RESUMEN
OBJECTIVE: To investigate the efficacy and safety of hu3S193, a humanized anti-Lewis-Y monoclonal antibody, as a consolidation strategy in patients with platinum-sensitive recurrent epithelial ovarian cancer who achieved a second complete response after salvage platinum-doublet chemotherapy. METHODS: This single-arm phase II study accrued patients with recurrent epithelial ovarian cancer with Lewis-Y expression by immunohistochemistry who had achieved a second complete response after five to eight cycles of platinum-based chemotherapy. Patients received intravenous infusions of hu3S193, 30 mg/m2 every 2 weeks starting no more than 8 weeks after the last dose of chemotherapy and continuing for 12 doses, until disease progression, or unacceptable toxicity. The primary endpoint was progression-free survival of the second remission. Secondary objectives were safety and pharmacokinetics. RESULTS: Twenty-nine patients were enrolled. Most had a papillary/serous histology tumor (94%), stage III disease at diagnosis (75%), and five (17%) underwent secondary cytoreduction before salvage chemotherapy. Two patients were not eligible for efficacy but were considered for toxicity analysis. Eighteen patients (62%) completed the full consolidation treatment while nine patients progressed on treatment. At the time of analysis, 23 patients (85%) of the eligible population had progressed and seven of these patients (26%) had died. Median progression-free survival of the second remission was 12.1 months (95% CI: 10.6-13.9), with a 1-year progression-free survival of the second remission rate of 50.1%. The trial was terminated early since it was unlikely that the primary objective would be achieved. The most commonly reported treatment-related adverse events were nausea (55%) and vomiting (51%). CONCLUSIONS: Hu3S193 did not show sufficient clinical activity as consolidation therapy in patients with recurrent epithelial ovarian cancer who achieved a second complete response after platinum-based chemotherapy. TRIAL REGISTRATION: NCT01137071.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Quimioterapia de Consolidación/métodos , Inducción de Remisión/métodos , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/farmacología , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana EdadRESUMEN
College students' use of digital communication technology has led to a rapid expansion of digital alcohol marketing efforts. Two surveys (total usable n = 637) were conducted to explore college students' experiences with alcohol-related social media, their decision making related to alcohol use, and their problematic drinking behaviors. Study results indicated that students' use of alcohol-related social media predicted their problem drinking behaviors. In addition, students' wishful identification, perceived desirability, perceived similarity, and normative beliefs predicted their expectancies for drinking alcohol. Finally, students' expectancies for drinking alcohol predicted their problematic drinking behaviors.
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Consumo de Alcohol en la Universidad/psicología , Alcoholismo/epidemiología , Toma de Decisiones , Medios de Comunicación Sociales/estadística & datos numéricos , Estudiantes/psicología , Femenino , Humanos , Masculino , Mercadotecnía , Normas Sociales , Universidades , Adulto JovenRESUMEN
OBJECTIVES: The primary objective was to evaluate the clinical efficacy of hu3S193, a humanized monoclonal antibody against the Lewis-Y antigen, in patients with platinum resistant/refractory ovarian, fallopian tube and primary peritoneal carcinoma. Secondary objectives were safety and pharmacokinetics. In addition, we sought to determine the potential interaction of clinical benefit and patient characteristics. METHODS: This two-stage, multicenter, single arm, phase II trial enrolled eligible patients to receive hu3S193 weekly at a dose of 20mg/m(2) intravenously for 8 weeks (1 cycle) to a maximum of 3 cycles. Efficacy was measured as clinical benefit rate (objective response or stable disease for at least 24 weeks). RESULTS: 26 of 31 patients were eligible for efficacy analysis. No complete/partial responses were observed. Six patients had stable disease for 24+weeks [clinical benefit rate 23% (95% CI=9.77%-46.71%)]. Median PFS was 8.4 weeks (95% CI=6.0 to 16.1). Median PFS differed between patients with no ascites and no visceral disease and patients with ascites and/or visceral disease [16.1 vs. 8.1 weeks (p=0.0058)]. The most commonly reported treatment-related adverse events were fatigue (19.3%) and nausea (16.2%). Allergic reactions occurred in 6 patients (5 with Grade 1/2; 1 with Grade 3). CONCLUSIONS: Hu3S193 lacked sufficient activity in the first stage of the study to open enrollment to the second stage. However, based on the longer PFS in patients with no ascites and no visceral disease, consolidation strategies in platinum sensitive disease are currently being tested.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Neoplasias de las Trompas Uterinas/terapia , Neoplasias Glandulares y Epiteliales/terapia , Neoplasias Ováricas/terapia , Neoplasias Peritoneales/terapia , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Monoclonales Humanizados/farmacocinética , Carcinoma Epitelial de Ovario , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos , Neoplasias de las Trompas Uterinas/inmunología , Neoplasias de las Trompas Uterinas/metabolismo , Femenino , Humanos , Antígenos del Grupo Sanguíneo de Lewis/inmunología , Persona de Mediana Edad , Neoplasias Glandulares y Epiteliales/inmunología , Neoplasias Glandulares y Epiteliales/metabolismo , Compuestos Organoplatinos/farmacología , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/metabolismo , Neoplasias Peritoneales/inmunología , Neoplasias Peritoneales/metabolismo , Adulto JovenRESUMEN
OBJECTIVE: Alcohol marketers have increasingly moved their advertising efforts into digital and social media venues. As a result, the purpose of this study is to investigate associations between students' use of social media, their exposure to alcohol marketing messages through social media, and their alcohol-related beliefs and behaviors. PARTICIPANTS: Public and private university students (N = 637) participated November and December 2011 and April 2012. METHODS: College students completed online surveys to measure their exposure to social and online media generally, as well as their alcohol-related digital media use and alcohol use. RESULTS: Use of social media related to alcohol marketing predicted alcohol consumption and engaging in risky behaviors, whereas the use of social media more generally did not. CONCLUSIONS: Students' use of alcohol-related social media-marketing content associates with their problem drinking. Results have implications for alcohol abuse reduction efforts targeted at college students and suggest the importance of considering social, cultural, and cognitive factors in campaign planning and design.
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Consumo de Bebidas Alcohólicas/psicología , Trastornos Relacionados con Alcohol/prevención & control , Conductas Relacionadas con la Salud , Medios de Comunicación Sociales/estadística & datos numéricos , Estudiantes/psicología , Consumo de Bebidas Alcohólicas/epidemiología , Consumo de Bebidas Alcohólicas/prevención & control , Trastornos Relacionados con Alcohol/epidemiología , Trastornos Relacionados con Alcohol/psicología , Estudios Transversales , Femenino , Promoción de la Salud , Humanos , Masculino , Evaluación de Necesidades , Medición de Riesgo , Asunción de Riesgos , Mercadeo Social , Estudiantes/estadística & datos numéricos , Encuestas y Cuestionarios , Estados Unidos , Universidades , Adulto JovenRESUMEN
Background Arginine deiminase (ADI) is an enzyme that degrades arginine, an amino acid that is important for growth and development of normal and neoplastic cells. Melanoma cells are auxotrophic for arginine, because they lack argininosuccinatesynthetase (ASS), a key enzyme required for the synthesis of arginine. Patients and methods Patients with advanced melanoma were treated with 40, 80 or 160 IU/m(2) ADI-PEG 20 i.m. weekly. Primary endpoints were toxicity and tumor response, secondary endpoints included metabolic response by (18)FDG-PET, pharmacodynamic (PD) effects upon circulating arginine levels, and argininosuccinate synthetase tumor expression by immunohistochemistry. Results 31 previously treated patients were enrolled. The main toxicities were grade 1 and 2 adverse events including injection site pain, rash, and fatigue. No objective responses were seen. Nine patients achieved stable disease (SD), with 2 of these durable for >6 months. Four of the 9 patients with SD had uveal melanoma. PD analysis showed complete plasma arginine depletion in 30/31 patients by day 8. Mean plasma levels of ADI-PEG 20 correlated inversely with ADI-PEG 20 antibody levels. Immunohistochemical ASS expression analysis in tumor tissue was negative in 24 patients, whereas 5 patients had <5 % cells positive. Conclusions ADI-PEG 20 is well tolerated in advanced melanoma patients and leads to consistent, but transient, arginine depletion. Although no RECIST responses were observed, the encouraging rate of SD in uveal melanoma patients indicates that it may be worthwhile to evaluate ADI-PEG 20 in this melanoma subgroup.
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Hidrolasas/uso terapéutico , Melanoma/tratamiento farmacológico , Polietilenglicoles/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias de la Úvea/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Hidrolasas/farmacocinética , Técnicas para Inmunoenzimas , Masculino , Dosis Máxima Tolerada , Melanoma/metabolismo , Melanoma/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Polietilenglicoles/farmacocinética , Pronóstico , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/secundario , Tasa de Supervivencia , Distribución Tisular , Neoplasias de la Úvea/metabolismo , Neoplasias de la Úvea/secundarioRESUMEN
PURPOSE: Long peptides are efficiently presented to both CD4(+) and CD8(+) T cells after intracellular processing by antigen-presenting cells. To investigate the safety and in vivo immunogenicity of synthetic overlapping long peptides (OLP) from a human tumor self-antigen, we conducted a phase I clinical trial with OLP from cancer-testis antigen NY-ESO-1 in various adjuvant combinations. EXPERIMENTAL DESIGN: Twenty-eight patients with advanced ovarian cancer in second or third remission were enrolled sequentially in three cohorts and received at least one vaccination. Patients in Cohort 1 (n = 4) received 1.0 mg OLP, Cohort 2 (n = 13) received OLP in Montanide-ISA-51, and Cohort 3 (n = 11) received OLP + 1.4 mg Poly-ICLC in Montanide-ISA-51 on weeks 1, 4, 7, 10, and 13. Humoral and cellular responses were evaluated by standardized immunomonitoring techniques (ELISA, ELISPOT assay, intracellular cytokine staining, and tetramer staining). RESULTS: The vaccine was generally well tolerated with injection site reactions and fatigue that resolved. NY-ESO-1-specific antibody and CD8(+) T cells were undetectable after vaccination with OLP alone, but were found in 6 of 13 (46%) and 8 of 13 (62%) patients, respectively, after vaccination with OLP+Montanide, and in 10 of 11 (91%) and 10 of 11 (91%) patients, respectively, after vaccination with OLP+Montanide+Poly-ICLC. NY-ESO-1-specific CD4(+) T cells were detected in all patients with greater frequency and polyclonality when Montanide-ISA-51 was used for vaccination. Inclusion of Poly-ICLC as an adjuvant further accelerated the induction of NY-ESO-1-specific immune responses. CONCLUSIONS: The current study shows that NY-ESO-1 OLP vaccine is safe and rapidly induces consistent integrated immune responses (antibody, CD8(+) and CD4(+)) in nearly all vaccinated patients when given with appropriate adjuvants.
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Antígenos de Neoplasias/inmunología , Autoantígenos/inmunología , Vacunas contra el Cáncer/inmunología , Carboximetilcelulosa de Sodio/análogos & derivados , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/terapia , Péptidos/inmunología , Poli I-C/inmunología , Polilisina/análogos & derivados , Adulto , Anciano , Anticuerpos/inmunología , Antígenos de Neoplasias/química , Autoantígenos/química , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/efectos adversos , Femenino , Estudios de Seguimiento , Humanos , Inmunidad Humoral , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Polilisina/inmunología , Linfocitos T Reguladores/inmunología , Resultado del Tratamiento , Vacunas de Subunidad/administración & dosificación , Vacunas de Subunidad/efectos adversos , Vacunas de Subunidad/inmunologíaRESUMEN
BACKGROUND: NY-ESO-1 protein formulated in ISCOMATRIX™ results in CD4+, CD8+ T cell and antibody-mediated immunity. We evaluated persistence of immunity, relapse-free survival and tumour antigen expression upon relapse in patients vaccinated in an earlier trial. METHODS: Immunity was measured in 28 patients with resected NY-ESO-1-expressing tumours (melanoma 25, breast 3) 252-1,155 days (median = 681) after vaccination. In the earlier vaccination, trial patients received NY-ESO-1 with ISCOMATRIX™ adjuvant at three protein doses 10 µg, 30 µg or 100 µg (n = 14); 100 µg NY-ESO-1 protein (n = 8) or placebo (n = 6), together with 1 µg of intradermal (ID) NY-ESO-1 protein twice for DTH skin testing. Immune responses assessed in the current study included antibody titres, circulating NY-ESO-1-specific T cells and DTH reactivity 2 days after DTH skin testing with NY-ESO-1 protein (1 µg) or peptides (10 µg). Relapse-free survival was determined for 42 melanoma patients. On relapse NY-ESO-1 and HLA, class I was assessed by immunohistochemistry in 17. RESULTS: Persisting anti-NY-ESO-1 immunity was detected in 10/14 recipients who had previously received vaccine with ISCOMATRIX™ adjuvant. In contrast, immunity only persisted in 3/14 who received 100 µg un-adjuvanted NY-ESO-1 protein (3/8) or 2 µg DTH protein (0/6) P = 0.02. Hence, persisting NY-ESO-1 immunity was associated with prior adjuvant. Tumour NY-ESO-1 or HLA class I was downregulated in participants who relapsed suggesting immunoediting had occurred. CONCLUSION: Immunoediting suggests that a signal of anti-tumour activity was observed in high-risk resected melanoma patients vaccinated with NY-ESO-1/ISCOMATRIX™. This was associated with measurable persisting immunity in the majority of vaccinated subjects tested. A prospective randomised trial has been undertaken to confirm these results.
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Antígenos de Neoplasias/administración & dosificación , Neoplasias de la Mama/terapia , Vacunas contra el Cáncer/administración & dosificación , Colesterol/administración & dosificación , Melanoma/terapia , Proteínas de la Membrana/administración & dosificación , Fosfolípidos/administración & dosificación , Saponinas/administración & dosificación , Adyuvantes Inmunológicos/administración & dosificación , Adulto , Anciano , Secuencia de Aminoácidos , Antígenos de Neoplasias/biosíntesis , Antígenos de Neoplasias/inmunología , Neoplasias de la Mama/inmunología , Vacunas contra el Cáncer/inmunología , Colesterol/inmunología , Supervivencia sin Enfermedad , Regulación hacia Abajo , Combinación de Medicamentos , Hipersensibilidad a las Drogas/etiología , Hipersensibilidad a las Drogas/inmunología , Femenino , Humanos , Inmunohistoquímica , Masculino , Melanoma/inmunología , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/inmunología , Persona de Mediana Edad , Datos de Secuencia Molecular , Fosfolípidos/inmunología , Estudios Prospectivos , Saponinas/inmunología , Piel/inmunologíaRESUMEN
We conducted a phase I clinical trial of a cancer vaccine using a 20-mer NY-ESO-1f peptide (NY-ESO-1 91-110) that includes multiple epitopes recognized by antibodies, and CD4 and CD8 T cells. Ten patients were immunized with 600 µg of NY-ESO-1f peptide mixed with 0.2 KE Picibanil OK-432 and 1.25 ml Montanide ISA-51. Primary end points of the study were safety and immune response. Subcutaneous injection of the NY-ESO-1f peptide vaccine was well tolerated. Vaccine-related adverse events observed were fever (Grade 1), injection-site reaction (Grade 1 or 2) and induration (Grade 2). Vaccination with the NY-ESO-1f peptide resulted in an increase or induction of NY-ESO-1 antibody responses in nine of ten patients. The sera reacted with recombinant NY-ESO-1 whole protein as well as the NY-ESO-1f peptide. An increase in CD4 and CD8 T cell responses was observed in nine of ten patients. Vaccine-induced CD4 and CD8 T cells responded to NY-ESO-1 91-108 in all patients with various HLA types with a less frequent response to neighboring peptides. The findings indicate that the 20-mer NY-ESO-1f peptide includes multiple epitopes recognized by CD4 and CD8 T cells with distinct specificity. Of ten patients, two with lung cancer and one with esophageal cancer showed stable disease. Our study shows that the NY-ESO-1f peptide vaccine was well tolerated and elicited humoral, CD4 and CD8 T cell responses in immunized patients.
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Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/uso terapéutico , Manitol/análogos & derivados , Proteínas de la Membrana/inmunología , Neoplasias/terapia , Ácidos Oléicos/inmunología , Fragmentos de Péptidos/inmunología , Vacunas de Subunidad/uso terapéutico , Adulto , Anciano , Antígenos/biosíntesis , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/inmunología , Femenino , Humanos , Inmunidad Humoral , Masculino , Manitol/inmunología , Persona de Mediana Edad , Neoplasias/inmunología , Picibanil/inmunología , Resultado del TratamientoRESUMEN
PURPOSE: NY-ESO-1 is a highly immunogenic antigen expressed in a variety of malignancies, making it an excellent target for cancer vaccination. We recently developed a vaccine consisting of full-length recombinant NY-ESO-1 protein formulated with ISCOMATRIX adjuvant, which generated strong humoral and T-cell-mediated immune responses and seemed to reduce the risk of disease relapse in patients with fully resected melanoma. This study examines the clinical and immunologic efficacy of the same vaccine in patients with advanced metastatic melanoma. EXPERIMENTAL DESIGN: Delayed-type hypersensitivity responses, circulating NY-ESO-1-specific CD4(+) and CD8(+) T cells, and proportions of regulatory T cells (Treg) were assessed in patients. RESULTS: In contrast to patients with minimal residual disease, advanced melanoma patients showed no clinical responses to vaccination. Although strong antibody responses were mounted, the generation of delayed-type hypersensitivity responses was significantly impaired. The proportion of patients with circulating NY-ESO-1-specific CD4(+) T cells was also reduced, and although many patients had CD8(+) T cells specific to a broad range of NY-ESO-1 epitopes, the majority of these responses were preexisting. Tregs were enumerated in the blood by flow cytometric detection of cells with a CD4(+)CD25(+)FoxP3(+) and CD4(+)CD25(+)CD127(-) phenotype. Patients with advanced melanoma had a significantly higher proportion of circulating Treg compared with those with minimal residual disease. CONCLUSIONS: Our results point to a tumor-induced systemic immune suppression, showing a clear association between the stage of melanoma progression, the number of Treg in the blood, and the clinical and immunologic efficacy of the NY-ESO-1 ISCOMATRIX cancer vaccine.
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Adyuvantes Inmunológicos/administración & dosificación , Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/inmunología , Colesterol/administración & dosificación , Melanoma/terapia , Proteínas de la Membrana/inmunología , Fosfolípidos/administración & dosificación , Saponinas/administración & dosificación , Linfocitos T Reguladores/fisiología , Linfocitos T/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Antígenos de Neoplasias/administración & dosificación , Vacunas contra el Cáncer/administración & dosificación , Combinación de Medicamentos , Femenino , Humanos , Hipersensibilidad Tardía/etiología , Masculino , Proteínas de la Membrana/administración & dosificación , Persona de Mediana Edad , VacunaciónRESUMEN
NY-ESO-1 antigen is a prototype of a class of cancer/testis antigens. We carried out a clinical trial using NY-ESO-1 whole protein as a cancer vaccine for 13 advanced cancer patients. We have recently reported that vaccine elicited humoral and cellular immune responses in 9 cancer patients including 4 esophageal cancer patients, and clinical responses were also observed in 4 of 5 evaluable patients. In this study, we analyzed the responses in 8 esophageal cancer patients including 4 newly enrolled patients. Patients were injected subcutaneously at biweekly intervals with NY-ESO-1 recombinant protein formulated with cholesterol-bearing hydrophobized pullulan. Induction of antibody, and CD4 and CD8 T-cell responses were observed in 7, 7 and 6 patients, respectively, out of 8 patients. 1 PR, 2 SD and 2 mixed clinical responses were observed in 6 evaluable patients. No significant adverse events were observed. Furthermore, we analyzed NY-ESO-1 and MHC class I expression and the infiltration of immune cells into tumor samples obtained before and after vaccination from 4 patients by immunohistochemistry. The results showed 2 patients with disappearance of CD4 and CD8 T-cell infiltration, 1 patient with increase in the number of CD68(+) macrophages and 1 patient with tumor antigen loss in the progressive tumors following vaccinations. The induction of NY-ESO-1 immunity and some preferable clinical outcomes were observed in esophageal cancer patients by vaccination with NY-ESO-1. However, the tumors grew eventually by various mechanisms after vaccination.
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Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/uso terapéutico , Neoplasias Esofágicas/inmunología , Proteínas de la Membrana/inmunología , Anciano , Vacunas contra el Cáncer/administración & dosificación , Neoplasias Esofágicas/terapia , Femenino , Humanos , Inmunidad Celular , Inmunohistoquímica , Masculino , Persona de Mediana EdadRESUMEN
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.
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Adyuvantes Inmunológicos/farmacología , Aminoquinolinas/farmacología , Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/inmunología , Inmunización , Melanoma/inmunología , Proteínas de la Membrana/inmunología , Receptor Toll-Like 7/agonistas , Adyuvantes Inmunológicos/efectos adversos , Adulto , Anciano , Aminoquinolinas/efectos adversos , Formación de Anticuerpos/inmunología , Biopsia , Vacunas contra el Cáncer/efectos adversos , Mapeo Epitopo , Eritema/inducido químicamente , Eritema/inmunología , Eritema/patología , Femenino , Humanos , Imiquimod , Masculino , Melanoma/metabolismo , Melanoma/patología , Melanoma/terapia , Persona de Mediana Edad , Proyectos Piloto , Receptor Toll-Like 7/metabolismoRESUMEN
BACKGROUND: NY-ESO-1 is a cancer/testis antigen highly immunogenic in cancer patients. Cholesterol-bearing hydrophobized pullulan (CHP) is a nanoparticle-forming antigen-delivery vehicle and CHP complexed with NY-ESO-1 protein (CHP-NY-ESO-1) efficiently activates CD4 and CD8 T cells in vitro. AIM: In this study we report on a 50-year-old male melanoma patient with multiple skin and organ metastases (T4N3M1c) who was vaccinated with CHP-NY-ESO-1 at biweekly intervals and who had an unusual disease course. We characterized in this patient humoral and cellular immune responses, immune regulatory cells, and cytokine profiles in the peripheral blood and at local tumor sites. RESULTS: Ten days after the second CHP-NY-ESO-1 vaccination (day 25), blisters appeared on the skin at the metastatic lesions associated with inflammatory changes. A skin biopsy showed the presence of many NY-ESO-1-expressing apoptotic melanoma cells as determined by a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) test. However, the tumors continued to grow, and the patient died of pulmonary failure due to multiple metastases on day 48. Serum antibody responses were detected after the second CHP-NY-ESO-1 vaccination and antibody titer increased with subsequent vaccinations. Th1 dependent IgG1 was the predominant immunoglobulin subtype. Both, NY-ESO-1-specific CD4 and CD8 T cell responses were detected in PBMC by IFN-gamma secretion assays. After CHP-NY-ESO-1 vaccination a slight decrease in CD4(+)CD25(+)Foxp3(+) Tregs was observed in PBMC but significantly increased numbers of CD4(+)CD25(+)Foxp3(+) Tregs and CD68(+) immunoregulatory macrophages were detected at the local tumor sites. CD4(+)CD25(+)Foxp3(+) Tregs were also increased in the blister fluid. Cytokines in the serum suggested a polarization towards a Th1 pattern in the PBMC and those in the blister fluid suggested a Th2-type response at the tumor site. CONCLUSIONS: Our observations indicate induction of specific humoral and cellular immune responses against NY-ESO-1 after CHP-NY-ESO-1 vaccination in a melanoma patient. The concomitant appearance of regulatory T cells and of immune regulatory macrophages and cytokines at the local tumor sites in this patient may explain immune escape.
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Antígenos de Neoplasias/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Glucanos/uso terapéutico , Melanoma/terapia , Proteínas de la Membrana/uso terapéutico , Neoplasias Cutáneas/terapia , Anticuerpos Antineoplásicos/sangre , Antígenos de Neoplasias/inmunología , Apoptosis , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Citocinas/análisis , Citocinas/inmunología , Técnica del Anticuerpo Fluorescente , Glucanos/inmunología , Humanos , Inmunoglobulina G/sangre , Etiquetado Corte-Fin in Situ , Macrófagos/inmunología , Masculino , Melanoma/inmunología , Melanoma/patología , Proteínas de la Membrana/inmunología , Persona de Mediana Edad , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Subgrupos de Linfocitos T/inmunologíaRESUMEN
We previously reported results of a phase II trial in which recombinant MAGE-A3 protein was administered with or without adjuvant AS02B to 18 non-small-cell lung cancer (NSCLC) patients after tumor resection. We found that the presence of adjuvant was essential for the development of humoral and cellular responses against selected MAGE-A3 epitopes. In our current study, 14 patients that still had no evidence of disease up to 3 years after vaccination with MAGE-A3 protein with or without adjuvant received an additional four doses of MAGE-A3 protein with adjuvant AS02B. After just one boost injection, six of seven patients originally vaccinated with MAGE-A3 protein plus adjuvant reached again their peak antibody titers against MAGE-A3 attained during the first vaccination. All seven patients subsequently developed even stronger antibody responses. Furthermore, booster vaccination widened the spectrum of CD4(+) and CD8(+) T cells against various new and known MAGE-A3 epitopes. In contrast, only two of seven patients originally vaccinated with MAGE-A3 protein alone developed high-titer antibodies to MAGE-A3, and all these patients showed very limited CD4(+) and no CD8(+) T cell reactivity, despite now receiving antigen in the presence of adjuvant. Our results underscore the importance of appropriate antigen priming using an adjuvant for generating persistent B and T cell memory and allowing typical booster responses with reimmunization. In contrast, absence of adjuvant at priming compromises further immunization attempts. These data provide an immunological rationale for vaccine design in light of recently reported favorable clinical responses in NSCLC patients after vaccination with MAGE-A3 protein plus adjuvant AS02B.
Asunto(s)
Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/inmunología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Inmunización Secundaria , Neoplasias Pulmonares/terapia , Proteínas de Neoplasias/inmunología , Vacunación , Anticuerpos Antineoplásicos/sangre , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Mapeo Epitopo , Femenino , Humanos , Tolerancia Inmunológica , Masculino , Linfocitos T/inmunologíaRESUMEN
The CHP-HER2 vaccine, comprising truncated 146HER2 protein complexed with nanogels of cholesteryl pullulan (CHP), is a novel protein antigen vaccine that elicits 146HER2-specific CD8(+) and CD4(+) T-cell immune responses in patients with HER2-expressing tumors. We analyzed the humoral responses in patients vaccinated with CHP-HER2 and those with CHP-HER2 plus granulocyte-macrophage colony-stimulating factor (GM-CSF). The vaccine was injected subcutaneously at a dose of 300 microg protein. Nine patients received the vaccine alone over the first four injections, followed by CHP-HER2 with GM-CSF or OK-432, whereas six received CHP-HER2 plus GM-CSF from the first cycle. 146HER2-specific IgG antibodies were induced in 14 patients, who were negative at baseline. The antibodies became detectable after the second or third vaccination and reached plateau levels after the third or fourth cycle in patients vaccinated with CHP-HER2 plus GM-CSF. In contrast, the antibodies appeared only after the third to sixth vaccination and the plateau appeared after the fourth to eighth cycle in patients vaccinated with the CHP-HER2 vaccine alone over the first four cycles. The antibodies induced by the vaccine were not reactive with HER2 antigen expressed on the cell surface in any of the patients. Epitope analysis using overlapping peptides revealed a single region in the 146HER2 protein, amino acids 127-146, in eight patients who were initially vaccinated with CHP-HER2 alone. Similarly, the same HER2 region was recognized dominantly in patients vaccinated with GM-CSF. Our results indicate that CHP-HER2 induced HER2-specific humoral responses in patients with HER2-expressing tumors and that GM-CSF seems to accelerate the responses.
Asunto(s)
Anticuerpos Antineoplásicos/sangre , Vacunas contra el Cáncer/inmunología , Receptor ErbB-2/inmunología , Adulto , Anciano , Vacunas contra el Cáncer/química , Vacunas contra el Cáncer/uso terapéutico , Línea Celular Tumoral , Ensayo de Inmunoadsorción Enzimática , Epítopos/química , Femenino , Citometría de Flujo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Receptor ErbB-2/química , Proteínas Recombinantes/metabolismoRESUMEN
The chimeric monoclonal antibody cG250 recognises the G250/CAIX/MN antigen found on 95% of clear cell renal cell carcinomas (RCCs). We performed a phase I clinical trial to evaluate the safety, blood pharmacokinetics (PK), and biodistribution of repeated doses of cG250. The primary endpoint was toxicity. Secondary endpoints were cG250 biodistribution and PK; measurement of human anti-chimeric-antibodies (HACA); and tumour response rates. Eligible patients had unresectable or metastatic clear cell RCC. Doses of 5, 10, 25, or 50 mg/m(2) were given weekly by intravenous infusion for six weeks. Three patients were treated at each dose level. Trace (131)I-labelled cG250 was administered on weeks 1 and 5. Thirteen patients participated and were evaluable. One patient developed brain metastases and was replaced. No grade 3 or 4 toxicities and no dose-limiting toxicity occurred. One patient died due to progressive disease within 30 days of receiving the study drug. One patient developed HACA during the second six-week cycle. PK analysis showed mean whole body and blood alpha and beta half-lives of cG250 of 18.99 +/- 6.84 and 180.19 +/- 86.68 hours, respectively. All patients had cG250 tumour localization by gamma camera imaging in week 1 and 5. One patient had a complete response, nine patients had stable disease, and three had progressive disease. One patient received 11 six-week cycles of treatment with no toxicity or HACA. In conclusion, repeated intravenous doses of up to 50 mg/m(2) of cG250 are safe. Furthermore cG250 has a long half-life and targets clear cell RCC effectively.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Antígenos de Neoplasias/inmunología , Anhidrasas Carbónicas/inmunología , Carcinoma de Células Renales/terapia , Neoplasias Renales/terapia , Anciano , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Anhidrasa Carbónica IX , Carcinoma de Células Renales/diagnóstico por imagen , Carcinoma de Células Renales/inmunología , Femenino , Humanos , Neoplasias Renales/diagnóstico por imagen , Neoplasias Renales/inmunología , Masculino , Persona de Mediana Edad , Cintigrafía , Distribución TisularRESUMEN
The chimeric monoclonal antibody cG250 recognizes the CAIX/MN antigen. cG250 induces antibody-dependent cellular cytotoxicity (ADCC) responses in vitro that can be enhanced by IL-2. We studied the effects of adding daily low-dose subcutaneous IL-2 to cG250 for treatment of clear cell renal cell carcinoma (RCC). The primary endpoints of the trial were toxicity and immunological effects (human anti-chimeric antibodies [HACA], ADCC, natural killer [NK] and lymphokine-activated killer cell [LAK] activity); secondary endpoints were cG250 biodistribution and pharmacokinetics (PK) and tumour response rates. Eligible patients had unresectable metastatic or locally advanced clear cell RCC with measurable or evaluable disease. Nine patients were treated with six doses of cG250 (10 mg/m(2)/week, first and fifth doses trace-labelled with (131)I), and 1.25 x 10(6) IU/m(2)/day IL-2 for six weeks. Treatment was generally well tolerated with no adverse events attributable to cG250. Two patients required a 50% dose reduction of IL-2 due to toxicity. No HACA was detected. (131)I-labeled cG250 showed excellent targeting of tumour deposits. (131)I cG250 PK: T(1/2)alpha 20.16 +/- 6.59 h, T(1/2)beta 126.21 +/- 34.04 h, CL 39.67 +/- 23.06 mL/h, Cmax 5.12 +/- 0.86 microg/mL, V(1) 3.88 +/- 1.05 L. IL-2 did not affect cG250 PK. A trend for increased percentage of circulating CD3-/CD16+CD56+ NK cells was observed. Some patients showed enhanced ADCC or LAK activity. No antitumour responses were observed. In conclusion, weekly cG250 with daily low-dose subcutaneous IL-2 is well tolerated. IL-2 does not influence cG250 biodistribution or increase HACA.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antígenos de Neoplasias/inmunología , Anhidrasas Carbónicas/inmunología , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/terapia , Interleucina-2/uso terapéutico , Neoplasias Renales/terapia , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Citotoxicidad Celular Dependiente de Anticuerpos , Anhidrasa Carbónica IX , Carcinoma de Células Renales/diagnóstico por imagen , Femenino , Humanos , Interleucina-2/administración & dosificación , Interleucina-2/efectos adversos , Neoplasias Renales/inmunología , Células Asesinas Activadas por Linfocinas/inmunología , Masculino , Persona de Mediana Edad , Proyectos Piloto , CintigrafíaRESUMEN
NY-ESO-1 is a "cancer-testis" antigen expressed in epithelial ovarian cancer (EOC) and is among the most immunogenic tumor antigens defined to date. The NY-ESO-1 peptide epitope, ESO(157-170), is recognized by HLA-DP4-restricted CD4+ T cells and HLA-A2- and A24-restricted CD8+ T cells. To test whether providing cognate helper CD4+ T cells would enhance the antitumor immune response, we conducted a phase I clinical trial of immunization with ESO(157-170) mixed with incomplete Freund's adjuvant (Montanide ISA51) in 18 HLA-DP4+ EOC patients with minimal disease burden. NY-ESO-1-specific Ab responses and/or specific HLA-A2-restricted CD8+ and HLA-DP4-restricted CD4+ T cell responses were induced by a course of at least five vaccinations at three weekly intervals in a high proportion of patients. There were no serious vaccine-related adverse events. Vaccine-induced CD8+ and CD4+ T cell clones were shown to recognize NY-ESO-1-expressing tumor targets. T cell receptor analysis indicated that tumor-recognizing CD4+ T cell clones were structurally distinct from non-tumor-recognizing clones. Long-lived and functional vaccine-elicited CD8+ and CD4+ T cells were detectable in some patients up to 12 months after immunization. These results confirm the paradigm that the provision of cognate CD4+ T cell help is important for cancer vaccine design and provides the rationale for a phase II study design using ESO(157-170) epitope or the full-length NY-ESO-1 protein for immunotherapy in patients with EOC.
Asunto(s)
Formación de Anticuerpos/inmunología , Vacunas contra el Cáncer/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Proteínas de Neoplasias/inmunología , Neoplasias Ováricas/inmunología , Fragmentos de Péptidos/inmunología , Linfocitos T/inmunología , Anticuerpos/sangre , Anticuerpos/inmunología , Vacunas contra el Cáncer/efectos adversos , Femenino , Adyuvante de Freund/inmunología , Humanos , Neoplasias Ováricas/patologíaRESUMEN
PURPOSE: We report a first-in-man trial of a humanized antibody (hu3S193) against the Le(y) antigen. EXPERIMENTAL DESIGN: Patients with advanced Le(y)-positive cancers received four infusions of hu3S193 at weekly intervals, with four dose levels (5, 10, 20, and 40 mg/m(2)). The first infusion of hu3S193 was trace labeled with Indium-111, and biodistribution, pharmacokinetics, tumor uptake, and immune response were evaluated in all patients. RESULTS: A total of 15 patients (7 male/8 female; age range, 42-76 years; 6 breast, 8 colorectal cancer, and 1 non-small-cell lung cancer) were entered into the study. Transient grade 1 to 2 nausea and vomiting was observed following infusion of hu3S193 at the 40 mg/m(2) dose level only. There was one episode of dose-limiting toxicity with self-limiting Common Toxicity Criteria grade 3 elevated alkaline phosphatase observed in one patient with extensive liver metastases. The biodistribution of (111)In-hu3S193 showed no evidence of any consistent normal tissue uptake, and (111)In-hu3S193 uptake was observed in cutaneous, lymph node, and hepatic metastases. Hu3S193 displayed a long serum half-life (T(1/2)beta = 189.63 +/- 62.17 h). Clinical responses consisted of 4 patients with stable disease and 11 patients with progressive disease, although one patient experienced a 89% decrease in a lymph node mass, and one patient experienced inflammatory symptoms in cutaneous metastases, suggestive of a biological effect of hu3S193. No immune responses (human anti-human antibody) to hu3S193 were observed. CONCLUSION: Hu3S193 is well tolerated and selectively targets tumors, and the long half-life and biological function in vivo of this antibody makes it an attractive potential therapy for patients with Le(y)-expressing cancers.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Inmunoterapia/métodos , Antígenos del Grupo Sanguíneo de Lewis/biosíntesis , Neoplasias/terapia , Neoplasias Cutáneas/terapia , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales Humanizados , Femenino , Humanos , Radioisótopos de Indio/farmacocinética , Masculino , Persona de Mediana Edad , Factores de Tiempo , Distribución Tisular , Resultado del TratamientoRESUMEN
An array of cell-surface antigens expressed by human cancers have been identified as targets for antibody-based therapies. The great majority of these antibodies do not have specificity for cancer but recognize antigens expressed on a range of normal cell types (differentiation antigens). Over the past two decades, our group has analyzed thousands of mouse monoclonal antibodies for cancer specificity and identified a battery of antibodies with limited representation on normal human cells. The most tumor-specific of these antibodies is 806, an antibody that detects a unique epitope on the epidermal growth factor receptor (EGFR) that is exposed only on overexpressed, mutant, or ligand-activated forms of the receptor in cancer. In vitro immunohistochemical specificity analysis shows little or no detectable 806 reactivity with normal tissues, even those with high levels of wild-type (wt)EGFR expression. Preclinical studies have demonstrated that 806 specifically targets a subset of EGFR expressed on tumor cells, and has significant anti-tumor effects on human tumor xenografts, primarily through abrogation of signaling pathways. The present clinical study was designed to examine the in vivo specificity of a chimeric form of mAb 806 (ch806) in a tumor targeting/biodistribution/pharmacokinetic analysis in patients with diverse tumor types. ch806 showed excellent targeting of tumor sites in all patients, no evidence of normal tissue uptake, and no significant toxicity. These in vitro and in vivo characteristics of ch806 distinguish it from all other antibodies targeting EGFR.
Asunto(s)
Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/uso terapéutico , Receptores ErbB/metabolismo , Inmunoterapia/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Anciano , Anticuerpos Monoclonales/química , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Membrana Celular/metabolismo , Femenino , Humanos , Inmunoterapia/instrumentación , Radioisótopos de Indio/farmacología , Masculino , Persona de Mediana Edad , Trasplante de Neoplasias , Transducción de SeñalRESUMEN
PURPOSE: We developed a complex of tumor antigen protein with a novel nanoparticle antigen delivery system of cholesteryl pullulan (CHP). To target HER2 antigen, we prepared truncated HER2 protein 1-146 (146HER2) complexed with CHP, the CHP-HER2 vaccine. We designed a clinical study to assess the safety of the vaccine and HER2-specific T-cell immune responses measured by the newly developed enzyme-linked immunospot assay with mRNA-transduced phytohemagglutinin-stimulated CD4(+) T cells in HLA-A2402-positive patients with therapy-refractory HER2-expressing cancers. EXPERIMENTAL DESIGN: Nine patients with various types of solid tumors were enrolled. Each patient was s.c. vaccinated biweekly with 300 microg of CHP-HER2 vaccine for three times followed by booster doses. HER2-specific T-cell responses were evaluated by enzyme-linked immunospot assay by targeting autologous phytohemagglutinin-stimulated CD4(+) T cells transduced with 146HER2-encoding mRNA to cover both identified peptides and unknown epitopes for MHC class I and class II that might exist in the sequence of the vaccine protein. RESULTS: CHP-HER2 vaccine was well tolerated; the only adverse effect was grade 1 transient skin reaction at the sites of vaccination. HER2-specific CD8(+) and/or CD4(+) T-cell immune responses were detected in five patients who received four to eight vaccinations, among whom both T-cell responses were detected in these patients. In four patients with CD8(+) T-cell responses, two patients reacted to previously identified HER2(63-71) peptide and the other two reacted only to 146HER2 mRNA-transduced cells. CONCLUSIONS: CHP-HER2 vaccine was safe and induced HER2-specific CD8(+) and/or CD4(+) T-cell immune responses.