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BACKGROUND: Mutant Ras oncogenes produce proteins that are unique to cancer cells and represent attractive targets for vaccine therapy. We have shown previously that vaccinating cancer patients with mutant ras peptides is feasible and capable of inducing a specific immune response against the relevant mutant proteins. Here, we tested the mutant ras peptide vaccine administered in combination with low dose interleukin-2 (IL-2) or/and granulocyte-macrophage colony-stimulating factor (GM-CSF) in order to enhance the vaccine immune response. METHODS: 5000 µg of the corresponding mutant ras peptide was given subcutaneously (SQ) along with IL-2 (Arm A), GM-CSF (Arm B) or both (Arm C). IL-2 was given SQ at 6.0 million IU/m²/day starting at day 5, 5 days/week for 2 weeks. GM-CSF was given SQ in a dose of 100 µg/day one day prior to each ras peptide vaccination for 4 days. Vaccines were repeated every 5 weeks on arm A and C, and every 4 weeks on arm B, for a maximum of 15 cycles or until disease progression. RESULTS: We treated 53 advanced cancer patients (38 with colorectal, 11 with pancreatic, 1 with common bile duct and 3 with lung) on 3 different arms (16 on arm A, 18 on arm B, and 19 on arm C). The median progression free survival (PFS) and overall survival (OS) was 3.6 and 16.9 months, respectively, for all patients evaluable for clinical response (n = 48). There was no difference in PFS or OS between the three arms (P = 0.73 and 0.99, respectively). Most adverse events were grade 1-2 toxicities and resolved spontaneously. The vaccine induced an immune response to the relevant ras peptide in a total of 20 out of 37 evaluable patients (54%) by ELISPOT, proliferative assay, or both. While 92.3% of patients on arm B had a positive immune response, only 31% of patients on arm A and 36% of patients on arm C had positive immune responses (P = 0.003, Fisher's exact test). CONCLUSIONS: The reported data showed that IL-2 might have a negative effect on the specific immune response induced by the relevant mutant ras vaccine in patients with advanced cancer. This observation deserves further investigations. TRIAL REGISTRATION: NCI97C0141.
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Vacunas contra el Cáncer/uso terapéutico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Interleucina-2/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Vacunas de Subunidad/uso terapéutico , Proteínas ras/genética , Adulto , Anciano , Secuencia de Aminoácidos , Vacunas contra el Cáncer/efectos adversos , Ensayo de Immunospot Ligado a Enzimas , Humanos , Inmunidad/inmunología , Persona de Mediana Edad , Datos de Secuencia Molecular , Neoplasias/prevención & control , Linfocitos T Reguladores/inmunología , Resultado del Tratamiento , Vacunas de Subunidad/efectos adversos , Vacunas de Subunidad/químicaRESUMEN
This study we examined ex vivo potential of the immune response after stimulation of whole blood with L. pneumophila SG 1, SG 2-14 and L. pneumophila standard strain ATCC 33152 in immunocompromised patients, such as: hemodialysis patients and patients after renal transplantation. The levels of TNF-α and IFN-γ in supernatants were measured with the use of commercial ELISA kits. The synthesis of TNF-α and IFN-γ after stimulation with L. pneumophila were analyzed in two aspects: differentiated stimulatory activity in relation to SG 1, SG 2-14 and ATCC 33152 L. pneumophila and differentiated response of the hemodialysis patients and patients after renal transplantation in relation to the control group. The positive and negative results of anti-L. pneumophila antibodies of two groups of our patients were found for the analysis of the stimulatory activity of L.pneumophila as a primary or secondary response. In patients with immunosuppression the response in the secretion of cytokines (TNF-α and IFN-γ) was reduced after stimulation of L. pneumophila SG 1 but in varying degrees after stimulation of L. pneumophila SG 2-14, which indicates that the risk of the infection is varied.
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Células Sanguíneas/inmunología , Inmunización/métodos , Huésped Inmunocomprometido/inmunología , Interferón gamma/metabolismo , Legionella pneumophila/inmunología , Diálisis Renal , Factor de Necrosis Tumoral alfa/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Células Cultivadas , Femenino , Humanos , Trasplante de Riñón , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: There is an unmet clinical need for interventions to prevent disease progression in patients with localized prostate cancer on active surveillance (AS). OBJECTIVE: To determine the immunologic response to the PROSTVAC vaccine and the clinical indicators of disease progression in patients with localized prostate cancer on AS. DESIGN, SETTING, AND PARTICIPANTS: This was a phase 2, double-blind, randomized controlled trial in 154 men with low- or intermediate-risk prostate cancer on AS. INTERVENTION: Participants were randomized (2:1) to receive seven doses of subcutaneous PROSTVAC, a vaccinia/fowlpox viral vector-based immunotherapy containing a prostate-specific antigen (PSA) transgene and three T-cell co-stimulatory molecules, or an empty fowlpox vector (EV) over 140 d. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the change from baseline in CD4 and CD8 T-cell infiltration in biopsy tumor tissue. Key secondary outcomes were safety and changes in prostate biopsy tumor pathology, peripheral antigen-specific T cells, and serum PSA. Continuous variables were compared using nonparametric tests. Categorical variables were compared using Fisher's exact test. RESULTS AND LIMITATIONS: The PROSTVAC/EV vaccination was well tolerated. All except one participant completed the vaccination series. Changes in CD4 or CD8 density in biopsy tumor tissue did not differ between the PROSTVAC and EV arms. The proportions of patients with Gleason upgrading to grade group 3 after treatment was similar between the arms. There were no differences in postvaccination peripheral T-cell responses or the PSA change from baseline to 6-mo post-treatment follow-up between the groups. CONCLUSIONS: In this first-of-kind trial of immunotherapy in patients on AS for prostate cancer, PROSTVAC did not elicit more favorable prostate tissue or peripheral T-cell responses than the EV. There was no difference between the arms in clinicopathologic effects. Despite the null findings, this is the first study reporting the feasibility and acceptability of an immunotherapy intervention in the AS setting. PATIENT SUMMARY: We looked at responses after an experimental prostate cancer vaccine in patients with prostate cancer on active surveillance (AS). Participants who received the vaccine did not show more favorable outcomes than those receiving the control. Despite these findings, this is the first report showing the feasibility and acceptability of immunotherapy for prostate cancer in patients on AS.
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Vacunas contra el Cáncer , Viruela Aviar , Neoplasias de la Próstata , Masculino , Animales , Humanos , Antígeno Prostático Específico , Espera Vigilante , Neoplasias de la Próstata/patología , Progresión de la EnfermedadRESUMEN
NeuVax is a vaccine comprised of the HER2-derived MHC class I peptide E75 (nelipepimut-S, NPS) combined with GM-CSF. We completed a randomized trial of preoperative vaccination with NeuVax versus GM-CSF alone in patients with ductal carcinoma in situ (DCIS). The primary objective was to evaluate for NPS-specific cytotoxic T lymphocyte (CTL) responses. Patients with human leukocyte antigen (HLA)-A2-positive DCIS were enrolled and randomized 2:1 to NeuVax versus GM-CSF alone and received two inoculations prior to surgery. The number of NPS-specific CTL was measured pre-vaccination, at surgery, and 1 and 3 to 6 months post-operation by dextramer assay. Differences in CTL responses between groups and between pre-vaccination and 1-month post-operation were analyzed using a two-sample t test or Wilcoxon rank sum test. The incidence and severity of adverse events were compared between groups. Overall, 45 patients were registered; 20 patients were HLA-A2 negative, 7 declined participation, 1 withdrew, and 4 failed screening for other reasons. The remaining 13 were randomized to NeuVax (n = 9) or GM-CSF alone (n = 4). Vaccination was well-tolerated with similar treatment-related toxicity between groups with the majority (>89%) of adverse events being grade 1. The percentage of NPS-specific CTLs increased in both arms between baseline (pre-vaccination) and 1-month post-operation. The increase was numerically greater in the NPS+GM-CSF arm, but the difference was not statistically significant. NPS+GM-CSF is safe and well-tolerated when given preoperatively to patients with DCIS. In patients with HLA-A2-positive DCIS, two inoculations with NPS+GM-CSF can induce in vivo immunity and a continued antigen-specific T-cell response 1-month postsurgery. PREVENTION RELEVANCE: This trial showed that vaccination of patients with HLA-A2-positive DCIS with NeuVax in the preoperative setting can induce a sustained antigen-specific T-cell response. This provides proof of principle that vaccination in the preoperative or adjuvant setting may stimulate an adaptive immune response that could potentially prevent disease recurrence.
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Vacunas contra el Cáncer , Carcinoma Intraductal no Infiltrante , Humanos , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Carcinoma Intraductal no Infiltrante/cirugía , Antígeno HLA-A2 , Recurrencia Local de Neoplasia/patología , Fragmentos de Péptidos , Vacunas de Subunidad/efectos adversos , Vacunas contra el Cáncer/efectos adversosRESUMEN
Consumption of cruciferous vegetables, rich in the isothiocyanate glucoraphanin, is associated with reduced risk of tobacco-related cancers. Sulforaphane, released by hydrolysis of glucoraphanin, potently induces cytoprotective phase II enzymes. Sulforaphane decreased the incidence of oral cancer in the 4NQO carcinogenesis model. In residents of Qidong, China, broccoli seed and sprout extracts (BSSE) increased detoxification of air pollutants benzene and acrolein, also found in tobacco smoke. This randomized, crossover trial evaluated detoxification of tobacco carcinogens by the BSSE Avmacol® in otherwise healthy smokers. Participants were treated for 2 weeks with both low and higher-dose BSSE (148 µmol vs. 296 µmol of glucoraphanin daily), separated by a 2-week washout, with randomization to low-high vs. high-low sequence. The primary endpoint was detoxification of benzene, measured by urinary excretion of its mercapturic acid, SPMA. Secondary endpoints included bioavailability, detoxification of acrolein and crotonaldehyde, modulation by GST genotype, and toxicity. Forty-nine participants enrolled, including 26 (53%) females with median use of 20 cigarettes/day. Low and higher-dose BSSE showed a mean bioavailability of 11% and 10%, respectively. Higher-dose BSSE significantly upregulated urinary excretion of the mercapturic acids of benzene (p = 0.04), acrolein (p < 0.01), and crotonaldehyde (p = 0.02), independent of GST genotype. Retention and compliance were high resulting in early study completion. In conclusion, BSSE significantly upregulated detoxification of the tobacco carcinogens benzene, acrolein, and crotonaldehyde in current tobacco smokers.
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The chemopreventive effect of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) on lung cancer risk is supported by epidemiologic and preclinical studies. Zileuton, a 5-lipoxygenase inhibitor, has additive activity with NSAIDs against tobacco carcinogenesis in preclinical models. We hypothesized that cyclooxygenase plus 5-lipoxygenase inhibition would be more effective than a placebo in modulating the nasal epithelium gene signatures of tobacco exposure and lung cancer. We conducted a randomized, double-blinded study of low-dose aspirin plus zileuton vs. double placebo in current smokers to compare the modulating effects on nasal gene expression and arachidonic acid metabolism. In total, 63 participants took aspirin 81 mg daily plus zileuton (Zyflo CR) 600 mg BID or the placebo for 12 weeks. Nasal brushes from the baseline, end-of-intervention, and one-week post intervention were profiled via microarray. Aspirin plus zilueton had minimal effects on the modulation of the nasal or bronchial gene expression signatures of smoking, lung cancer, and COPD but favorably modulated a bronchial gene expression signature of squamous dysplasia. Aspirin plus zileuton suppressed urinary leukotriene but not prostaglandin E2, suggesting shunting through the cyclooxygenase pathway when combined with 5-lipoxygenase inhibition. Continued investigation of leukotriene inhibitors is needed to confirm these findings, understand the long-term effects on the airway epithelium, and identify the safest, optimally dosed agents.
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Intravesical BCG is a highly effective treatment for high-grade nonmuscle invasive bladder cancer and carcinoma in situ (CIS); however, for patients who are either resistant or become unresponsive to BCG therapy there is a need for alternative treatment approaches. This study examined the safety and feasibility of intravesically administered recombinant fowlpox virus encoding GM-CSF (Arm A) or TRICOM (Arm B); and the local and systemic immunologic responses generated to the vector(s). Twenty bladder cancer patients scheduled for cystectomy as their standard of care received preoperatively four weekly doses of intravesical recombinant fowlpox. Treatment was well tolerated, however, three patients experienced transient elevations of liver transaminases, with one rising to the level of a DLT. Cystectomy derived tumor and normal bladder mucosa demonstrated mRNA for the virally encoded LacZ gene supporting effective infection/transfection. Detected serum antibody to the LacZ encoding ß-galactosidase indicated successful expression of vector-encoding gene products and the ability to immunize via the bladder site. H&E and IHC using a panel of immune cell specific antigens demonstrated immune cell infiltration of the bladder wall. These findings demonstrate good safety profile, successful infection/transfection, ability to generate systemic immune response, and local recruitment of immune cell populations with intravesical administration of fowlpox-based constructs encoding for GM-CSF(rF-GM-CSF) or TRICOM (rF-TRICOM), and support further evaluation of this treatment modality for bladder cancer.
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Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Vejiga Urinaria/fisiopatología , Administración Intravesical , Anciano , Animales , Relación Dosis-Respuesta a Droga , Virus de la Viruela de las Aves de Corral/genética , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/genética , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
A chemopreventive effect of aspirin (ASA) on lung cancer risk is supported by epidemiologic and preclinical studies. We conducted a randomized, double-blinded study in current heavy smokers to compare modulating effects of intermittent versus continuous low-dose ASA on nasal epithelium gene expression and arachidonic acid (ARA) metabolism. Fifty-four participants were randomized to intermittent (ASA 81 mg daily for one week/placebo for one week) or continuous (ASA 81 mg daily) for 12 weeks. Low-dose ASA suppressed urinary prostaglandin E2 metabolite (PGEM; change of -4.55 ± 11.52 from baseline 15.44 ± 13.79 ng/mg creatinine for arms combined, P = 0.02), a surrogate of COX-mediated ARA metabolism, but had minimal effects on nasal gene expression of nasal or bronchial gene-expression signatures associated with smoking, lung cancer, and chronic obstructive pulmonary disease. Suppression of urinary PGEM correlated with favorable changes in a smoking-associated gene signature (P < 0.01). Gene set enrichment analysis (GSEA) showed that ASA intervention led to 1,079 enriched gene sets from the Canonical Pathways within the Molecular Signatures Database. In conclusion, low-dose ASA had minimal effects on known carcinogenesis gene signatures in nasal epithelium of current smokers but results in wide-ranging genomic changes in the nasal epithelium, demonstrating utility of nasal brushings as a surrogate to measure gene-expression responses to chemoprevention. PGEM may serve as a marker for smoking-associated gene-expression changes and systemic inflammation. Future studies should focus on NSAIDs or agent combinations with broader inhibition of pro-inflammatory ARA metabolism to shift gene signatures in an anti-carcinogenic direction.
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Aspirina/farmacología , Biomarcadores/análisis , Regulación de la Expresión Génica/efectos de los fármacos , Inflamación/genética , Mucosa Nasal/metabolismo , Fumadores/estadística & datos numéricos , Fumar/genética , Antiinflamatorios no Esteroideos/farmacología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Estudios de Seguimiento , Perfilación de la Expresión Génica , Humanos , Inflamación/tratamiento farmacológico , Inflamación/epidemiología , Masculino , Persona de Mediana Edad , Mucosa Nasal/efectos de los fármacos , Pronóstico , Fumar/tratamiento farmacológico , Fumar/epidemiologíaRESUMEN
The aim of this work was to evaluate three currently available isolation methods for Legionella using water samples and swabs of a single pediatric hospital water system. Additionally, high risk patients were screened for the presence of Legionella pneumophila antigen in urine. Fifteen water samples and 11 swab samples were collected from distal sites at 18 sampling locations. The International Standard Method (PN-ISO11731-2) based on membrane filtration and direct culture of bacteria on selective media were compared with amoebic co-culture. The numbers of legionellae detected exceeded 10(2) cfu/100 ml in 50% of the samples. All the positive samples contained L. pneumophila SGs 2-14. Urine samples were obtained from 57 immunosuppressed children and screened for the presence of L. pneumophila serogroup (SG) 1 antigen by Legionella urinary antigen EIA. Of the 57 urine samples tested for the presence of Legionella pneumophila SG 1 antigen, none were positive. Our results highlight the value of combined membrane filtration and amoebic co-culture methods in detecting viable L. pneumophila strains. Direct plating of 0.2 ml water is a useful screening method for samples containing large bacterial amount.
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Recuento de Colonia Microbiana , Hospitales/normas , Legionella/aislamiento & purificación , Microbiología del Agua , Abastecimiento de Agua/análisis , Adolescente , Antígenos Bacterianos/orina , Técnicas de Cultivo de Célula , Niño , Preescolar , Recuento de Colonia Microbiana/instrumentación , Recuento de Colonia Microbiana/métodos , Recuento de Colonia Microbiana/normas , Femenino , Filtración , Humanos , Lactante , Recién Nacido , Legionella/inmunología , Masculino , Membranas Artificiales , Polonia , Medición de Riesgo , Sensibilidad y Especificidad , Abastecimiento de Agua/normasRESUMEN
The potential of the immune system to recognize and reject tumors has been investigated for more than a century. However, only recently impressive breakthroughs in cancer immunotherapy have been seen with the use of checkpoint inhibitors. The experience with various immune-based strategies in the treatment of late cancer highlighted the importance of negative impact advanced disease has on immunity. Consequently, use of immune modulation for cancer prevention rather than therapy has gained considerable attention, with many promising results seen already in preclinical and early clinical studies. Although not without challenges, these results provide much excitement and optimism that successful cancer immunoprevention could be within our reach. In this review we will discuss the current state of predominantly primary and secondary cancer immunoprevention, relevant research, potential barriers, and future directions.
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Antígenos de Neoplasias/inmunología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/prevención & control , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/prevención & control , Inmunoterapia , Neoplasias Pancreáticas/inmunología , Inmunidad Adaptativa , Animales , Autoantígenos/inmunología , Neoplasias Colorrectales/genética , Femenino , Mutación del Sistema de Lectura , Vacunas contra Hepatitis B/uso terapéutico , Humanos , Inmunidad Innata , Vigilancia Inmunológica , Lactalbúmina/inmunología , Mamoglobina A/inmunología , Vacunas contra Papillomavirus/uso terapéutico , Receptor ErbB-2/inmunología , Telomerasa/antagonistas & inhibidores , Telomerasa/inmunologíaRESUMEN
PURPOSE: The aim of the study was to evaluate antimicrobial properties of silicon oil in vitro against Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, which are considered the major causative agents of endophthalmitis. MATERIAL AND METHODS: The clinical isolates of representative microorganisms (S. aureus, P. aeruginosa, C. albicans) were selected. The bacteria and the fungus were separately inoculated in PDMS 5000 (produced by AcriMed, Germany). Control inoculations in physiological saline and sugar bouillon were performed. The samples of 0.01 ml from each medium were diluted, according to serial dilution procedure and inoculate on Petri plate dishes 5% sheep blood agar for bacteria and Sabouraud medium for Candida albicans. After 24 h incubations for bacteria and 48 h incubations for fungus, CFUs were counted. RESULTS: All the microorganisms revealed an apparent decrease in CFUs in PDMS 5000. The total elimination was observed for S. aureus after 5 days. For P. aerugisosa solitary colonies (less than 25 CFUs) were observed up to 7 days. After 7 days of incubation no growth of P. aeruginosa was observed. High C. albicans CFU values were counted up to 3 day of the incubation. After 5 days single fungal colonies were observed. CFUs of the examined microorganisms declined slightly in physiologic saline. A growth pattern similar to the growth curve of microorganisms was observed in sugar boullion. CONCLUSIONS: Our study indicates that silicon oil could have an antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, which are considered the major causative agents of postoperative endophthalmitis.