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1.
Int J Cancer ; 150(1): 100-111, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34449877

RESUMO

Ipilimumab was the first treatment that improved survival in advanced melanoma. Efficacy and toxicity in a real-world setting may differ from clinical trials, due to more liberal eligibility criteria and less intensive monitoring. Moreover, high costs and lack of biomarkers have raised cost-benefit concerns about ipilimumab in national healthcare systems and limited its use. Here, we report the prospective, interventional study, Ipi4 (NCT02068196), which aimed to investigate the toxicity and efficacy of ipilimumab in a real-world population with advanced melanoma. This national, multicentre, phase IV trial included 151 patients. Patients received ipilimumab 3 mg/kg intravenously and were followed for at least 5 years or until death. Treatment interruption or cessation occurred in 38%, most frequently due to disease progression (19%). Treatment-associated grade 3 to 4 toxicity was observed in 28% of patients, and immune-related toxicity in 56%. The overall response rate was 9%. Median overall survival was 12.1 months (95% CI: 8.3-15.9); and progression-free survival 2.7 months (95% CI: 2.6-2.8). After 5 years, 20% of patients were alive. In a landmark analysis from 6 months, improved survival was associated with objective response (HR 0.16, P = .001) and stable disease (HR 0.49, P = .005) compared to progressive disease. Poor performance status, elevated lactate dehydrogenase and C-reactive protein were identified as biomarkers. This prospective trial represents the longest reported follow-up of a real-world melanoma population treated with ipilimumab. Results indicate safety and efficacy comparable to phase III trials and suggest that the use of ipilimumab can be based on current cost-benefit estimates.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Ipilimumab/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Neoplasias Cutâneas/secundário , Taxa de Sobrevida
2.
Prostate ; 82(2): 245-253, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34762317

RESUMO

BACKGROUND: Patients with high-risk prostate cancer (PC) can experience biochemical relapse (BCR), despite surgery, and develop noncurative disease. The present study aimed to reduce the risk of BCR with a personalized dendritic cell (DC) vaccine, given as adjuvant therapy, after robot-assisted laparoscopic prostatectomy (RALP). METHODS: Twelve weeks after RALP, 20 patients with high-risk PC and undetectable PSA received DC vaccinations for 3 years or until BCR. The primary endpoint was the time to BCR. The immune response was assessed 7 weeks after surgery (baseline) and at one-time point during the vaccination period. RESULTS: Among 20 patients, 11 were BCR-free over a median of 96 months (range: 84-99). The median time from the end of vaccinations to the last follow-up was 57 months (range: 45-60). Nine patients developed BCR, either during (n = 4) or after (n = 5) the vaccination period. Among five patients diagnosed with intraductal carcinoma, three experienced early BCR during the vaccination period. All patients that developed BCR remained in stable disease within a median of 99 months (range: 74-99). The baseline immune response was significantly associated with the immune response during the vaccination period (p = 0.015). For patients diagnosed with extraprostatic extension (EPE), time to BCR was longer in vaccine responders than in non-responders (p = 0.09). Among 12 patients with the International Society of Urological Pathology (ISUP) grade 5 PC, five achieved remission after 84 months, and all mounted immune responses. CONCLUSION: Patients diagnosed with EPE and ISUP grade 5 PC were at particularly high risk of developing postsurgical BCR. In this subgroup, the vaccine response was related to a reduced BCR incidence. The vaccine was safe, without side effects. This adjuvant first-in-man Phase I/II DC vaccine study showed promising results. DC vaccines after curative surgery should be investigated further in a larger cohort of patients with high-risk PC.


Assuntos
Vacinas Anticâncer/administração & dosagem , Metástase Neoplásica/prevenção & controle , Próstata , Prostatectomia/efeitos adversos , Neoplasias da Próstata , Prevenção Secundária/métodos , Biomarcadores/sangue , Células Dendríticas/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Próstata/imunologia , Próstata/patologia , Antígeno Prostático Específico/sangue , Prostatectomia/métodos , Neoplasias da Próstata/sangue , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Análise de Sobrevida , Tempo , Vacinas Sintéticas/administração & dosagem
3.
Int J Mol Sci ; 23(10)2022 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-35628499

RESUMO

Alveolar soft part sarcoma (ASPS) is a rare subtype of soft tissue sarcoma characterized by an unbalanced translocation, resulting in ASPSCR1-TFE3 fusion that transcriptionally upregulates MET expression. The European Organization for Research and Treatment of Cancer (EORTC) 90101 "CREATE" phase II trial evaluated the MET inhibitor crizotinib in ASPS patients, achieving only limited antitumor activity. We performed a comprehensive molecular analysis of ASPS tissue samples collected in this trial to identify potential biomarkers correlating with treatment outcome. A tissue microarray containing 47 ASPS cases was used for the characterization of the tumor microenvironment using multiplex immunofluorescence. DNA isolated from 34 available tumor samples was analyzed to detect recurrent gene copy number alterations (CNAs) and mutations by low-coverage whole-genome sequencing and whole-exome sequencing. Pathway enrichment analysis was used to identify diseased-associated pathways in ASPS sarcomagenesis. Kaplan-Meier estimates, Cox regression, and the Fisher's exact test were used to correlate histopathological and molecular findings with clinical data related to crizotinib treatment, aiming to identify potential factors associated with patient outcome. Tumor microenvironment characterization showed the presence of PD-L1 and CTLA-4 in 10 and 2 tumors, respectively, and the absence of PD-1 in all specimens. Apart from CD68, other immunological markers were rarely expressed, suggesting a low level of tumor-infiltrating lymphocytes in ASPS. By CNA analysis, we detected a number of broad and focal alterations. The most common alteration was the loss of chromosomal region 1p36.32 in 44% of cases. The loss of chromosomal regions 1p36.32, 1p33, 1p22.2, and 8p was associated with shorter progression-free survival. Using whole-exome sequencing, 13 cancer-associated genes were found to be mutated in at least three cases. Pathway enrichment analysis identified genetic alterations in NOTCH signaling, chromatin organization, and SUMOylation pathways. NOTCH4 intracellular domain dysregulation was associated with poor outcome, while inactivation of the beta-catenin/TCF complex correlated with improved outcome in patients receiving crizotinib. ASPS is characterized by molecular heterogeneity. We identify genetic aberrations potentially predictive of treatment outcome during crizotinib therapy and provide additional insights into the biology of ASPS, paving the way to improve treatment approaches for this extremely rare malignancy.


Assuntos
Sarcoma Alveolar de Partes Moles , Neoplasias de Tecidos Moles , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Crizotinibe/uso terapêutico , Humanos , Sarcoma Alveolar de Partes Moles/diagnóstico , Sarcoma Alveolar de Partes Moles/tratamento farmacológico , Sarcoma Alveolar de Partes Moles/genética , Neoplasias de Tecidos Moles/patologia , Translocação Genética , Microambiente Tumoral/genética
4.
Cancer Immunol Immunother ; 64(2): 173-80, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25319807

RESUMO

Matrix metalloproteinases (MMPs) are important enzymes in tissue turnover and various inflammatory processes. In this study, it was evaluated whether serum MMP-8 can predict the response to adjuvant interferon alfa-2b (IFN-α) therapy in patients with operated high-risk cutaneous melanoma. Pre-treatment sera from 460 patients with stage IIB-IIIC melanoma were analyzed for MMP-8. The patients were randomized after surgery to adjuvant IFN-α for 12 or 24 months (n = 313) or observation only (n = 147). The median serum MMP-8 level was used to classify the patients into a low MMP-8 (n = 232) and a high MMP-8 (n = 228) group. In the high MMP-8 subgroup, IFN-α therapy significantly improved relapse-free survival (RFS). RFS was 36.8 months in patients with high MMP-8 levels receiving IFN-α therapy, whereas RFS for those with high MMP-8 levels with observation only was 10.6 months (P = 0.027). Median overall survival for patients with high MMP-8 and observation only was 36.7 versus 71.7 months in those receiving IFN-α (P = 0.13). In a multivariate model, IFN-α therapy was a significant predictor of favorable RFS (HR 0.74; 95 % CI 0.55-0.99; P = 0.048), after adjustment for pre-treatment MMP-8 (HR 1.17; 95 % CI 0.88-1.55; P = 0.28), gender (HR 1.16; 95 % CI 0.86-1.56; P = 0.32), age (HR 1.00; 95 % CI 1.00-1.02; P = 0.12), ulceration (HR 1.09; 95 % CI 0.81-1.46; P = 0.58), and the presence of node metastases (HR 1.36; 95 % CI 1.17-1.58; P < 0.0001). In conclusion, patients with high serum MMP-8 levels may benefit from adjuvant IFN-α therapy, but this observation should be further investigated.


Assuntos
Antineoplásicos/uso terapêutico , Interferon-alfa/uso terapêutico , Metaloproteinase 8 da Matriz/sangue , Melanoma/sangue , Melanoma/tratamento farmacológico , Adolescente , Adulto , Idoso , Quimioterapia Adjuvante , Feminino , Humanos , Interferon alfa-2 , Masculino , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento , Adulto Jovem
5.
Cancer Immunol Immunother ; 64(6): 769-76, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25832001

RESUMO

Malignant melanoma is highly aggressive cancer with poor prognosis and few therapeutic options. Interferon alpha (IFN-α) has been tested as adjuvant immunotherapy in high-risk melanoma patients in a number of studies, but its beneficial role is controversial. Although IFN-α treatment can prolong relapse-free survival, the effect on overall survival is not significant. However, a small subset of patients benefits from the treatment, signifying the need for biomarkers able to identify a responding subgroup. Here we evaluated whether serum osteopontin (OPN) could function as a biomarker identifying patients with poor prognosis that might benefit from IFN-α. The choice of osteopontin was based on the knowledge about the dual role of this protein in cancer and immune response, an apparent association between OPN and IFN signaling and a prognostic value of OPN in multiple other tumor types. Serum samples from 275 high-risk melanoma patients enrolled in the Nordic Adjuvant IFN Melanoma trial were analyzed for circulating OPN concentrations and OPN promoter polymorphisms in position -443. The potential relation between serum OPN levels, the genotypes and survival in non-treated patients and patients receiving adjuvant IFN-α was investigated. Although slightly better survival was observed in the treated patients that had high levels of OPN, the difference was not statistically significant. In conclusion, serum OPN (its level or the genotype) cannot distinguish melanoma patients with poor prognosis, or patients that might benefit from adjuvant treatment with IFN-α.


Assuntos
Melanoma/sangue , Melanoma/genética , Osteopontina/sangue , Osteopontina/genética , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/genética , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Feminino , Humanos , Interferon-alfa/administração & dosagem , Masculino , Melanoma/tratamento farmacológico , Melanoma/patologia , Polimorfismo de Nucleotídeo Único , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia
6.
Int J Cancer ; 134(1): 102-13, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-23784959

RESUMO

Cancer cells escape T-cell-mediated destruction by losing human leukocyte antigen (HLA) class I expression via various mechanisms, including loss of beta2-microglobulin (ß2m). Our study illustrates the immune escape of HLA class I-negative tumor cells and chronological sequence of appearance of tumor ß2m gene mutation in successive lesions obtained from a patient with metastatic melanoma. We observed a gradual decrease in HLA expression in consecutive lesions with few HLA-negative nodules in the primary tumor and the emergence of a totally negative lesion at later stages of the disease. We detected loss of ß2m in ß2m-negative nests of the primary tumor caused by a combination of two alterations: (i) a mutation (G to T substitution) in codon 67 in exon 2 of ß2m gene, producing a stop codon and (ii) loss of the second gene copy by loss of heterozygosity (LOH) in chromosome 15. The same ß2m mutation was found in a homogeneously ß2m-negative metastasis 10 months later and in a cell line established from a biopsy of a postvaccination lymph node. Microsatellite analysis revealed the presence of LOH in chromosomes 6 and 15 in tumor samples, showing an accumulation of chromosomal loss at specific short tandem repeats in successive metastases during disease progression. HLA loss correlated with decreased tumor CD8+ T-cell infiltration. Early incidence of ß2m defects can cause an immune selection and expansion of highly aggressive melanoma clones with irreversible genetic defects causing total loss of HLA class I expression and should be taken into consideration as a therapeutic target in the development of cancer immunotherapy protocols.


Assuntos
Antígenos de Histocompatibilidade Classe I/biossíntese , Melanoma/genética , Evasão Tumoral/genética , Microglobulina beta-2/genética , Idoso , Linhagem Celular Tumoral , Citometria de Fluxo , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imuno-Histoquímica , Perda de Heterozigosidade , Melanoma/imunologia , Melanoma/patologia , Mutação , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Evasão Tumoral/imunologia , Microglobulina beta-2/imunologia
7.
Cancer Immunol Immunother ; 62(9): 1499-509, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23817721

RESUMO

BACKGROUND: The growth and recurrence of several cancers appear to be driven by a population of cancer stem cells (CSCs). Glioblastoma, the most common primary brain tumor, is invariably fatal, with a median survival of approximately 1 year. Although experimental data have suggested the importance of CSCs, few data exist regarding the potential relevance and importance of these cells in a clinical setting. METHODS: We here present the first seven patients treated with a dendritic cell (DC)-based vaccine targeting CSCs in a solid tumor. Brain tumor biopsies were dissociated into single-cell suspensions, and autologous CSCs were expanded in vitro as tumorspheres. From these, CSC-mRNA was amplified and transfected into monocyte-derived autologous DCs. The DCs were aliquoted to 9-18 vaccines containing 10(7) cells each. These vaccines were injected intradermally at specified intervals after the patients had received a standard 6-week course of post-operative radio-chemotherapy. The study was registered with the ClinicalTrials.gov identifier NCT00846456. RESULTS: Autologous CSC cultures were established from ten out of eleven tumors. High-quality RNA was isolated, and mRNA was amplified in all cases. Seven patients were able to be weaned from corticosteroids to receive DC immunotherapy. An immune response induced by vaccination was identified in all seven patients. No patients developed adverse autoimmune events or other side effects. Compared to matched controls, progression-free survival was 2.9 times longer in vaccinated patients (median 694 vs. 236 days, p = 0.0018, log-rank test). CONCLUSION: These findings suggest that vaccination against glioblastoma stem cells is safe, well-tolerated, and may prolong progression-free survival.


Assuntos
Neoplasias Encefálicas/terapia , Vacinas Anticâncer/administração & dosagem , Células Dendríticas/imunologia , Glioblastoma/terapia , Imunoterapia Adotiva/métodos , Células-Tronco Neoplásicas/imunologia , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Vacinas Anticâncer/imunologia , Terapia Combinada , Células Dendríticas/patologia , Intervalo Livre de Doença , Feminino , Glioblastoma/imunologia , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/patologia , RNA Mensageiro/genética , Telomerase/genética , Telomerase/imunologia , Transfecção
8.
Acta Oncol ; 52(6): 1086-93, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23621752

RESUMO

PURPOSE: To investigate the role of health-related quality of life (HRQoL) at randomization as independent prognostic factors for survival and time to failure, and to explore associations between HRQoL and treatment effects. MATERIAL AND METHODS: In the Nordic adjuvant interferon trial, a randomized trial evaluating if adjuvant therapy with intermediate-dose IFN had the same beneficial effects on overall and disease-free survival in high-risk melanoma as high-dose IFN, 855 patients in Denmark, Finland, Norway, and Sweden were included. The EORTC QLQ-C30 questionnaire was used to assess HRQoL before randomization. RESULTS: A total of 785 (92%) agreed to participate in the HRQoL-study and provided baseline HRQoL data. Prognostic variables included in the multivariate model were age, sex, performance status, tumor thickness, stage, and number of positive lymph nodes. Univariate analyses revealed an association between prolonged survival and age, stage/ number of metastatic lymph nodes and the HRQoL variable role functioning (p ≤ 0.01). After controlling for other prognostic factors, these variables remained independently statistically significant for survival. The univariate analyses of time to failure showed significant associations with the clinical variable stage/nodes and with the HRQoL variables physical functioning and role functioning. Adjusted multivariate analyses including the same clinical conditions as above showed statistically significant relationships between time to failure and global quality of life, physical functioning, role functioning, social functioning and fatigue (p ≤ 0.01). No interactions between HRQoL variables and treatment were found, with the exception for cognitive functioning. CONCLUSION: Role functioning was found to be an independent prognostic factor for time to failure and survival in patients with high-risk melanoma. Thus, also in this early stage of melanoma, HRQoL variables might be useful as important prognostic factors for time to failure and overall survival.


Assuntos
Antineoplásicos/administração & dosagem , Interferons/administração & dosagem , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adolescente , Adulto , Idoso , Quimioterapia Adjuvante , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Prognóstico , Qualidade de Vida , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Inquéritos e Questionários , Adulto Jovem
9.
Tidsskr Nor Laegeforen ; 133(20): 2154-9, 2013 Oct 29.
Artigo em Inglês, Norueguês | MEDLINE | ID: mdl-24172628

RESUMO

BACKGROUND: The incidence of malignant melanoma in Norway is among the highest in the world and rising, with approximately 1 500 persons receiving the diagnosis annually. Correct surgical primary treatment cures 80-90%, while 10-20% experience relapses. The treatment of a metastatic malignant melanoma has changed considerably in the last 1-2 years as a result of clinical experience with new drugs. The current publication provides an updated overview of the treatment of malignant melanoma in Norway. METHOD: The article is based on a search in PubMed and on the authors' own research and clinical experience. RESULTS: After several decades with almost no change in the treatment of malignant melanoma, we have seen a positive development over the past couple of years. New treatment methods for malignant melanoma with distant spreading metastases have yielded favourable results in selected patients and are currently established in cancer departments in Norway. INTERPRETATION: Rapid and correct primary treatment is curing most patients with malignant melanoma. New drugs offer hope for selected patient groups with metastatic disease. Several new types of targeted treatment are being tested in clinical studies in Norway and elsewhere in the world.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/diagnóstico , Melanoma/epidemiologia , Melanoma/patologia , Melanoma/terapia , Metástase Neoplásica , Noruega/epidemiologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia
10.
Lancet Oncol ; 12(2): 144-52, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21256809

RESUMO

BACKGROUND: Adjuvant high-dose interferon alfa-2b improves relapse-free survival (RFS) in patients with high-risk melanoma, although benefits in overall survival are uncertain. Because of the toxic effects of high-dose regimens, intermediate doses are being explored. We investigated whether adjuvant therapy with intermediate-dose interferon alfa-2b for 1 or 2 years would improve outcomes in patients with stage IIB-IIC or III resected cutaneous melanoma. METHODS: This randomised, open-label, phase 3, parallel-group trial was undertaken between 1996 and 2004. 855 patients were randomly assigned at 35 centres in the Nordic countries by block randomisation to three groups: observation only (group A); 4 weeks of induction (interferon alfa-2b 10 million units flat dose subcutaneously 5 days per week) followed by 12 months of maintenance therapy (interferon alfa-2b 10 million units flat dose subcutaneously 3 days per week; group B); or 1 month of induction and 24 months of maintenance (group C). Neither investigators nor patients were masked to treatment assignment. Patients were stratified for country and tumour stage; patients with stage III disease were further stratified for presence of metastatic lymph nodes at primary diagnosis versus at relapse, palpable versus non-palpable lymph-node metastases, and number of metastatic lymph nodes. The primary endpoint was overall survival in the two interferon alfa-2b groups combined. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01259934. FINDINGS: 284 patients were assigned to group A, 285 to group B, and 286 to group C; all patients were analysed. The median follow-up time was 72·4 months (IQR 46·9-98·0). We recorded no significant improvement in overall survival in patients given interferon alfa-2b compared with observation: median overall survival was 56·1 months (IQR 22·3 to >120·0) in group A, 72·1 months (25·8 to >120) in group B, and 64·3 months (24·7 to >120) in group C (p=0·600). Hazard ratios (HR) for overall survival were 0·91 (95% CI 0·74-1·10; p=0·642) for groups B and C combined versus observation; 0·91 (0·72-1·14; p=0·652) for group B versus observation; and 0·91 (0·72-1·15; p=0·858) for group C versus observation. Median RFS was 23·2 months (IQR 5·6 to <120) in group A, 37·8 months (10·8 to >120) in group B, and 28·6 months (8·6 to >120) in group C (p=0·034). HRs for RFS were 0·80 (0·67-0·96; p=0·030) for groups B and C combined versus observation, 0·77 (0·63-0·96; p=0·034) for group B versus observation, and 0·83 (0·68-1·03; p=0·178) for group C versus observation. The most common grade 3 and 4 adverse events were fatigue (five in group A [1·8%], 28 in group B [9·8%], and 32 in group C [11·2%]), myalgia (three [1·1%], 15 [5·3%], 14 [4·9%], respectively), and thrombocytopenia (15 [5·3%], 23 [8·1%], eight [2·8%], respectively). INTERPRETATION: Adjuvant therapy with intermediate-dose interferon alfa-2b did not significantly improve overall survival. Interferon alfa-2b with 1-year maintenance therapy significantly improved RFS, but we recorded no significant effect for 2-year maintenance therapy. Further research is in progress to define the subgroup of patients who benefit from adjuvant interferon alfa-2b. FUNDING: Schering-Plough (now Merck); the Radiumhemmet Research Funds, Stockholm; the Stockholm County Council; and the Swedish Cancer Society.


Assuntos
Quimioterapia Adjuvante , Relação Dose-Resposta a Droga , Interferon-alfa/uso terapêutico , Melanoma/tratamento farmacológico , Adolescente , Adulto , Idoso , Antineoplásicos/uso terapêutico , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Feminino , Humanos , Interferon alfa-2 , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Fatores de Risco , Fatores de Tempo
11.
J Immunother Cancer ; 10(5)2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35613827

RESUMO

BACKGROUND: Therapeutic cancer vaccines represent a promising approach to improve clinical outcomes with immune checkpoint inhibition. UV1 is a second generation telomerase-targeting therapeutic cancer vaccine being investigated across multiple indications. Although telomerase is a near-universal tumor target, different treatment combinations applied across indications may affect the induced immune response. Three phase I/IIa clinical trials covering malignant melanoma, non-small cell lung cancer, and prostate cancer have been completed, with patients in follow-up for up to 8 years. METHODS: 52 patients were enrolled across the three trials. UV1 was given as monotherapy in the lung cancer trial and concurrent with combined androgen blockade in the prostate cancer trial. In the melanoma study, patients initiated ipilimumab treatment 1 week after the first vaccine dose. Patients were followed for UV1-specific immune responses at frequent intervals during vaccination, and every 6 months for up to 8 years in a follow-up period. Phenotypic and functional characterizations were performed on patient-derived vaccine-specific T cell responses. RESULTS: In total, 78.4% of treated patients mounted a measurable vaccine-induced T cell response in blood. The immune responses in the malignant melanoma trial, where UV1 was combined with ipilimumab, occurred more rapidly and frequently than in the lung and prostate cancer trials. In several patients, immune responses peaked years after their last vaccination. An in-depth characterization of the immune responses revealed polyfunctional CD4+ T cells producing interferon-γ and tumor necrosis factor-α on interaction with their antigen. CONCLUSION: Long-term immunomonitoring of patients showed highly dynamic and persistent telomerase peptide-specific immune responses lasting up to 7.5 years after the initial vaccination, suggesting a plausible functional role of these T cells in long-term survivors. The superior immune response kinetics observed in the melanoma study substantiate the rationale for future combinatorial treatment strategies with UV1 vaccination and checkpoint inhibition for rapid and frequent induction of anti-telomerase immune responses in patients with cancer.


Assuntos
Vacinas Anticâncer , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Melanoma , Neoplasias da Próstata , Telomerase , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Ensaios Clínicos Fase I como Assunto , Seguimentos , Humanos , Imunidade , Ipilimumab/uso terapêutico , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Melanoma/tratamento farmacológico , Peptídeos , Neoplasias da Próstata/patologia , Neoplasias Cutâneas , Vacinação , Vacinas de Subunidades Antigênicas , Melanoma Maligno Cutâneo
12.
Cancer Immunol Immunother ; 60(6): 809-18, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21365467

RESUMO

Immunotherapy targeting the hTERT subunit of telomerase has been shown to induce robust immune responses in cancer patients after vaccination with single hTERT peptides. Vaccination with dendritic cells (DCs) transfected with hTERT mRNA has the potential to induce strong immune responses to multiple hTERT epitopes and is therefore an attractive approach to more potent immunotherapy. Blood samples from such patients provide an opportunity for identification of new, in vivo processed T-cell epitopes that may be clinically relevant. A 62-year-old female patient underwent radical surgery for a pancreatic adenocarcinoma. After relapse, she obtained stable disease on gemcitabine treatment. Due to severe neutropenia, the chemotherapy was terminated. The patient has subsequently been treated with autologous DCs loaded with hTERT mRNA for 3 years. Immunomonitoring was performed at regular intervals following start of vaccination and clinical outcome measured by CT and PET/CT evaluation. The patient developed an immune response against several hTERT-derived Th and CTL epitopes. She presently shows no evidence of active disease based on PET/CT scans. No serious adverse events were experienced and the patient continues to receive regular booster injections. We here provide evidence for the induction of hTERT-specific immune responses following vaccination of a pancreas cancer patient with DCs loaded with hTERT mRNA. These responses are associated with complete remission. A thorough analysis of this patient immune response has provided a unique opportunity to identify novel epitopes, associated with clinical effects. These will be included in future hTERT vaccines.


Assuntos
Vacinas Anticâncer/uso terapêutico , Carcinoma Ductal Pancreático/terapia , Células Dendríticas/imunologia , Neoplasias Pancreáticas/terapia , RNA Mensageiro/imunologia , Telomerase/imunologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologia , Processos de Crescimento Celular/imunologia , Linhagem Celular Tumoral , Epitopos/genética , Epitopos/imunologia , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , RNA Mensageiro/genética , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Telomerase/genética , Transfecção
13.
J Transl Med ; 9: 204, 2011 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-22123319

RESUMO

BACKGROUND: Ipilimumab, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4, has demonstrated an improvement in overall survival in two phase III trials of patients with advanced melanoma. The primary objective of the current trial was to prospectively explore candidate biomarkers from the tumor microenvironment for associations with clinical response to ipilimumab. METHODS: In this randomized, double-blind, phase II biomarker study (ClinicalTrials.gov NCT00261365), 82 pretreated or treatment-naïve patients with unresectable stage III/IV melanoma were induced with 3 or 10 mg/kg ipilimumab every 3 weeks for 4 doses; at Week 24, patients could receive maintenance doses every 12 weeks. Efficacy was evaluated per modified World Health Organization response criteria and safety was assessed continuously. Candidate biomarkers were evaluated in tumor biopsies collected pretreatment and 24 to 72 hours after the second ipilimumab dose. Polymorphisms in immune-related genes were also evaluated. RESULTS: Objective response rate, response patterns, and safety were consistent with previous trials of ipilimumab in melanoma. No associations between genetic polymorphisms and clinical activity were observed. Immunohistochemistry and histology on tumor biopsies revealed significant associations between clinical activity and high baseline expression of FoxP3 (p = 0.014) and indoleamine 2,3-dioxygenase (p = 0.012), and between clinical activity and increase in tumor-infiltrating lymphocytes (TILs) between baseline and 3 weeks after start of treatment (p = 0.005). Microarray analysis of mRNA from tumor samples taken pretreatment and post-treatment demonstrated significant increases in expression of several immune-related genes, and decreases in expression of genes implicated in cancer and melanoma. CONCLUSIONS: Baseline expression of immune-related tumor biomarkers and a post-treatment increase in TILs may be positively associated with ipilimumab clinical activity. The observed pharmacodynamic changes in gene expression warrant further analysis to determine whether treatment-emergent changes in gene expression may be associated with clinical efficacy. Further studies are required to determine the predictive value of these and other potential biomarkers associated with clinical response to ipilimumab.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Biomarcadores Tumorais/metabolismo , Melanoma/tratamento farmacológico , Melanoma/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Microambiente Tumoral , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Ipilimumab , Masculino , Melanoma/genética , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polimorfismo Genético , Estudos Prospectivos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Neoplasias Cutâneas/genética , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Adulto Jovem
14.
J Transl Med ; 9: 214, 2011 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-22168571

RESUMO

Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer.


Assuntos
Imunoterapia , Neoplasias/terapia , Humanos , Cooperação Internacional , Pesquisa Translacional Biomédica
15.
Front Immunol ; 12: 663865, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34046035

RESUMO

Background: Ipilimumab improves survival for patients with metastatic malignant melanoma. Combining a therapeutic cancer vaccine with ipilimumab may increase efficacy by providing enhanced anti-tumor immune responses. UV1 consists of three synthetic long peptides from human telomerase reverse transcriptase (hTERT). These peptides comprise epitopes recognized by T cells from cancer patients experiencing long-term survival following treatment with a first-generation hTERT vaccine, and generate long-lasting immune responses in cancer patients when used as monotherapy. The objective of this trial was to investigate the safety and efficacy of combining UV1 with ipilimumab in metastatic melanoma. Patients and Methods: In this phase I/IIa, single center trial [NCT02275416], patients with metastatic melanoma received repeated UV1 vaccinations, with GM-CSF as an adjuvant, in combination with ipilimumab. Patients were evaluated for safety, efficacy and immune response. Immune responses against vaccine peptides were monitored in peripheral blood by measuring antigen-specific proliferation and IFN-γ production. Results: Twelve patients were recruited. Adverse events were mainly diarrhea, injection site reaction, pruritus, rash, nausea and fatigue. Ten patients showed a Th1 immune response to UV1 peptides, occurring early and after few vaccinations. Three patients obtained a partial response and one patient a complete response. Overall survival was 50% at 5 years. Conclusion: Treatment was well tolerated. The rapid expansion of UV1-specific Th1 cells in the majority of patients indicates synergy between UV1 vaccine and CTLA-4 blockade. This may have translated into clinical benefit, encouraging the combination of UV1 vaccination with standard of care treatment regimes containing ipilimumab/CTLA-4 blocking antibodies.


Assuntos
Vacinas Anticâncer/imunologia , Ipilimumab/uso terapêutico , Melanoma/terapia , Telomerase/antagonistas & inibidores , Adulto , Idoso , Biomarcadores , Biópsia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Terapia Combinada , Feminino , Seguimentos , Humanos , Ipilimumab/administração & dosagem , Ipilimumab/efeitos adversos , Masculino , Melanoma/imunologia , Melanoma/patologia , Pessoa de Meia-Idade , Telomerase/imunologia , Resultado do Tratamento
16.
Front Immunol ; 11: 572172, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33324397

RESUMO

Human telomerase reverse transcriptase (hTERT) is a target antigen for cancer immunotherapy in patients with non-small cell lung cancer (NSCLC). We have tested a novel hTERT vaccine, UV1, designed to give high population coverage. UV1 is composed of three synthetic long peptides containing multiple epitopes identified by epitope spreading data from long-term survivors from previous hTERT vaccination trials. Eighteen non-HLA-typed patients with stage III/IV NSCLC with no evidence of progression after prior treatments, were enrolled in a phase I dose-escalation study of UV1 vaccination with GM-CSF as adjuvant, evaluating safety, immune response, and long-term clinical outcome. Treatment with UV1 was well tolerated with no serious adverse events observed. Seventeen patients were evaluable for tumor response; 15 patients had stable disease as best response. The median progression free survival (PFS) was 10.7 months, and the median overall survival (OS) was 28.2 months. The OS at 4 years was 39% (7/18). Five patients are alive (median survival 5.6 years), and none of these are known to have received checkpoint therapy after vaccination. UV1 induced specific T-cell responses in the majority (67%) of patients. Immune responses were dynamic and long lasting. Both immune response (IR) and OS were dose related. More patients in the highest UV1 dosage group (700 µg) developed IRs compared to the other groups, and the IRs were stronger and occurred earlier. Patients in this group had a 4-year OS of 83%. The safety and clinical outcome data favor 700 µg as the preferred UV1 dose in this patient population. These results provide a rationale for further clinical studies in NSCLC with UV1 vaccination in combination with immune checkpoint blockade. Clinical Trial Registration: https://www.clinicaltrials.gov, identifier NCT0178909.


Assuntos
Vacinas Anticâncer/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Epitopos de Linfócito T/imunologia , Imunoterapia/métodos , Neoplasias Pulmonares/imunologia , Linfócitos T/imunologia , Telomerase/imunologia , Idoso , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Células Cultivadas , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Neoplasias Pulmonares/mortalidade , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Análise de Sobrevida , Resultado do Tratamento , Vacinas de Subunidades Antigênicas
17.
BMC Med Res Methodol ; 9: 28, 2009 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-19405936

RESUMO

BACKGROUND: Health-related quality of life is a topic of current interest. This paper considers a randomized phase III study of radiation therapy with concurrent chemotherapy (docetaxel) versus radiation therapy alone in non-small cell lung cancer, stage III A/B. Longitudinal data on quality of life have been obtained through repeated administration of a multi-item questionnaire (EORTC QLQ-C30) developed by the European Organisation for Research and Treatment of Cancer. Missingness in the data is owing to patients having failed to complete the questionnaire at some of the scheduled filling-in times. METHODS: We have analysed a monotone (in terms of missingness) subset of the data as regards estimation of the mean score of a summary measure of self-reported quality of life in a hypothetical drop-out-free population at different points in time. Missingness is a difficult issue of great importance. We have therefore chosen to compare three different methods that are relatively easy to implement: the linear-increments method, the inverse-probability-weighting method and the Markov-process method. Single imputation has been applied in a supplementary analysis to fill in for all the non-consecutive missing score values prior to the execution of the estimation procedure. RESULTS: For the response in focus, the observed mean score at a certain time is larger than the estimated mean scores, which implies that the true mean score is easily overestimated unless the missingness is appropriately adjusted for. Comparison of the treatment arms shows a significant difference in mean score at the end of treatment. CONCLUSION: Use of proper methodology developed for analysing data subject to missingness is necessary to reduce potential estimation bias. The quality of life of patients receiving radiation therapy with concurrent chemotherapy (docetaxel) appears somewhat worse than that of patients receiving radiation therapy alone in the period during which treatment is given. The conclusions are robust for the choice of statistical methods.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Qualidade de Vida , Estatística como Assunto/métodos , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Quimioterapia Adjuvante , Docetaxel , Feminino , Humanos , Modelos Lineares , Estudos Longitudinais , Masculino , Cadeias de Markov , Probabilidade , Inquéritos e Questionários , Taxoides/uso terapêutico
18.
Acta Oncol ; 48(1): 137-45, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-18607882

RESUMO

PURPOSE: Cytarabine (ara-C) has limited activity in solid tumours. CP-4055 (ELACYT) is a novel ara-C-5'-elaidic acid ester that may circumvent this limitation. CP-4055 maximum tolerated dose (MTD), pharmacokinetics and antitumor activity have been investigated in patients with solid tumours. MATERIAL AND METHODS: Thirty-four patients (19 malignant melanoma, 8 ovarian cancers and 7 NSCLC) received CP-4055 as a 30 min, or 2 hr intravenous (IV) infusion daily for 5 consecutive days every 3 or 4 weeks (D1-5 q3w or D1-5 q4w) in a dose escalation designed study with doses ranging from 30 to 240 mg/m(2)/day. RESULTS: The most frequent CTC grade 1-2 adverse events (AEs) were nausea, fatigue, vomiting, anorexia and pyrexia. Most of the grade 3-4 AEs were neutropenia. The MTD was 200 mg/m(2)/day and 240 mg/m(2)/day for D1-5 q3w and D1-5 q4w, respectively. The MTD was independent of infusion time in the 4 week schedule. CP-4055 was maintained in plasma for up to 5-10 hr at dose levels >150 mg/m(2)/day. One objective partial response (PR) with time to progression (TTP) of 22 months was reported in an advanced malignant melanoma patient. CONCLUSION: CP-4055 was well tolerated; the majority of the AEs were of CTC grade 1. The 3 week schedule was not recommended due to neutropenic nadir between days 18-26. The recommended dose was 200 mg/m(2)/day in a D1-5 q4w schedule. Efficacy data suggest that CP-4055 might be active in treatment of solid tumours.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Citarabina/análogos & derivados , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Citarabina/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Infusões Intravenosas , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo
19.
Genes Chromosomes Cancer ; 47(2): 175-84, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18023021

RESUMO

The presence of multiple primary cutaneous melanomas (MPM) has been advocated as guidance to identifying melanoma families. Frequencies of CDKN2A mutations in materials of sporadic MPM cases from pigmented lesion clinics vary between 8 and 15%. Patients with MPM have therefore been regarded as good candidates for CDKN2A mutational screening. We describe a population-based study where all persons in Norway diagnosed with MPM between 1953 and 2004 (n = 738 alive per April 2004) were invited to participate. Three-hundred-and-ninety patients (52.8%) responded confidentially. Mutations in CDKN2A were found in 6.9% of the respondents. Eighty-one MPM patients (20.8%) reported that they belonged to melanoma families, and 17 (21.0%) of these harboured a CDKN2A mutation, compared to 3.2% of the nonfamilial cases. The probability of finding a CDKN2A mutation increased when the patients had three or more melanomas, or a young age of onset of first melanoma. We identified five novel CDKN2A variants (Ala57Gly, Pro81Arg, Ala118Val, Leu130Val, and Arg131Pro) and four that previously have been reported in melanoma families (Glu27X, Met53Ile, Arg87Trp, and Ala127Pro). A large deletion (g.13623_23772del10150) encompassing exon 1alpha and the 5' part of exon 2 was detected in six patients with a family history of melanoma. Three patients, belonging to the same family, had the CDK4 Arg24His mutation. The frequency of CDKN2A mutations was lower than previously reported in other studies, an observation which probably is due to the population-based design of our study.


Assuntos
Quinase 4 Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Genes p16 , Melanoma/genética , Mutação , Neoplasias Cutâneas/genética , Adulto , Substituição de Aminoácidos/genética , Sequência de Bases , Estudos Transversais , Feminino , Variação Genética , Humanos , Masculino , Melanoma/epidemiologia , Pessoa de Meia-Idade , Dados de Sequência Molecular , Prevalência , Neoplasias Cutâneas/epidemiologia
20.
Lung Cancer ; 61(2): 170-6, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18261824

RESUMO

BACKGROUND: The clinical relevance of bone marrow micrometastases in non-small cell lung cancer (NSCLC) is undetermined, and the value of such analyses in advanced stage patients has not been assessed previously. METHODS: Immunomagnetic selection with the MOC31 (anti-EpCam) antibody was performed to isolate and detect tumor cells in bone marrow aspirates obtained from 196 patients with NSCLC, and the patients were subjected to follow-up for the assessment of survival. Repeated bone marrow samples, 2-7 samples per patient, were obtained from 13 long-term survivors. RESULTS: MOC31 positive tumor cells were detected in 107 of 196 (55%) samples, a frequency similar to results reported in low-stage patients prior to curative surgical resection for NSCLC. No association was found between the presence of bone marrow micrometastases and disease stage or histological subgroup, and survival was similar in patients with and without detectable tumor cells in bone marrow. Repeated bone marrow analysis revealed, for the first time in this group of patients, the continued presence of tumor cells regardless of the given therapy and treatment response. CONCLUSION: The immunomagnetic method utilized is a feasible strategy for the detection of bone marrow micrometastases in NSCLC. In advanced stage patients, the presence of MOC31 positive cells in bone marrow does not predict survival. Repeated analyses of bone marrow samples from long-term survivors revealed tumor cells in bone marrow which may represent dormant cells of particular interest for further characterization and follow-up.


Assuntos
Antígenos de Neoplasias/metabolismo , Neoplasias da Medula Óssea/secundário , Medula Óssea/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Moléculas de Adesão Celular/metabolismo , Neoplasias Pulmonares/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/imunologia , Medula Óssea/patologia , Neoplasias da Medula Óssea/metabolismo , Neoplasias da Medula Óssea/mortalidade , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Moléculas de Adesão Celular/imunologia , Molécula de Adesão da Célula Epitelial , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Separação Imunomagnética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sobrevida , Fatores de Tempo
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