COVID-19 , ARN Viral , Animales , Humanos , Ratones , Adyuvantes Inmunológicos , Cationes , COVID-19/prevención & control , Ácidos Grasos Monoinsaturados , Inmunidad , Lípidos , SARS-CoV-2 , Vacunas Sintéticas/genética , Anticuerpos Antivirales/inmunologíaRESUMEN
BACKGROUND: Despite recent advances, there is an urgent need for agents targeting HER2-expressing cancers other than breast cancer. We report a phase I study (NCT01730118) of a dendritic cell (DC) vaccine targeting HER2 in patients with metastatic cancer or bladder cancer at high risk of relapse. PATIENTS AND METHODS: Part 1 of the study enrolled patients with HER2-expressing metastatic cancer that had progressed after at least standard treatment and patients who underwent definitive treatment for invasive bladder cancer with no evidence of disease at the time of enrollment. Part 2 enrolled patients with HER2-expressing metastatic cancer who had progressed after anti-HER2 therapy. The DC vaccines were prepared from autologous monocytes and transduced with an adenoviral vector expressing the extracellular and transmembrane domains of HER2 (AdHER2). A total of five doses were planned, and adverse events were recorded in patients who received at least one dose. Objective response was evaluated by unidimensional immune-related response criteria every 8 weeks in patients who received at least two doses. Humoral and cellular immunogenicity were assessed in patients who received more than three doses. RESULTS: A total of 33 patients were enrolled at four dose levels (5 × 106, 10 × 106, 20 × 106, and 40 × 106 DCs). Median follow-up duration was 36 weeks (4-124); 10 patients completed five doses. The main reason for going off-study was disease progression. The main adverse events attributable to the vaccine were injection-site reactions. No cardiac toxicity was noted. Seven of 21 evaluable patients (33.3%) demonstrated clinical benefit (1 complete response, 1 partial response, and 5 stable disease). After ≥3 doses, an antibody response was detected in 3 of 13 patients (23.1%), including patients with complete and partial responses. Lymphocytes from 10 of 11 patients (90.9%) showed induction of anti-HER2 responses measured by the production of at least one of interferon-gamma, granzyme B, or tumor necrosis factor-alpha, and there were multifunctional responses in 8 of 11 patients (72.7%). CONCLUSIONS: The AdHER2 DC vaccine showed evidence of immunogenicity and preliminary clinical benefit in patients with HER2-expressing cancers, along with an excellent safety profile. It shows promise for further clinical applications, especially in combination regimens.
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Importance: Human papillomavirus (HPV) infection is found in about 40% of women who survive allogeneic hematopoietic stem cell transplant and can induce subsequent neoplasms. Objective: To determine the safety and immunogenicity of the quadrivalent HPV vaccine (HPV-6, -11, -16, and -18) in clinically stable women post-allogeneic transplant compared with female healthy volunteers. Interventions: Participants received the quadrivalent HPV vaccine in intramuscular injections on days 1 and 2 and then 6 months later. Design, Setting, and Participants: This prospective, open-label phase-1 study was conducted in a government clinical research hospital and included clinically stable women posttransplant who were or were not receiving immunosuppressive therapy compared with healthy female volunteers age 18 to 50 years who were followed up or a year after first receiving quadrivalent HPV vaccination. The study was conducted from June 2, 2010, until July 19, 2016. After all of the results of the study assays were completed and available in early 2018, the analysis took place from February 2018 to May 2019. Main Outcomes and Measures: Anti-HPV-6, -11, -16, and -18-specific antibody responses using L1 virus-like particle enzyme-linked immunosorbent assay were measured in serum before (day 1) and at months 7 and 12 postvaccination. Anti-HPV-16 and -18 neutralization titers were determined using a pseudovirion-based neutralization assay. Results: Of 64 vaccinated women, 23 (35.9%) were receiving immunosuppressive therapy (median age, 34 years [range, 18-48 years]; median 1.2 years posttransplant), 21 (32.8%) were not receiving immunosuppression (median age, 32 years [range, 18-49 years]; median 2.5 years posttransplant), and 20 (31.3%) were healthy volunteers (median age, 32 years [range, 23-45 years]). After vaccine series completion, 18 of 23 patients receiving immunosuppression (78.3%), 20 of 21 not receiving immunosuppression (95.2%), and all 20 volunteers developed antibody responses to all quadrivalent HPV vaccine types (P = .04, comparing the 3 groups). Geometric mean antibody levels for each HPV type were higher at months 7 and 12 than at baseline in each group (all geometric mean ratios >1; P < .001) but not significantly different across groups. Antibody and neutralization titers for anti-HPV-16 and anti-HPV-18 correlated at month 7 (Spearman ρ = 0.92; P < .001 for both). Adverse events were mild and not different across groups. Conclusions and Relevance: Treatment with the HPV vaccination was followed by strong, functionally active antibody responses against vaccine-related HPV types and no serious adverse events. These findings suggest that HPV vaccination may be safely administered to women posttransplant to potentially reduce HPV infection and related neoplasia. Trial Registration: ClinicalTrials.gov Identifier: NCT01092195.
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Trasplante de Células Madre Hematopoyéticas/métodos , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/inmunología , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo/métodos , Adolescente , Adulto , Femenino , Voluntarios Sanos , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Adulto JovenRESUMEN
We translated two cancer vaccine strategies from mice into human clinical trials. (1) In preclinical studies on TARP, an antigen expressed in most prostate cancers, we mapped epitopes presented by HLA-A*0201, modified them to increase affinity and immunogenicity in HLA transgenic mice, and induced human T cells that killed human cancer cells ("epitope enhancement"). In a clinical trial, HLA-A2+ prostate cancer patients with PSA biochemical recurrence (Stage D0) were vaccinated with two peptides either in Montanide-ISA51 or on autologous dendritic cells (DCs). In stage D0, the Prostate-Specific Antigen (PSA) slope is prognostic of time to radiographic evidence of metastases and death. With no difference between arms, 74% of combined subjects had a decreased PSA slope at 1 year compared to their own baseline slopes (p = 0.0004). For patients vaccinated with DCs, response inversely correlated with a tolerogenic DC signature. A randomized placebo-controlled phase II trial is underway. (2) HER2 is a driver surface oncogene product expressed in multiple tumors. We made an adenoviral vector vaccine expressing the extracellular and transmembrane domains of HER2 and cured mice with large established HER2+ tumors, dependent on antibodies to HER2, not T cells. The mechanism differed from that of trastuzumab. We tested a human version in advanced metastatic cancer patients naïve to HER2-directed therapies. At the second and third dose levels, 45% of evaluable patients showed clinical benefit. Circulating tumor cells also declined in some vaccinated patients. Thus, cancer vaccines developed in mice were successfully translated to humans with promising early results.
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Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Neoplasias/inmunología , Neoplasias/terapia , Animales , Antígenos de Neoplasias/inmunología , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/inmunología , Vacunas contra el Cáncer/efectos adversos , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Antígenos HLA/inmunología , Humanos , Inmunoterapia/efectos adversos , Inmunoterapia/métodos , Ratones , Neoplasias/diagnóstico , Neoplasias/mortalidad , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Investigación Biomédica Traslacional , Resultado del TratamientoRESUMEN
Purpose: Despite the vast number of clinical trials conducted so far, dendritic cell (DC)-based cancer vaccines have mostly shown unsatisfactory results. Factors and manufacturing procedures essential for these therapeutics to induce effective antitumor immune responses have yet to be fully characterized. We here aimed to identify DC markers correlating with clinical and immunologic response in a prostate carcinoma vaccination regimen.Experimental Design: We performed an extensive characterization of DCs used to vaccinate 18 patients with prostate carcinoma enrolled in a pilot trial of T-cell receptor gamma alternate reading frame protein (TARP) peptide vaccination (NCT00908258). Peptide-pulsed DC preparations (114) manufactured were analyzed by gene expression profiling, cell surface marker expression and cytokine release secretion, and correlated with clinical and immunologic responses.Results: DCs showing lower expression of tolerogenic gene signature induced strong antigen-specific immune response and slowing in PSA velocity, a surrogate for clinical response. These DCs were also characterized by lower surface expression of CD14, secretion of IL10 and MCP-1, and greater secretion of MDC. When combined, these four factors were able to remarkably discriminate DCs that were sufficiently potent to induce strong immunologic response.Conclusions: DC factors essential for the activation of immune responses associated with TARP vaccination in prostate cancer patients were identified. This study highlights the importance of in-depth characterization of DC vaccines and other cellular therapies, to understand the critical factors that hinder potency and potential efficacy in patients. Clin Cancer Res; 23(13); 3352-64. ©2017 AACR.
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Vacunas contra el Cáncer/administración & dosificación , Células Dendríticas/inmunología , Proteínas Nucleares/inmunología , Neoplasias de la Próstata/terapia , Adolescente , Adulto , Anciano , Vacunas contra el Cáncer/inmunología , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Quimiocina CCL2/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Interleucina-10/genética , Receptores de Lipopolisacáridos/genética , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/patología , Resultado del TratamientoRESUMEN
The safety, tolerability, and pharmacokinetics of the liposomal formulation of amphotericin B (L-AMB) were evaluated in 40 immunocompromised children and adolescents. The protocol was an open-label, sequential-dose-escalation, multidose pharmacokinetic study with 10 to 13 patients in each of the four dosage cohorts. Each cohort received daily dosages of 2.5, 5.0, 7.5, or 10 mg of amphotericin B in the form of L-AMB per kg of body weight. Neutropenic patients between the ages of 1 and 17 years were enrolled to receive empirical antifungal therapy or treatment of documented invasive fungal infections. The pharmacokinetic parameters of L-AMB were measured as those of amphotericin B by high-performance liquid chromatography and calculated by noncompartmental methods. There were nine adverse-event-related discontinuations, four of which were related to infusions. Infusion-related side effects occurred for 63 (11%) of 565 infusions, with 5 patients experiencing acute infusion-related reactions (7.5- and 10-mg/kg dosage levels). Serum creatinine levels increased from 0.45 ± 0.04 mg/dl to 0.63 ± 0.06 mg/dl in the overall population (P = 0.003), with significant increases in dosage cohorts receiving 5.0 and 10 mg/kg/day. At the higher dosage level of 10 mg/kg, there was a trend toward greater hypokalemia and vomiting. The area under the concentration-time curve from 0 to 24 h (AUC0-24) values for L-AMB on day 1 increased from 54.7 ± 32.9 to 430 ± 566 µg · h/ml in patients receiving 2.5 and 10.0 mg/kg/day, respectively. These findings demonstrate that L-AMB can be administered to pediatric patients at dosages similar to those for adults and that azotemia may develop, especially in those receiving ≥5.0 mg/kg/day.
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Anfotericina B/efectos adversos , Anfotericina B/farmacocinética , Antifúngicos/efectos adversos , Antifúngicos/farmacocinética , Anfotericina B/administración & dosificación , Antifúngicos/administración & dosificación , Niño , Preescolar , Creatinina/sangre , Femenino , Humanos , Huésped Inmunocomprometido , Infusiones Intravenosas , Masculino , Neutropenia/tratamiento farmacológico , Neutropenia/microbiología , Resultado del Tratamiento , Vómitos/inducido químicamenteRESUMEN
Liposomal amphotericin B (LAmB) is widely used in the treatment of invasive fungal disease (IFD) in adults and children. There are relatively limited pharmacokinetic (PK) data to inform optimal dosing in children that achieves systemic drug exposures comparable to those of adults. Our objective was to describe the pharmacokinetics of LAmB in children aged 1 to 17 years with suspected or documented IFD. Thirty-five children were treated with LAmB at doses of 2.5 to 10 mg kg-1 daily. Samples were taken at baseline and at 0.5- to 2.0-h intervals for 24 h after receipt of the first dose (n = 35 patients) and on the final day of therapy (n = 25 patients). LAmB was measured using high-performance liquid chromatography (HPLC). The relationship between drug exposure and development of toxicity was explored. An evolution in PK was observed during the course of therapy, resulting in a proportion of patients (n = 13) having significantly higher maximum serum concentrations (Cmax) and areas under the concentration-time curve from 0 to 24 h (AUC0-24) later in the course of therapy, without evidence of drug accumulation (trough plasma concentration accumulation ratio of <1.2). The fit of a 2-compartment model incorporating weight and an exponential decay function describing volume of distribution best described the data. There was a statistically significant relationship between mean AUC0-24 and probability of nephrotoxicity (odds ratio, 2.37; 95% confidence interval, 1.84 to 3.22; P = 0.004). LAmB exhibits nonlinear pharmacokinetics. A third of children appear to experience a time-dependent change in PK, which is not explained by weight, maturation, or observed clinical factors.
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Anfotericina B/farmacocinética , Anfotericina B/uso terapéutico , Antifúngicos/farmacocinética , Antifúngicos/uso terapéutico , Huésped Inmunocomprometido , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Adolescente , Anfotericina B/efectos adversos , Antifúngicos/efectos adversos , Área Bajo la Curva , Niño , Preescolar , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Lactante , MasculinoRESUMEN
T-cell receptor alternate reading frame protein (TARP) is a 58-residue protein over-expressed in prostate and breast cancer. We investigated TARP peptide vaccination's impact on the rise in PSA (expressed as Slope Log(PSA) or PSA Doubling Time (PSADT)), validated tumor growth measures, and tumor growth rate in men with Stage D0 prostate cancer. HLA-A*0201 positive men were randomized to receive epitope-enhanced (29-37-9V) and wild-type (27-35) TARP peptides administered as a Montanide/GM-CSF peptide emulsion or as an autologous peptide-pulsed dendritic cell vaccine every 3 weeks for a total of five vaccinations with an optional 6th dose of vaccine at 36 weeks based on immune response or PSADT criteria with a booster dose of vaccine for all patients at 48 and 96 weeks. 41 patients enrolled with median on-study duration of 75 weeks at the time of this analysis. Seventy-two percent of patients reaching 24 weeks and 74% reaching 48 weeks had a decreased Slope Log(PSA) compared to their pre-vaccination baseline (p = 0.0012 and p = 0.0004 for comparison of overall changes in Slope Log(PSA), respectively). TARP vaccination also resulted in a 50% decrease in median tumor growth rate (g): pre-vaccine g = 0.0042/day, post-vaccine g = 0.0021/day (p = 0.003). 80% of subjects exhibited new vaccine-induced TARP-specific IFNγ ELISPOT responses but they did not correlate with decreases in Slope Log(PSA). Thus, vaccination with TARP peptides resulted in significant slowing in PSA velocity and reduction in tumor growth rate in a majority of patients with PSA biochemical recurrence.
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A high index of suspicion is needed when a patient presents with thyroid mass in the settings of an advanced CRC. Secondary thyroid malignancy should be considered unless proven otherwise. reatment should be determined considering extent of CRC metastasis, patient's general condition, and presence of local symptoms.
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UNLABELLED: This prospective pilot study evaluated the ability of Na(18)F PET/CT to detect and monitor bone metastases over time and its correlation with clinical outcomes and survival in advanced prostate cancer. METHODS: Sixty prostate cancer patients, including 30 with and 30 without known bone metastases by conventional imaging, underwent Na(18)F PET/CT at baseline, 6 mo, and 12 mo. Positive lesions were verified on follow-up scans. Changes in SUVs and lesion number were correlated with prostate-specific antigen change, clinical impression, and overall survival. RESULTS: Significant associations included the following: SUV and prostate-specific antigen percentage change at 6 mo (P = 0.014) and 12 mo (P = 0.0005); SUV maximal percentage change from baseline and clinical impression at 6 mo (P = 0.0147) and 6-12 mo (P = 0.0053); SUV change at 6 mo and overall survival (P = 0.018); number of lesions on Na(18)F PET/CT and clinical impression at baseline (P < 0.0001), 6 mo (P = 0.0078), and 12 mo (P = 0.0029); and number of lesions on Na(18)F PET/CT per patient at baseline and overall survival (P = 0.017). In an exploratory analysis, paired (99m)Tc-methylene diphosphonate bone scans ((99m)Tc-BS) were available for 35 patients at baseline, 19 at 6 mo, and 14 at 12 mo (68 scans). Malignant lesions on Na(18)F PET/CT (n = 57) were classified on (99m)Tc-BS as malignant 65% of the time, indeterminate 25% of the time, and negative 10% of the time. Additionally, 69% of paired scans showed more lesions on Na(18)F PET/CT than on (99m)Tc-BS. CONCLUSION: The baseline number of malignant lesions and changes in SUV on follow-up Na(18)F PET/CT significantly correlate with clinical impression and overall survival. Na(18)F PET/CT detects more bone metastases earlier than (99m)Tc-BS and enhances detection of new bone disease in high-risk patients.
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Radioisótopos de Flúor , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Fluoruro de Sodio , Adulto , Anciano de 80 o más Años , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios ProspectivosRESUMEN
Tumors persist by occupying immunosuppressive microenvironments that inhibit the activity of tumoricidal T and NK cells. Monocytic myeloid-derived suppressor cells (mMDSC) are an important component of this immunosuppressive milieu. We find that the suppressive activity of mMDSC isolated from cancer patients can be reversed by treatment with TLR7/8 agonists, which induce human mMDSC to differentiate into tumoricidal M1-like macrophages. In contrast, agonists targeting TLR1/2 cause mMDSC to mature into immunosuppressive M2-like macrophages. These two populations of macrophage are phenotypically and functionally discrete and differ in gene expression profile. The ability of TLR7/8 agonists to reverse mMDSC-mediated immune suppression suggests that they might be useful adjuncts for tumor immunotherapy.
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Diferenciación Celular/efectos de los fármacos , Imidazoles/farmacología , Tolerancia Inmunológica/efectos de los fármacos , Monocitos/citología , Monocitos/efectos de los fármacos , Células Mieloides/citología , Células Mieloides/efectos de los fármacos , Receptores Toll-Like/agonistas , Humanos , Tolerancia Inmunológica/inmunología , Monocitos/inmunología , Células Mieloides/inmunología , Relación Estructura-Actividad , Receptores Toll-Like/inmunologíaRESUMEN
INTRODUCTION: Peripheral blood mononuclear cells (PBMC) concentrates collected by apheresis are frequently used as starting material for cellular therapies, but the cell of interest must often be isolated prior to initiating manufacturing. STUDY DESIGN AND METHODS: The results of enriching 59 clinical PBMC concentrates for monocytes or lymphocytes from patients with solid tumors or multiple myeloma using a commercial closed system semi-automated counter-flow elutriation instrument (Elutra, Terumo BCT) were evaluated for quality and consistency. Elutriated monocytes (n = 35) were used to manufacture autologous dendritic cells and elutriated lymphocytes (n = 24) were used manufacture autologous T cell therapies. Elutriated monocytes with >10% neutrophils were subjected to density gradient sedimentation to reduce neutrophil contamination and elutriated lymphocytes to RBC lysis. RESULTS: Elutriation separated the PBMC concentrates into 5 fractions. Almost all of the lymphocytes, platelets and red cells were found in fractions 1 and 2; in contrast, most of the monocytes, 88.6 ± 43.0%, and neutrophils, 74.8 ± 64.3%, were in fraction 5. In addition, elutriation of 6 PBMCs resulted in relatively large quantities of monocytes in fractions 1 or 2. These 6 PBMCs contained greater quantities of monocytes than the other 53 PBMCs. Among fraction 5 isolates 38 of 59 contained >10% neutrophils. High neutrophil content of fraction 5 was associated with greater quantities of neutrophils in the PBMC concentrate. Following density gradient separation the neutrophil counts fell to 3.6 ± 3.4% (all products contained <10% neutrophils). Following red cell lysis of the elutriated lymphocyte fraction the lymphocyte recovery was 86.7 ± 24.0% and 34.3 ± 37.4% of red blood cells remained. CONCLUSIONS: Elutriation was consistent and effective for isolating monocytes and lymphocytes from PBMC concentrates for manufacturing clinical cell therapies, but further processing is often required.
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Tratamiento Basado en Trasplante de Células y Tejidos , Células Dendríticas , Monocitos , Linfocitos T , Separación Celular , Humanos , Masculino , Mieloma Múltiple/terapia , Neoplasias de la Próstata/terapiaRESUMEN
Cell-based immunotherapies are among the most promising approaches for developing effective and targeted immune response. However, their clinical usefulness and the evaluation of their efficacy rely heavily on complex quality control assessment. Therefore, rapid systematic methods are urgently needed for the in-depth characterization of relevant factors affecting newly developed cell product consistency and the identification of reliable markers for quality control. Using dendritic cells (DCs) as a model, we present a strategy to comprehensively characterize manufactured cellular products in order to define factors affecting their variability, quality and function. After generating clinical grade human monocyte-derived mature DCs (mDCs), we tested by gene expression profiling the degrees of product consistency related to the manufacturing process and variability due to intra- and interdonor factors, and how each factor affects single gene variation. Then, by calculating for each gene an index of variation we selected candidate markers for identity testing, and defined a set of genes that may be useful comparability and potency markers. Subsequently, we confirmed the observed gene index of variation in a larger clinical data set. In conclusion, using high-throughput technology we developed a method for the characterization of cellular therapies and the discovery of novel candidate quality assurance markers.
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Células Dendríticas/citología , Células Dendríticas/inmunología , Perfilación de la Expresión Génica/métodos , Inmunoterapia/métodos , Diferenciación Celular , Biología Computacional , Citometría de Flujo , Humanos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/inmunología , Análisis por Micromatrices , Monocitos/citología , Monocitos/inmunología , Control de CalidadRESUMEN
Little is known about the immunological and virological impact of diagnosis disclosure among HIV-positive children and adolescents. The current cross-sectional study examined medication hiding as a mediator of the relationship between disclosure to friends and three medical outcomes: CD4+ absolute count, CD4+ percentage, and viral load. Participants included 25 perinatally infected, HIV-positive children and adolescents ages 11-18 years from the US. Diagnosis disclosure and medication hiding were self-reported by participants and medical markers were derived from blood samples drawn during the same clinic visit. Bootstrapping analyses revealed that disclosure to at least one friend (versus no friends) was associated with less medication hiding, which was associated with higher CD4+ absolute counts and percentages but not viral load. Further, among the subset of participants who had disclosed to at least one friend (n = 19), those who reported disclosing to 11 or more versus 1-10 friends were less likely to hide medication taking, which was associated with higher CD4+ absolute counts. Findings suggest HIV-positive children and adolescents' diagnosis disclosure to friends corresponds to less medication hiding, ultimately yielding better immune functioning. Health care providers should be cognizant of these potential medical benefits associated with disclosure when offering support around disclosure decision-making.
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Infecciones por VIH/inmunología , Infecciones por VIH/psicología , Autorrevelación , Adolescente , Terapia Antirretroviral Altamente Activa/psicología , Recuento de Linfocito CD4 , Niño , Estudios Transversales , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Grupo Paritario , Autoinforme , Resultado del Tratamiento , Estados Unidos , Carga ViralRESUMEN
Cancers so much resemble self that they prove difficult for the immune system to eliminate, and those that have already escaped natural immunosurveillance have gotten past the natural immune barriers to malignancy. A successful therapeutic cancer vaccine must overcome these escape mechanisms. Our laboratory has focused on a multistep "push-pull" approach in which we combine strategies to overcome each of the mechanisms of escape. If tumor epitopes are insufficiently immunogenic, we increase their immunogenicity by epitope enhancement, improving their binding affinity to major histocompatibility complex (MHC) molecules. If the anti-tumor response is too weak or of the wrong phenotype, we use cytokines, costimulatory molecules, Toll-like receptor ligands, and other molecular adjuvants to increase not only the quantity of the response but also its quality, to push the response in the right direction. Finally, the tumor invokes multiple immunosuppressive mechanisms to defend itself, so we need to overcome those as well, including blocking or depleting regulatory cells or inhibiting regulatory molecules, to pull the response by removing the brakes. Some of these strategies individually have now been translated into human clinical trials in cancer patients. Combinations of these in a push-pull approach are promising for the successful immunotherapy of cancer.
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Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/farmacología , Factores Inmunológicos/farmacología , Neoplasias/inmunología , Escape del Tumor/efectos de los fármacos , Animales , Humanos , Factores Inmunológicos/inmunología , Neoplasias/tratamiento farmacológico , Escape del Tumor/inmunologíaRESUMEN
The focus of extensive research in the area of prostate cancer vaccines has led to the approval of the first therapeutic vaccine by the US FDA, sipuleucel-T. As our understanding of immunotherapy has increased, novel approaches have been investigated that have shown considerable promise. As the field has continued to evolve, questions have arisen regarding the potential role of immunotherapy: which populations of patients are most likely to benefit from immunotherapy and how and when should these therapies be administered? In addition, what are the best tools that can be used as surrogates to monitor immune responses to cancer vaccines that truly can give meaningful insight toward improving clinical outcomes? Finally, how can combination approaches be applied to prostate cancer vaccines in terms of both standard of care and experimental therapies? This review will address many of these important concepts with regard to prostate cancer vaccine therapy.
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Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/inmunología , Inmunoterapia Activa/métodos , Neoplasias de la Próstata/terapia , Biomarcadores , Humanos , Masculino , Resultado del TratamientoRESUMEN
This study sought to elucidate methodological issues in adherence research by comparing multiple methods of assessing adherence to antiretroviral medication. From 2003 to 2004, 24 youths with vertically infected HIV disease (mean age = 14.0 years; range, 8-18) and their caregivers participated in a 6-month study. These children were all on highly active antiretroviral therapy (HAART) and were relatively healthy (mean CD4 absolute count = 711.8 +/- 604.5). Adherence was assessed with the Medication Event Monitoring System (MEMS), pill counts, and interviews. Patients and caregivers completed the Perceptions of Adherence Study Participation (PASP) questionnaire. MEMS provided the most detailed adherence information, and good reliability was indicated by significant correlations with medical markers. Pill counts provided similar adherence rates, while patients and caregivers reported nearly perfect adherence in interviews. Problems were experienced with each method: MEMS were expensive, had cap malfunctions, and lack a consistent guiding principle for data interpretation. With pill counts, families forgot to bring all medication bottles to clinic, and interviews were compromised by social desirability and difficulty reaching families by telephone. Most patients and caregivers believed study participation improved the child's adherence, although PASP ratings were unrelated to adherence at the study endpoint. While MEMS may be most reliable, pill counts offer comparable data and are less costly, while interviews seemed least accurate in this study. Most participants reported positive perceptions of their research experience. A consensus among researchers is needed for defining and measuring adherence, and specific recommendations are offered for achieving this goal.
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Terapia Antirretroviral Altamente Activa , Monitoreo de Drogas/instrumentación , Infecciones por VIH/tratamiento farmacológico , Cooperación del Paciente/estadística & datos numéricos , Proyectos de Investigación , Adolescente , Cuidadores , Niño , Familia , Personal de Salud , Humanos , Entrevistas como Asunto , Padres , Encuestas y Cuestionarios , Estados UnidosRESUMEN
BACKGROUND: Individuals with HIV disease often must adhere to complex medication regimens. To date, regimen complexity has not been examined in the literature using standardized procedures incorporating all important elements of antiretroviral (ARV) regimens. OBJECTIVE: This article presents a novel method of quantifying regimen complexity using objective criteria addressing the factors that may complicate adherence to ARV regimens. METHODS: Part 1 of this article describes the development of the Antiretroviral Regimen Complexity (ARC) Index scoring system. Based on input from pediatric and adult patients, caregivers of pediatric patients, and health care professionals, this comprehensive system includes the number of medications, dosing schedules, administration methods, special instructions, and required preparations associated with ARV regimens. Weights are applied for each of these factors to produce an overall score representing the regimen's level of complexity. Part 2 of this article presents reliability and validity data for the system. RESULTS: The ARC Index demonstrates excellent test-retest and interrater reliability as well as strong construct and discriminant validity. An on-line version of this system minimizes computation errors. CONCLUSIONS: Although modifications may be necessary for patients requiring nonstandard dosing instructions, preliminary evidence supports the utility of this measure as a reliable and valid indicator of the complexity of antiretroviral treatment regimens.