Asunto(s)
Antineoplásicos Alquilantes , Melanoma , Melfalán , Neoplasias de la Úvea , Humanos , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/secundario , Melfalán/administración & dosificación , Neoplasias de la Úvea/tratamiento farmacológico , Neoplasias de la Úvea/patología , Antineoplásicos Alquilantes/administración & dosificación , Tasa de Supervivencia , Pronóstico , Estudios de Seguimiento , Sistemas de Liberación de Medicamentos , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/tratamiento farmacológicoRESUMEN
BACKGROUND: Uveal melanoma (UM) has a poor prognosis once liver metastases occur. The melphalan/Hepatic Delivery System (melphalan/HDS) is a drug/device combination used for liver-directed treatment of metastatic UM (mUM) patients. The purpose of the FOCUS study was to assess the efficacy and safety of melphalan/HDS in patients with unresectable mUM. METHODS: Eligible patients with mUM received treatment with melphalan (3.0 mg/kg ideal body weight) once every 6 to 8 weeks for a maximum of six cycles. The primary end point was the objective response rate (ORR). The secondary end points included duration of response (DOR), overall survival (OS), and progression-free survival (PFS). RESULTS: The study enrolled 102 patients with mUM. Treatment was attempted in 95 patients, and 91 patients received treatment. In the treated population (n = 91), the ORR was 36.3 % (95 % confidence interval [CI], 26.44-47.01), including 7.7 % of patients with a complete response. Thus, the study met its primary end point because the lower bound of the 95 % CI for ORR exceeded the upper bound (8.3 %) from the benchmark meta-analysis. The median DOR was 14 months, and the median OS was 20.5 months, with an OS of 80 % at 1 year. The median PFS was 9 months, with a PFS of 65 % at 6 months. The most common serious treatment-emergent adverse events were thrombocytopenia (15.8 %) and neutropenia (10.5 %), treated mostly on an outpatient basis with observation. No treatment-related deaths were observed. CONCLUSION: Treatment with melphalan/HDS provides a clinically meaningful response rate and demonstrates a favorable benefit-risk profile in patients with unresectable mUM (study funded by Delcath; ClinicalTrials.gov identifier: NCT02678572; EudraCT no. 2015-000417-44).
Asunto(s)
Antineoplásicos Alquilantes , Neoplasias Hepáticas , Melanoma , Melfalán , Neoplasias de la Úvea , Humanos , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/secundario , Melanoma/mortalidad , Melfalán/administración & dosificación , Masculino , Femenino , Persona de Mediana Edad , Neoplasias de la Úvea/tratamiento farmacológico , Neoplasias de la Úvea/patología , Neoplasias de la Úvea/mortalidad , Anciano , Adulto , Tasa de Supervivencia , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/tratamiento farmacológico , Estudios de Seguimiento , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/uso terapéutico , Pronóstico , Anciano de 80 o más Años , Sistemas de Liberación de MedicamentosRESUMEN
PURPOSE: Uveal melanoma (UM) is an orphan cancer of high unmet medical need. Current patterns of care and surveillance remain unclear as they are situated in an interdisciplinary setting. METHODS: A questionnaire addressing the patterns of care and surveillance in the management of patients with uveal melanoma was distributed to 70 skin cancer centers in Austria, Germany and Switzerland. Frequency distributions of responses for each item of the questionnaire were calculated. RESULTS: 44 of 70 (62.9%) skin cancer centers completed the questionnaire. Thirty-nine hospitals were located in Germany (88.6%), three in Switzerland (6.8%) and two in Austria (4.5%). The majority (68.2%) represented university hospitals. Most patients with metastatic disease were treated in certified skin cancer centers (70.7%, 29/41). Besides, the majority of patients with UM were referred to the respective skin cancer center by ophthalmologists (87.2%, 34/39). Treatment and organization of follow-up of patients varied across the different centers. 35.1% (14/37) of the centers stated to not perform any screening measures. CONCLUSION: Treatment patterns of patients with uveal melanoma in Germany, Austria and Switzerland remain extremely heterogeneous. A guideline for the treatment and surveillance is urgently needed.
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Cuidados Posteriores , Melanoma/terapia , Monitoreo Fisiológico , Pautas de la Práctica en Medicina/estadística & datos numéricos , Neoplasias de la Úvea/terapia , Cuidados Posteriores/métodos , Cuidados Posteriores/estadística & datos numéricos , Austria/epidemiología , Estudios Transversales , Estudios de Seguimiento , Alemania/epidemiología , Necesidades y Demandas de Servicios de Salud/estadística & datos numéricos , Humanos , Tamizaje Masivo/métodos , Tamizaje Masivo/estadística & datos numéricos , Melanoma/epidemiología , Melanoma/patología , Monitoreo Fisiológico/métodos , Monitoreo Fisiológico/estadística & datos numéricos , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/epidemiología , Vigilancia de la Población/métodos , Derivación y Consulta/normas , Derivación y Consulta/estadística & datos numéricos , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , Encuestas y Cuestionarios , Suiza/epidemiología , Neoplasias de la Úvea/epidemiología , Neoplasias de la Úvea/patologíaRESUMEN
BACKGROUND: Erosive oral lichen planus (OLP) is, at times, extremely difficult to treat and has a major impact on patients' quality of life. There are only limited therapeutic options, such as topical and systemic glucocorticoids, retinoids, and immunosuppressants with considerable side effects and limited efficacy upon chronic use. OBJECTIVES: In the present individualised clinical trial, we assessed the efficacy of adjuvant intravenous immunoglobulins (IVIG; 2 g/kg/monthly cycle) in addition to the oral retinoid, acitretin, in three patients with refractory OLP over a period of two to six months. MATERIALS & METHODS: The efficacy of adjuvant IVIG treatment was evaluated using the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) which measures both extent of mucosal lesions and functional sequelae. RESULTS: The three OLP patients showed mixed responses to adjuvant IVIG treatment, ranging from therapeutic efficacy to a lack of response to IVIG. CONCLUSIONS: In light of the observed therapeutic responses and a lack of good therapeutic options, adjuvant IVIG, although costly, warrants further investigation as a treatment option for OLP.
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Inmunoglobulinas Intravenosas/administración & dosificación , Factores Inmunológicos/administración & dosificación , Liquen Plano Oral/tratamiento farmacológico , Acitretina/uso terapéutico , Anciano , Quimioterapia Combinada , Femenino , Humanos , Queratolíticos/uso terapéutico , Persona de Mediana Edad , Retratamiento , Índice de Severidad de la EnfermedadRESUMEN
PURPOSE: Biomarkers for outcome after immune-checkpoint blockade are strongly needed as these may influence individual treatment selection or sequence. We aimed to identify baseline factors associated with overall survival (OS) after pembrolizumab treatment in melanoma patients. EXPERIMENTAL DESIGN: Serum lactate dehydrogenase (LDH), routine blood count parameters, and clinical characteristics were investigated in 616 patients. Endpoints were OS and best overall response following pembrolizumab treatment. Kaplan-Meier analysis and Cox regression were applied for survival analysis. RESULTS: Relative eosinophil count (REC) ≥1.5%, relative lymphocyte count (RLC) ≥17.5%, ≤2.5-fold elevation of LDH, and the absence of metastasis other than soft-tissue/lung were associated with favorable OS in the discovery (n = 177) and the confirmation (n = 182) cohort and had independent positive impact (all P < 0.001). Their independent role was subsequently confirmed in the validation cohort (n = 257; all P < 0.01). The number of favorable factors was strongly associated with prognosis. One-year OS probabilities of 83.9% versus 14.7% and response rates of 58.3% versus 3.3% were observed in patients with four of four compared to those with none of four favorable baseline factors present, respectively. CONCLUSIONS: High REC and RLC, low LDH, and absence of metastasis other than soft-tissue/lung are independent baseline characteristics associated with favorable OS of patients with melanoma treated with pembrolizumab. Presence of four favorable factors in combination identifies a subgroup with excellent prognosis. In contrast, patients with no favorable factors present have a poor prognosis, despite pembrolizumab, and additional treatment advances are still needed. A potential predictive impact needs to be further investigated. Clin Cancer Res; 22(22); 5487-96. ©2016 AACR.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Biomarcadores de Tumor/metabolismo , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/metabolismo , Anciano , Estudios de Cohortes , Femenino , Humanos , Estimación de Kaplan-Meier , L-Lactato Deshidrogenasa/metabolismo , Masculino , Melanoma/patología , Persona de Mediana Edad , Pronóstico , Neoplasias Cutáneas/patología , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
OBJECTIVE: Psycho-neuro-immune research suggests an association between cancer outcomes and psychosocial distress. Objective criteria to determine patients' levels of distress are important to establish potential links to disease outcomes. METHODS: We compared three patient-reported with one doctor-reported measures of psycho-oncologic distress frequently used in routine cancer care and investigated associations with standard disease severity parameters in melanoma patients. We enrolled n = 361 patients, successively seen at two outpatient university clinics in Germany. In the naturalistic study, n = 222 patients had been diagnosed <180 days and were seen for the first time (Group I); n = 139 had been diagnosed >180 days and were in after-care (Group II). RESULTS: Across groups, only moderate associations were seen between patient- reported and doctor-reported measures. Regarding clinical variables, disease severity and perceived need of psycho-oncologic support reported by patients or doctors showed hardly any association. After subgroup stratification, in patients of Group II, patient-reported and doctor-reported instruments showed some small associations with disease parameters commonly linked to more rapid cancer progression in patients who are in cancer after-care. CONCLUSIONS: Overall, the few and low associations suggest that need of psycho-oncologic support and clinical variables were largely independent of each other and doctors' perception may not reflect the patient's view. Therefore, the assessment of the patient perspective is indispensable to ensure that melanoma patients receive appropriate support, as such need cannot be derived from other disease parameters or proxy report. More research is needed applying psychometrically robust instruments that are ideally combined with sensitive biomarkers to disentangle psycho-neuro-immune implications in melanoma patients. Copyright © 2015 John Wiley & Sons, Ltd.
Asunto(s)
Melanoma/psicología , Prioridad del Paciente/psicología , Relaciones Médico-Paciente , Médicos/psicología , Neoplasias Cutáneas/psicología , Adulto , Cuidados Posteriores , Anciano , Estudios Transversales , Femenino , Alemania , Humanos , Masculino , Melanoma/terapia , Persona de Mediana Edad , Psicometría , Neoplasias Cutáneas/terapia , Estrés Psicológico/psicologíaRESUMEN
PURPOSE: NY-ESO-1, one of the most immunogenic tumor antigens, is expressed in 15% to 25% of metastatic prostate cancers. The immunological and clinical effects of vaccination with recombinant NY-ESO-1 protein combined with CpG as adjuvant were evaluated. EXPERIMENTAL DESIGN: In a phase I clinical study, patients with advanced prostate cancer were vaccinated with recombinant NY-ESO-1 protein (100 µg) mixed with CpG 7909 (2.5 mg) every 3 weeks intradermally for 4 doses. Objectives of the study were the safety of the vaccine and changes of specific humoral and cellular immunological responses to NY-ESO-1 in relation to detectable NY-ESO-1 expression in the individual tumor. RESULTS: All 12 baseline sero-negative patients developed high-titer NY-ESO-1 antibody responses. B-cell epitope mapping identified NY-ESO-1 p91-110 to be recognized most frequently by vaccine-induced antibodies. Two patients developed significant antibody titers against the adjuvant CpG. NY-ESO-1-specific CD4+ and/or CD8+ T-cell responses were induced in 9 patients (69%). Five of these 9 patients did not express NY-ESO-1 in the autologous tumor. Postvaccine CD8+ T-cell clones recognized and lyzed HLA-matched tumor cell lines in an antigen-specific manner. CONCLUSION: Our data provide clear evidence for the capacity of NY-ESO-1 protein/CpG vaccine to induce integrated antigen-specific immune responses in vivo and to efficiently prime CD8+ T-cell responses in NY-ESO-1 antigen-negative patients. Our results may also support further clinical vaccination protocols with NY-ESO-1 protein not only focused on the treatment of existing cancer, but also to prevent further development of NY-ESO-1 positive cancers in vivo.
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Adyuvantes Inmunológicos/administración & dosificación , Antígenos de Neoplasias/administración & dosificación , Vacunas contra el Cáncer/administración & dosificación , Proteínas de la Membrana/administración & dosificación , Oligodesoxirribonucleótidos/administración & dosificación , Neoplasias de la Próstata/terapia , Inmunidad Adaptativa , Adyuvantes Inmunológicos/efectos adversos , Antígenos de Neoplasias/efectos adversos , Antígenos de Neoplasias/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/efectos adversos , Quimioterapia Adyuvante , Humanos , Inyecciones Intradérmicas , Masculino , Proteínas de la Membrana/efectos adversos , Proteínas de la Membrana/inmunología , Oligodesoxirribonucleótidos/efectos adversos , Oligodesoxirribonucleótidos/inmunología , Neoplasias de la Próstata/inmunología , Resultado del TratamientoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bleomicina/efectos adversos , Cisplatino/efectos adversos , Erupciones por Medicamentos/etiología , Erupciones por Medicamentos/patología , Eritema/inducido químicamente , Eritema/patología , Etopósido/efectos adversos , Adulto , Antibióticos Antineoplásicos/efectos adversos , Antineoplásicos Fitogénicos/efectos adversos , Erupciones por Medicamentos/prevención & control , Eritema/prevención & control , Humanos , MasculinoRESUMEN
Peptide-based vaccines have led to the induction of antigen-specific CD8(+) T-cell responses in patients with NY-ESO-1 positive cancers. However, vaccine-induced T-cell responses did not generally correlate with improved survival. Therefore, we tested whether a synthetic CpG 7909 ODN (deoxycytidyl-deoxyguanosin oligodeoxy-nucleotides) mixed with NY-ESO-1 peptide p157-165 and incomplete Freund's adjuvants (Montanide(R) ISA-51) led to enhanced NY-ESO-1 antigen-specific CD8(+) immune responses in patients with NY-ESO-1 or LAGE-1 expressing tumors. Of 14 HLA-A2+ patients enrolled in the study, 5 patients withdrew prematurely because of progressive disease and 9 patients completed 1 cycle of immunization. Nine of 14 patients developed measurable and sustained antigen-specific CD8(+) T-cell responses: Four had detectable CD8+ T-cells against NY-ESO-1 after only 2 vaccinations, whereas 5 patients showed a late-onset but durable induction of NY-ESO-1 p157-165 specific T-cell response during continued vaccination after 4 months. In 6 patients, vaccine-induced antigen-specific T-cells became detectable ex vivo and reached frequencies of up to 0.16 % of all circulating CD8(+) T-cells. Postvaccine T-cell clones were shown to recognize and lyse NY-ESO-1 expressing tumor cell lines in vitro. In 6 of 9 patients developing NY-ESO-1-specific immune responses, a favorable clinical outcome with overall survival times of 43+, 42+, 42+, 39+, 36+ and 27+ months, respectively, was observed.
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Antígenos de Neoplasias/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/uso terapéutico , Manitol/análogos & derivados , Proteínas de la Membrana/uso terapéutico , Neoplasias/inmunología , Ácidos Oléicos/uso terapéutico , Oligodesoxirribonucleótidos/uso terapéutico , Vacunación/métodos , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Citometría de Flujo , Humanos , Inmunoterapia/métodos , Manitol/uso terapéutico , Melanoma/inmunología , Estadificación de Neoplasias , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/patología , Sarcoma/inmunología , Sarcoma/patologíaRESUMEN
NY-ESO-1 is a cancer-testis antigen and an attractive target for immunotherapy in patients with different malignancies. Here we report the results of a phase I clinical study of intensive course NY-ESO-1 peptide vaccination, evaluating the safety, immunogenicity and clinical response in HLA-A2 positive patients with NY-ESO-1 expressing cancers. Of 20 patients enrolled in the trial, 14 completed at least 2 cycles of immunization and were evaluable for clinical and immunological response. Five of these evaluable patients were treated in cohort 1 (baseline seropositive) and 9 patients were treated in cohort 2 (baseline seronegative). During vaccination, NY-ESO-1-specific CD8+ T-cells were induced in 3 of 9 baseline seronegative patients. In patients with pre-existing antigen-specific CD8+ T-cells, their number increased or remained stable. In contrast to previous immunization protocols with less intensive immunization schedules, we observed a rapid induction of high magnitude NY-ESO-1 peptide-specific T-cell responses detectable already on day 15-22 of immunization. A specific immune response of high magnitude and early onset may be more effective in eliminating minimal residual disease in adjuvant treatment situations and in preventing tumor progression due to immune escape mechanisms.
Asunto(s)
Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/administración & dosificación , Antígeno HLA-A2/metabolismo , Inmunoterapia , Proteínas de la Membrana/inmunología , Proteínas de Neoplasias/inmunología , Neoplasias/terapia , Fragmentos de Péptidos/inmunología , Adolescente , Adulto , Anciano , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/inmunología , Estudios de Cohortes , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Humanos , Hipersensibilidad Tardía/inmunología , Inmunización , Metástasis Linfática , Masculino , Persona de Mediana Edad , Neoplasias/inmunología , Linfocitos T Citotóxicos/inmunología , Resultado del TratamientoRESUMEN
A major objective of peptide vaccination is the induction of tumor-reactive CD8+ T-cells. We have shown that HLA-A2 positive cancer patients frequently develop an antigen-specific CD8+ T-cell response after vaccination with NY-ESO-1 peptides p157-165/p157-167. These T-cells are highly reactive with the peptides used for vaccination, but only rarely recognize HLA-matched, NY-ESO-1 expressing tumor cell lines. To address the apparent lack of tumor recognition of vaccine-induced CD8+ T-cell responses, we used autologous tumor cells for in vitro stimulation and expansion of pre- and postvaccine CD8+ T-cells. In contrast to standard presensitization methods with peptide-pulsed antigen-presenting cells, mixed lymphocyte tumor culture favored the selective expansion of low-frequency tumor-reactive T-cells. In four patients, we were able to demonstrate that antigen-specific and tumor-reactive T-cells are detectable and are indeed elicited as a result of NY-ESO-1 peptide vaccination. Further analyses of postvaccine antigen-specific T-cells at a clonal level show that vaccine-induced antigen-specific T-cells are heterogeneous in functional activity. These results suggest that the methods of immunomonitoring are critical to identify the proportion of tumor-reactive T-cells within the population of vaccine-induced antigen-specific effector cells. Our results show that immunization with NY-ESO-1 peptides leads to strong tumor-reactive CD8+ T-cell responses. Our findings suggest that approaches to peptide vaccination may be improved to induce higher numbers of antigen-specific T-cells and to selectively increase the proportion of CD8+ T-cells that have the capacity to recognize and eliminate tumor cells.
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Antígenos de Neoplasias/inmunología , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/inmunología , Separación Celular/métodos , Proteínas de la Membrana/inmunología , Neoplasias/inmunología , Fragmentos de Péptidos/inmunología , Línea Celular Tumoral , Células Cultivadas , Células Dendríticas/inmunología , Humanos , Sensibilidad y EspecificidadRESUMEN
NY-ESO-1 is a cancer/testis antigen expressed in a range of human malignancies, and a number of vaccine strategies targeting NY-ESO-1 are being developed. In the present study, the safety and immunogenicity of recombinant vaccinia-NY-ESO-1 and recombinant fowlpox-NY-ESO-1 were analyzed in a series of 36 patients with a range of different tumor types. Each construct was first tested individually at two different dose levels and then in a prime-boost setting with recombinant vaccinia-NY-ESO-1 followed by recombinant fowlpox-NY-ESO-1. The vaccines were well tolerated either individually or together. NY-ESO-1-specific antibody responses and/or specific CD8 and CD4 T cell responses directed against a broad range of NY-ESO-1 epitopes were induced by a course of at least four vaccinations at monthly intervals in a high proportion of patients. CD8 T cell clones derived from five vaccinated patients were shown to lyse NY-ESO-1-expressing melanoma target cells. In several patients with melanoma, there was a strong impression that the natural course of the disease was favorably influenced by vaccination.
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Formación de Anticuerpos/inmunología , Vacunas contra el Cáncer/inmunología , Inmunidad Celular/inmunología , Proteínas de Neoplasias/inmunología , Neoplasias/inmunología , Fragmentos de Péptidos/inmunología , Vacunas Sintéticas/inmunología , Anticuerpos/sangre , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/genética , Células Clonales , Estudios de Cohortes , Citotoxicidad Inmunológica/inmunología , Epítopos/inmunología , Virus de la Viruela de las Aves de Corral/metabolismo , Humanos , Proteínas de la Membrana/inmunología , Vacunación , Vacunas Sintéticas/efectos adversos , Vacunas Sintéticas/genética , Virus Vaccinia/genéticaRESUMEN
NY-ESO-1 is one of the most immunogenic cancer antigens eliciting strong humoral and cellular immune responses in patients with NY-ESO-1-expressing malignancies. Since CD4+ T cells play a critical role in generating and maintaining antigen-specific cellular and humoral immune responses, we searched for new NY-ESO-1 epitopes presented by MHC class II molecules. CD4+ T cells of patients with NY-ESO-1-expressing cancer were presensitized with 18-mer overlapping synthetic peptides spanning the entire sequence of NY-ESO-1. Two partly overlapping NY-ESO-1 epitopes p49-66 and p55-72 were identified as targets for NY-ESO-1-specific CD4+ T cells. Peptide-specific CD4+ T-cell clones were generated by repetitive stimulation with NY-ESO-1 p49-66 and p55-72. Further experiments confirmed distinct specificities for the CD4+ T-cell clones indicating that at least 2 different CD4+ T-cell epitopes are located in the region p49-72 of the NY-ESO-1 sequence. Using a set of partially histocompatible EBV-B cell lines and MHC class II-specific antibodies, we found that both CD4+ T-cell epitopes were presented in the context of HLA-DQ B1 03011(DQ7). Natural processing and presentation of these epitopes was demonstrated by recognition of an HLA-DQ B1 03011- and NY-ESO-1-expressing lymphoma cell line and by recognition of dendritic cells (DC) exogenously loaded with NY-ESO-1 protein or infected with recombinant NY-ESO-1 adenoviral constructs. The specific production of IFN-gamma and TNF-alpha suggests that the NY-ESO-1-specific CD4+ T-cell clones belong to the Th1 subtype. The characterization of the new HLA-DQ B1 03011-restricted NY-ESO-1 peptides broadens the repertoire of epitopes that can be used to monitor NY-ESO-1-specific spontaneous and vaccine-induced T-cell responses in cancer patients.
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Antígenos de Neoplasias/inmunología , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Epítopos/inmunología , Antígenos HLA-DQ/inmunología , Proteínas de la Membrana/inmunología , Adenoviridae/genética , Secuencia de Aminoácidos , Células Presentadoras de Antígenos/inmunología , Línea Celular Transformada/inmunología , Línea Celular Transformada/metabolismo , Células Dendríticas , Neoplasias Endometriales/inmunología , Neoplasias Endometriales/secundario , Femenino , Antígenos HLA-DQ/química , Antígenos HLA-DQ/genética , Herpesvirus Humano 4 , Humanos , Linfoma/inmunología , Masculino , Melanoma/inmunología , Melanoma/secundario , Datos de Secuencia Molecular , Fragmentos de Péptidos/inmunología , Proteínas Recombinantes/inmunología , Sarcoma Sinovial/inmunología , Sarcoma Sinovial/secundario , TestículoRESUMEN
The infiltration of tumors by T cells has been shown to correlate with prolonged patients' survival. However, it remains unclear why only some tumors are infiltrated with T cells. This study was designed to investigate possible correlations between intratumoral T-cell infiltrates and the expression of cancer-associated antigens and MHC class I and II molecules in patients with melanoma. Fresh frozen samples from 124 stage IV melanoma patients were analyzed by immunohistochemistry for the expression of Melan-A/MART-1, tyrosinase, gp100, NY-ESO-1, and MHC class I and II. Intratumoral T-cell and B-cell infiltrates were detected by staining with anti-CD4, anti-CD8, anti-CD3, and L26 antibodies. The NY-ESO-1 serum antibody status was assessed by Western blot analysis. Intratumoral CD8+ and CD4+ T cells were detected in 63.9% and 71.3% of patients, respectively. We observed a significant heterogeneity of the expression of the melanocyte differentiation antigens, NY-ESO-1, and MHC class I and II molecules. The only significant correlation was found between the expression of MHC class I and the presence of CD4+ and CD8+ T cells (P < 0.0001). There was a strong association between these two variables with respect to the density and distribution of infiltrating T cells and the pattern of MHC class I expression (focal versus homogenous). Intratumoral T-cell infiltration is closely correlated with the MHC class I expression but not with the expression of differentiation antigens, cancer-associated antigens, or MHC class II molecules. These results may have implications for the definition of prognostic variables and for the identification of patients who may benefit from antigen-specific cancer immunotherapy.
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Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma/inmunología , Anticuerpos Antineoplásicos/inmunología , Antígenos de Neoplasias/biosíntesis , Antígenos de Neoplasias/inmunología , Humanos , Inmunohistoquímica , Antígeno MART-1 , Melanoma/patología , Glicoproteínas de Membrana/inmunología , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/inmunología , Monofenol Monooxigenasa/inmunología , Proteínas de Neoplasias/inmunología , Estadificación de Neoplasias , Antígeno gp100 del MelanomaRESUMEN
NY-ESO-1 is one of the most immunogenic cancer antigens known to date, eliciting spontaneous immune responses in approximately 50% of patients with NY-ESO-1+ cancers. Spontaneous CD4+ and CD8+ T cell responses were found in patients with detectable NY-ESO-1 serum antibody, indicating an integrated type of immune response induced by NY-ESO-1+ malignancies. A close association between spontaneous NY-ESO-1 immunity and the HLA-DP4 allele was suggested in a recent study. To address these results, we assessed the NY-ESO-1 antibody and HLA-DP4 status of 102 patients with NY-ESO-1+ malignancies. However, no correlation between HLA-DP4 and NY-ESO-1 immunity was found. To explore the role of HLA-DP4-restricted CD4+ T cells in cancer immunity, we established HLA-DP4- restricted NY-ESO-1-specific CD4+ T cell clones by limiting dilution and repeated stimulation with NY-ESO-1 peptide p157-170 from NY-ESO-1 seropositive patients. A subset of CD4+ T cell clones was reactive with naturally processed NY-ESO-1 presented by autologous DCs that were pulsed with recombinant NY-ESO-1 protein, lysates of NY-ESO-1-expressing tumor cell lines, or transduced with recombinant NY-ESO-1 viral constructs in ELISPOT assays. Three different CD4+ T cell clones were used to mediate the specific lysis of allogeneic HLA-DP4+ Epstein-Barr virus-transformed B cells (EBV-B) pulsed with NY-ESO-1 p157-170. The Th1 phenotype and effector functions of the CD4+ T cell clones described here provide an important rationale for the activation of antigen-specific CD4+ T cells along with CD8+ T cells in cancer vaccination strategies.
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Antígenos de Neoplasias/inmunología , Linfocitos T CD4-Positivos/química , Linfocitos T CD4-Positivos/fisiología , Linfocitos T CD8-positivos/química , Linfocitos T CD8-positivos/fisiología , Antígenos HLA-DP/biosíntesis , Proteínas de la Membrana/inmunología , Receptores de Interleucina-2/biosíntesis , Linfocitos T Citotóxicos/química , Linfocitos T Citotóxicos/fisiología , Células Presentadoras de Antígenos/metabolismo , Antígenos de Neoplasias/sangre , Antígenos de Neoplasias/genética , Linfocitos T CD4-Positivos/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Células Clonales/química , Células Clonales/metabolismo , Células Clonales/fisiología , Femenino , Regulación Neoplásica de la Expresión Génica/inmunología , Regulación Neoplásica de la Expresión Génica/fisiología , Antígenos HLA-DP/genética , Cadenas beta de HLA-DP , Humanos , Inmunofenotipificación/métodos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Melanoma/genética , Melanoma/metabolismo , Proteínas de la Membrana/sangre , Proteínas de la Membrana/genética , Neoplasias/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Subgrupos de Linfocitos T/química , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/metabolismoRESUMEN
There is consensus that an optimized cancer vaccine will have to induce not only CD8+ cytotoxic but also CD4+ T helper (Th) cells, particularly interferon (IFN)-gamma-producing, type 1 Th cells. The induction of strong, ex vivo detectable type 1 Th cell responses has not been reported to date. We demonstrate now that the subcutaneous injection of cryopreserved, mature, antigen-loaded, monocyte-derived dendritic cells (DCs) rapidly induces unequivocal Th1 responses (ex vivo detectable IFN-gamma-producing effectors as well as proliferating precursors) both to the control antigen KLH and to major histocompatibility complex (MHC) class II-restricted tumor peptides (melanoma-antigen [Mage]-3.DP4 and Mage-3.DR13) in the majority of 16 evaluable patients with metastatic melanoma. These Th1 cells recognized not only peptides, but also DCs loaded with Mage-3 protein, and in case of Mage-3DP4-specific Th1 cells IFN-gamma was released even after direct recognition of viable, Mage-3-expressing HLA-DP4+ melanoma cells. The capacity of DCs to rapidly induce Th1 cells should be valuable to evaluate whether Th1 cells are instrumental in targeting human cancer and chronic infections.