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Interleukin-2 (IL-2) was historically one of the few treatments for adults with stage IV solid tumors that could produce complete responses (CRs) that were often durable for decades without further therapy. The majority of complete responders with metastatic renal cell carcinoma (mRCC) and metastatic melanoma (mM) could probably be classified as "cures". Recent publications have suggested improved efficacy, perhaps due to improved patient selection based on a better understanding of clinical features predicting outcomes. Guidelines for clinical management were established from experience at the National Cancer Institute (NCI) and an affiliation of institutions known as the Cytokine Working Group (CWG), who were among the first to utilize HD IL-2 treatment outside of the NCI. As new centers have opened, further management variations have emerged based upon center-specific experience, to optimize administration of IL-2 and provide high quality care for patients at each individual site. Twenty years of evolution in differing environments has led to a plethora of clinical experience and effective management approaches. The goal of this review is to summarize the spectrum of HD IL-2 treatment approaches, describing various effective strategies that incorporate newer adjunctive treatments for managing the side effects of IL-2 in patients with mRCC and mM. The goal for IL-2 therapy is typically to administer the maximum number of doses of IL-2 without putting the patient at unacceptable risk for severe, irreversible toxicity. This review is based upon a consensus meeting and includes guidelines on pre-treatment screening, criteria for administration and withholding doses, and defines consensus criteria for safe administration and toxicity management. The somewhat heterogeneous best practices of 2014 will be compared and contrasted with the guidelines provided in 2001 and the package inserts from 1992 and 1998.
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OBJECTIVES: Selective internal radiation therapy (SIRT) with yttrium-90 (Y) microspheres has emerged as an effective liver-directed therapy with a favorable therapeutic ratio for treatment of colorectal cancer liver metastases. The aim of this study was to investigate the objective responses obtained by Y microsphere treatment when combined with contemporary chemotherapy in the front-line (first or second line) setting in patients with CRCLM. METHODS: This study used an in vivo comparison between the right and left liver lobes; systemic chemotherapy was supplied to both liver lobes by virtue of systemic administration, whereas SIRT was administered selectively to the target liver lobe only. Response to treatment was evaluated by serial fludeoxyglucose positron emission tomography computed tomography performed at 4 weeks, 2 to 4 months, and 6 to 8 months. Standard uptake value, anatomic volume, functional tumor volume, and total lesion glycolysis (TLG) calculations were obtained at each time point. RESULTS: A decrease in TLG on fludeoxyglucose positron emission tomography computed tomography imaging was seen in 19 of the 20 patients. The mean decrease in TLG values in the tumors receiving chemo-SIRT and chemo-only treatment were 86.26%±18.57% and 31.74%±80.99% (P<0.01), 93.13%±11.81% and 40.80%±73.32% (P=0.01), and 90.55%±19.75% and 54.91%±38.55% (P<0.01) at 4 weeks, 2 to 4 months, 6 to 8 months posttreatment, respectively. Functional and anatomic tumor volume changes were in concordance with the TLG changes. CONCLUSIONS: The study demonstrated that, under near identical conditions in terms of patient and tumor characteristics, the chemo-SIRT combination produced superior objective responses compared with chemo-only treatment in a front-line treatment setting in patients with colorectal cancer liver metastases.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Braquiterapia , Quimiorradioterapia , Neoplasias Colorretais/terapia , Neoplasias Hepáticas/terapia , Microesferas , Radioisótopos de Ítrio , Adulto , Idoso , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/patologia , Feminino , Fluordesoxiglucose F18 , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Irinotecano , Leucovorina/administração & dosagem , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Tomografia por Emissão de Pósitrons , Prognóstico , Estudos Prospectivos , Compostos Radiofarmacêuticos , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: The Proteus syndrome is characterized by the overgrowth of skin, connective tissue, brain, and other tissues. It has been hypothesized that the syndrome is caused by somatic mosaicism for a mutation that is lethal in the nonmosaic state. METHODS: We performed exome sequencing of DNA from biopsy samples obtained from patients with the Proteus syndrome and compared the resultant DNA sequences with those of unaffected tissues obtained from the same patients. We confirmed and extended an observed association, using a custom restriction-enzyme assay to analyze the DNA in 158 samples from 29 patients with the Proteus syndrome. We then assayed activation of the AKT protein in affected tissues, using phosphorylation-specific antibodies on Western blots. RESULTS: Of 29 patients with the Proteus syndrome, 26 had a somatic activating mutation (c.49GâA, p.Glu17Lys) in the oncogene AKT1, encoding the AKT1 kinase, an enzyme known to mediate processes such as cell proliferation and apoptosis. Tissues and cell lines from patients with the Proteus syndrome harbored admixtures of mutant alleles that ranged from 1% to approximately 50%. Mutant cell lines showed greater AKT phosphorylation than did control cell lines. A pair of single-cell clones that were established from the same starting culture and differed with respect to their mutation status had different levels of AKT phosphorylation. CONCLUSIONS: The Proteus syndrome is caused by a somatic activating mutation in AKT1, proving the hypothesis of somatic mosaicism and implicating activation of the PI3K-AKT pathway in the characteristic clinical findings of overgrowth and tumor susceptibility in this disorder. (Funded by the Intramural Research Program of the National Human Genome Research Institute.).
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Mosaicismo , Mutação , Síndrome de Proteu/genética , Proteínas Proto-Oncogênicas c-akt/genética , Criança , Análise Mutacional de DNA , Éxons/genética , Genótipo , Humanos , Masculino , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
BACKGROUND: Stimulating an immune response against cancer with the use of vaccines remains a challenge. We hypothesized that combining a melanoma vaccine with interleukin-2, an immune activating agent, could improve outcomes. In a previous phase 2 study, patients with metastatic melanoma receiving high-dose interleukin-2 plus the gp100:209-217(210M) peptide vaccine had a higher rate of response than the rate that is expected among patients who are treated with interleukin-2 alone. METHODS: We conducted a randomized, phase 3 trial involving 185 patients at 21 centers. Eligibility criteria included stage IV or locally advanced stage III cutaneous melanoma, expression of HLA*A0201, an absence of brain metastases, and suitability for high-dose interleukin-2 therapy. Patients were randomly assigned to receive interleukin-2 alone (720,000 IU per kilogram of body weight per dose) or gp100:209-217(210M) plus incomplete Freund's adjuvant (Montanide ISA-51) once per cycle, followed by interleukin-2. The primary end point was clinical response. Secondary end points included toxic effects and progression-free survival. RESULTS: The treatment groups were well balanced with respect to baseline characteristics and received a similar amount of interleukin-2 per cycle. The toxic effects were consistent with those expected with interleukin-2 therapy. The vaccine-interleukin-2 group, as compared with the interleukin-2-only group, had a significant improvement in centrally verified overall clinical response (16% vs. 6%, P=0.03), as well as longer progression-free survival (2.2 months; 95% confidence interval [CI], 1.7 to 3.9 vs. 1.6 months; 95% CI, 1.5 to 1.8; P=0.008). The median overall survival was also longer in the vaccine-interleukin-2 group than in the interleukin-2-only group (17.8 months; 95% CI, 11.9 to 25.8 vs. 11.1 months; 95% CI, 8.7 to 16.3; P=0.06). CONCLUSIONS: In patients with advanced melanoma, the response rate was higher and progression-free survival longer with vaccine and interleukin-2 than with interleukin-2 alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00019682.).
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Antineoplásicos/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Interleucina-2/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Antineoplásicos/efeitos adversos , Vacinas Anticâncer/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Interleucina-2/efeitos adversos , Masculino , Melanoma/mortalidade , Pessoa de Meia-Idade , Neoplasias Cutâneas/mortalidade , Análise de SobrevidaRESUMO
Progress in understanding the molecular basis of melanoma has made possible the identification of molecular targets with important implications in clinical practice. In fact, new therapeutic approaches are emerging from basic science and it will be important to implement their rapid translation into clinical practice by active clinical investigation. The first meeting of Melanoma Research: a bridge Naples-USA, organized by Paolo A. Ascierto (INT, Naples, Italy) and Francesco Marincola (NIH, Bethesda, USA) took place in Naples, on 6-7 December 2010. This international congress gathered more than 30 international and Italian faculty members and was focused on recent advances in melanoma molecular biology, immunology and therapy, and created an interactive discussion across Institutions belonging to Government, Academy and Pharmaceutical Industry, in order to stimulate new approaches in basic, translational and clinical research. Four topics of discussion were identified: New pathways in Melanoma, Biomarkers, Clinical Trials and New Molecules and Strategies.
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Melanoma/terapia , Pesquisa/tendências , Animais , Biomarcadores Tumorais/metabolismo , Ensaios Clínicos como Assunto , Humanos , Itália , Melanoma/metabolismo , Camundongos , Transdução de Sinais , Estados UnidosRESUMO
INTRODUCTION: Parallel to the advances in diagnostic imaging using positron emission tomography (PET), and availability of new systemic treatment options, the treatment paradigm in oncology has shifted towards more aggressive therapeutic interventions to include cytoreductive techniques and metastasectomies. Intraoperative localization of PET positive recurrent/metastatic lesions can be facilitated using a hand-held PET probe. MATERIALS AND METHODS: Records of patients who underwent PET probe-guided surgery were reviewed. Surgical indications and operative targets were determined based on diagnostic PET/PET-CT images performed prior to probe-guided surgical planning. PET probe-guided surgery was performed on a separate day using a high-energy gamma probe (PET probe, Care Wise Medical, Morgan Hills CA) 2-6 hours post-injection of 5-15 mCi FDG. Probe count rates, target-to-background ratios, and lesion detection success were analyzed. RESULTS: Twenty-four patients underwent PET probe-guided surgery; one patient had two PET-probe guided surgeries resulting in a total of 25 cases (5 colorectal cancer cases, 4 thyroid cancer cases, 6 lymphoma cancer cases, and 10 other cancer cases). Surgical indication was diagnostic exploration in 6 cases with lymphoma and 1 case with head and neck cancer (28%). The remaining 18 cases (72%) underwent PET probe-guided surgery with a therapeutic intent in a recurrent or metastatic disease setting. All the lesions identified and targeted on a preoperative FDG-PET scan were detected by the PET probe with satisfactory in-vivo lesion count rates and a TBR of >/= 1.5. PET probe allowed localization of lesions that were non-palpable and non-obvious at surgical exploration in 8 patients. CONCLUSION: The use of the PET probe improves the success of surgical exploration in selected indications. Separate day protocol is clinically feasible allowing for flexible operating room scheduling.
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Neoplasias/cirurgia , Tomografia por Emissão de Pósitrons , Cirurgia Assistida por Computador , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico por imagem , Compostos Radiofarmacêuticos , Adulto JovemRESUMO
Proteus syndrome (PS) is a severe, variable, and rare disorder with asymmetric and disproportionate overgrowth of body parts, cerebriform connective tissue nevi, epidermal nevi, dysregulated adipose tissue, and vascular malformations. It is associated with benign and occasionally malignant tumors. We report the first case of ductal carcinoma in situ (DCIS) in a 28-yr-old woman with PS who underwent a mastectomy for asymmetric overgrowth. The cut surface of the tissue showed a discrete, white, lobulated, solid mass with multiple cysts with occasional small polypoid nodules. Microscopically, the tissue was characterized by neoplastic and non-neoplastic changes. The former consisted of multiple intraductal papillomas and low-grade intraductal papillary, solid, and cribriform carcinoma. The non-neoplastic changes were characterized by cysts of various sizes, lined by cuboidal or apocrine cells, focally with epithelial papillary proliferation; the lumens contained eosinophilic, mucicarmine-positive, and PAS-positive material. Variable ductal proliferation and periductal, peri- and intra-lobular fibrosis with loose fibrous connective tissue was present. The carcinoma was positive for ER, PR, CK7, and MIB-1 (40%), and negative for p53 and CK20 staining. We conclude that DCIS may be one of the tumors associated with PS and that the proliferative phenotype serves as an initiator for carcinogenesis. This case highlights the difficulty of recognizing small foci of carcinoma in an asymmetrical overgrowth of the breast in a young woman with PS.
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Neoplasias da Mama/patologia , Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Síndrome de Proteu/patologia , Adulto , Biomarcadores Tumorais/análise , Mama/cirurgia , Neoplasias da Mama/química , Neoplasias da Mama/cirurgia , Carcinoma Intraductal não Infiltrante/química , Carcinoma Intraductal não Infiltrante/cirurgia , Feminino , Humanos , Mastectomia , Síndrome de Proteu/cirurgiaRESUMO
The purpose of this study was to describe and compare the cardiac magnetic resonance (CMR) characteristics of myocarditis caused by high dose interleukin-2 (7 patients) with community-acquired myocarditis (14 patients). A total of 21 patients with suspected myocarditis and elevated cardiac enzymes underwent cine CMR followed by delayed enhancement. The mean ejection fraction was mildly decreased in both groups. The location, pattern, and extent of DE were similar in both groups of patients. The CMR similarities between these two populations suggest that cytokine-mediated cytotoxicity may play an important role in community-acquired myocarditis.
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Antineoplásicos/efeitos adversos , Interleucina-2/efeitos adversos , Imagem Cinética por Ressonância Magnética/métodos , Miocardite/induzido quimicamente , Idoso , Antineoplásicos/administração & dosagem , Feminino , Humanos , Interleucina-2/administração & dosagem , Masculino , Melanoma/tratamento farmacológico , Pessoa de Meia-Idade , Estudos Retrospectivos , Estatísticas não ParamétricasRESUMO
The identification of many tumor-associated epitopes as nonmutated "self" Ags led to the hypothesis that the induction of large numbers of self/tumor Ag-specific T cells would be prevented because of central and peripheral tolerance. We report in this study on vaccination efforts in 95 HLA-A*0201 patients at high risk for recurrence of malignant melanoma who received prolonged immunization with the "anchor-modified" synthetic peptide, gp100209-217(210M). Vaccination using this altered peptide immunogen was highly effective at inducing large numbers of self/tumor-Ag reactive T cells in virtually every patient tested, with levels as high as 42% of all CD8+ T cells assessed by tetramer analysis. From 1 to 10% of all CD8+ cells were tumor-Ag reactive in 44% of patients and levels >10% were generated in 17% of patients. These studies were substantiated using the ELISPOT assay and a bulk cytokine release assay. Although our data regarding "tumor escape" were inconclusive, some patients had growing tumors that expressed Ag and HLA-A*0201 in the presence of high levels of antitumor T cells. There was no difference in the levels of antitumor Ag-specific T cells in patients who recurred compared with those that remained disease-free. Thus, the mere presence of profoundly expanded numbers of vaccine-induced, self/tumor Ag-specific T cells cannot by themselves be used as a "surrogate marker" for vaccine efficacy. Further, the induction of even high levels of antitumor T cells may be insufficient to alter tumor progression.
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Antígenos de Neoplasias/imunologia , Autoantígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/imunologia , Melanoma/imunologia , Glicoproteínas de Membrana/imunologia , Fragmentos de Peptídeos/imunologia , Neoplasias Cutâneas/imunologia , Adulto , Idoso , Progressão da Doença , Feminino , Humanos , Imunização , Masculino , Melanoma/mortalidade , Melanoma/terapia , Pessoa de Meia-Idade , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/terapia , Antígeno gp100 de MelanomaRESUMO
High-dose interleukin-2 (IL-2) results in objective clinical regression in up to 17% of patients with metastatic melanoma and renal cell carcinoma, with about half of these patients experiencing a complete regression of all lesions. Gastrointestinal (GI) perforation is a rare but potentially serious complication of IL-2 administration. A retrospective review of all patients treated with IL-2 in the Surgery Branch of the National Cancer Institute (NCI) between Nov. 1, 1984, and May 1, 2002, was performed. In addition, a review of the published English literature on GI perforation in conjunction with IL-2 therapy was performed. Among the 1,797 patients treated at the NCI, there were eight (0.44%) cases of GI perforation. Seven of the eight patients were treated with high-dose (720,000 IU/kg every 8 hours) intravenous IL-2 (7/1,680, 0.42%) and one was treated with subcutaneous IL-2 (1/117, 0.85%). These patients developed various signs and symptoms of GI perforation. Six patients developed abdominal pain, yet only two of the eight patients had a fever. All six patients who underwent radiographic evaluation prior to diagnosis had free intraperitoneal air seen on the study. The location of the perforation included the stomach, small bowel, appendix, and colon. All underwent surgical treatment successfully, and four patients received further IL-2 therapy after recovering from the perforation. With the patients presented in this article, there have now been 20 cases reported in the English literature. Two of the patients at the NCI had a ruptured appendix, which has not been previously reported in the literature. The key to early diagnosis of GI perforation during IL-2 therapy is radiographic evaluation. Patients with GI perforation can be safely retreated with IL-2 if they are given adequate time to recover from their surgical intervention and if careful assessment is performed to rule out residual infection.
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Sistema Digestório/efeitos dos fármacos , Interleucina-2/efeitos adversos , Interleucina-2/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Carcinoma de Células Renais/tratamento farmacológico , Feminino , Gastroenteropatias/etiologia , Humanos , Masculino , Melanoma/tratamento farmacológico , Pessoa de Meia-IdadeRESUMO
The development of effective autologous cell transfer therapies for the treatment of patients with cancer has been difficult, in part because the cells used to treat each patient are different, as are the patient's tumor and immune status. Much can thus be learned by sequential treatments of the same patient with the same cells, making single modifications in the treatments to determine which factors are critical. The authors have treated a single patient with five sequential administrations of the same cells with minor modifications in the mode of administration and the immune status of the patient. The treatment of this patient strongly suggested that 1) the highly avid recognition of tumor antigens in vitro by a transferred lymphocyte population does not necessarily predict in vivo antitumor activity; 2) the administration of highly avid antitumor autologous lymphocyte populations can be far more active in mediating tumor regression in vivo when administered after nonmyeloablative chemotherapy than when administered without this prior chemotherapy; 3) intra-arterial administration of highly avid antitumor autologous lymphocytes into the blood supply of the tumor can be more effective in mediating tumor regression than the intravenous administration of these same tumor infiltrating lymphocytes; 4) one mechanism of tumor escape from immunotherapy is loss of class I MHC antigen expression by the tumor due to mutation of the beta-2 microglobulin gene.
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Imunoterapia Adotiva , Linfócitos do Interstício Tumoral/imunologia , Linfócitos/imunologia , Melanoma/terapia , Neoplasias Cutâneas/terapia , Adulto , Anticorpos Monoclonais , Antígenos de Neoplasias/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/transplante , Células Cultivadas , Terapia Combinada , Ciclofosfamida/administração & dosagem , Feminino , Antígeno HLA-A2/imunologia , Humanos , Interleucina-2/administração & dosagem , Transfusão de Linfócitos , Linfócitos do Interstício Tumoral/transplante , Melanoma/imunologia , Melanoma/secundário , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/imunologia , Resultado do Tratamento , Células Tumorais Cultivadas , Microglobulina beta-2/genéticaRESUMO
OBJECTIVE: To provide a review of cancer vaccines, how they work, and the current state of the science underlying these treatments. DATA SOURCES: Research studies, review articles, book chapters, personal communications. CONCLUSION: Vaccines have been studied in a variety of malignancies; however, melanoma has provided the best tumor model for vaccination. Clinical trials continue to investigate the optimal vaccine, route, and immunization schedule. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses must grasp a widening array of therapeutic options for cancer patients. The educational needs of the patient will be better met through a thorough understanding of basic concepts of newer cancer therapies.
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Vacinas Anticâncer/administração & dosagem , Imunoterapia/enfermagem , Neoplasias/enfermagem , Neoplasias/prevenção & controle , Enfermagem Oncológica , Adjuvantes Imunológicos/administração & dosagem , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/classificação , Vacinas Anticâncer/imunologia , Humanos , Neoplasias/tratamento farmacológico , Evasão Tumoral/imunologiaRESUMO
BACKGROUND: Mutations in the tumor-suppressor gene VHL cause oversecretion of vascular endothelial growth factor by clear-cell renal carcinomas. We conducted a clinical trial to evaluate bevacizumab, a neutralizing antibody against vascular endothelial growth factor, in patients with metastatic renal-cell carcinoma. METHODS: A randomized, double-blind, phase 2 trial was conducted comparing placebo with bevacizumab at doses of 3 and 10 mg per kilogram of body weight, given every two weeks; the time to progression of disease and the response rate were primary end points. Crossover from placebo to antibody treatment was allowed, and survival was a secondary end point. RESULTS: Minimal toxic effects were seen, with hypertension and asymptomatic proteinuria predominating. The trial was stopped after the interim analysis met the criteria for early stopping. With 116 patients randomly assigned to treatment groups (40 to placebo, 37 to low-dose antibody, and 39 to high-dose antibody), there was a significant prolongation of the time to progression of disease in the high-dose--antibody group as compared with the placebo group (hazard ratio, 2.55; P<0.001). There was a small difference, of borderline significance, between the time to progression of disease in the low-dose--antibody group and that in the placebo group (hazard ratio, 1.26; P=0.053). The probability of being progression-free for patients given high-dose antibody, low-dose--antibody, and placebo was 64 percent, 39 percent, and 20 percent, respectively, at four months and 30 percent, 14 percent, and 5 percent at eight months. At the last analysis, there were no significant differences in overall survival between groups (P>0.20 for all comparisons). CONCLUSIONS: Bevacizumab can significantly prolong the time to progression of disease in patients with metastatic renal-cell cancer.
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Anticorpos Monoclonais/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Fatores de Crescimento Endotelial/antagonistas & inibidores , Neoplasias Renais/tratamento farmacológico , Linfocinas/antagonistas & inibidores , Proteínas Supressoras de Tumor , Ubiquitina-Proteína Ligases , Adenocarcinoma de Células Claras/tratamento farmacológico , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/secundário , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Bevacizumab , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/secundário , Progressão da Doença , Método Duplo-Cego , Fatores de Crescimento Endotelial/imunologia , Feminino , Genes Supressores de Tumor , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Ligases/genética , Metástase Linfática , Linfocinas/imunologia , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular , Proteína Supressora de Tumor Von Hippel-LindauRESUMO
PURPOSE: This three-arm randomized study compares response rates and overall survival of patients with metastatic renal cell cancer (RCC) receiving high-dose or one of two low-dose interleukin-2 (IL-2) regimens. PATIENTS AND METHODS: Patients with measurable metastatic RCC and a good performance status were randomized to receive either 720,000 U/kg (high-dose [HD]) or 72,000 U/kg (low-dose [LD]), both given by intravenous (IV) bolus every 8 hours. After randomly assigning 117 patients, a third arm of low-dose daily subcutaneous IL-2 was added, and an additional 283 patients were randomly assigned. RESULTS: A total of 156 patients were randomly assigned to HD IV IL-2, and 150 patients to LD IV IL-2. Toxicities were less frequent with LD IV IL-2 (especially hypotension), but there were no IL-2-related deaths in any arm. There was a higher response proportion with HD IV IL-2 (21%) versus LD IV IL-2 (13%; P =.048) but no overall survival difference. The response rate of subcutaneous IL-2 (10%, partial response and complete response) was similar to that of LD IV IL-2, differing from HD IV (P =.033). Response durability and survival in completely responding patients was superior with HD IV compared with LD IV therapy (P =.04). CONCLUSION: Major tumor regressions, as well as complete responses, were seen with all regimens tested. IL-2 was more clinically active at maximal doses, although this did not produce an overall survival benefit. The immunological factors which constrain the curative potential of IL-2 to only a small percentage of patients need to be further elucidated.
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Carcinoma de Células Renais/tratamento farmacológico , Interleucina-2/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de SobrevidaRESUMO
PURPOSE: The purpose of this study was to evaluate the immunological responses and therapeutic effectiveness of immunization with fowlpox vaccines encoding the gp100 melanoma antigen in patients with metastatic melanoma. EXPERIMENTAL DESIGN: In three consecutive clinical trials, patients were immunized with recombinant fowlpox viruses encoding three different forms of the melanoma/melanocyte-associated antigen gp100: (a) the native, full-length gp100 molecule; (b) the gp100 molecule with two amino acids modified to increase binding to HLA-A*0201 molecules; and (c) a "minigene" construct encoding a single, modified epitope gp100:209-217(210M) targeted to the endoplasmic reticulum. The immunogenicity of these constructs was studied using peripheral blood mononuclear cells to measure epitope-specific release of IFN-gamma. RESULTS: Reactivity against gp100 was not seen in any patient before receiving fowlpox immunization. Whereas just one of seven patients developed reactivity after receiving fowlpox encoding native gp100, 10 of 14 patients who received fowlpox encoding the anchor modified full-length gp100 exhibited reactivity against the native gp100 molecule, and 12 of 16 patients were successfully immunized after inoculation with the modified minigene construct (p2 = 0.02). There was no difference in the latter group between those randomized to vaccination by i.v. or i.m. routes. There was one partial cancer regression in the group of 46 patients receiving virus in the absence of interleukin (IL)-2. Once patients showed evidence of progressive disease, they were eligible for "cross-over" treatment to IL-2 alone or with the fowlpox virus. None of the 13 patients receiving the full-length or modified full-length forms of gp100 responded when receiving IL-2, whereas 6 of 12 patients who received the fowlpox containing the minigene construct and then received IL-2 showed objective cancer regressions, including three patients with complete regression. CONCLUSIONS: These data underscore the importance of modifying anchor residues of nonmutated self-antigen peptides to generate cellular immune responses after immunization and support the further investigation of recombinant fowlpox viruses encoding modified epitopes administered in combination with IL-2.
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Vírus da Varíola das Aves Domésticas/química , Melanoma/metabolismo , Glicoproteínas de Membrana/química , Proteínas de Neoplasias/química , Adulto , Idoso , Antígenos de Neoplasias/química , Linfócitos T CD8-Positivos/metabolismo , Vacinas Anticâncer , Linhagem Celular Tumoral , Epitopos/química , Feminino , Antígenos HLA-A/genética , Antígeno HLA-A2 , Humanos , Imunoglobulina G/química , Interferon gama/metabolismo , Interleucina-2/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Peptídeos/química , Vacinas/química , Vaccinia virus/metabolismo , Antígeno gp100 de MelanomaRESUMO
Cancer vaccines targeting CD8+ T cells have been successful in eliciting immunologic responses but disappointing in inducing clinical responses. Strong evidence supports the importance of CD4+ T cells in "helping" cytotoxic CD8+ cells in antitumor immunity. We report here on two consecutive clinical trials evaluating the impact of immunization with both human leukocyte antigen class I- and class II-restricted peptides from the gp100 melanoma antigen. In Protocol 1, 22 patients with metastatic melanoma were immunized with two modified class I A*0201-restricted peptides, gp100:209-217(210M) and MART-1:26-35(27L). In Protocol 2, 19 patients received the same class I-restricted peptides in combination with a class II DRB1*0401-restricted peptide, gp100:44-59. As assessed by in vitro sensitization assays using peripheral blood mononuclear cells (PBMC) against the native gp100:209-217 peptide, 95% of patients in Protocol 1 were successfully immunized after two vaccinations in contrast to 50% of patients in Protocol 2 (P(2) < 0.005). Furthermore, the degree of sensitization was significantly lower in patients in Protocol 2 (P = 0.01). Clinically, one patient in Protocol 2 had an objective response, and none did in Protocol 1. Thus, the addition of the class II-restricted peptide gp100:44-59 did not improve clinical response but might have diminished the immunologic response of circulating PBMC to the class I-restricted peptide gp100:209-217. The reasons for this decreased immune reactivity are unclear but may involve increased CD4+CD25+ regulatory T-cell activity, increased apoptosis of activated CD8+ T cells, or the trafficking of sensitized CD8+ reactive cells out of the peripheral blood. Moreover, the sequential, nonrandomized nature of patient enrollment for the two trials may account for the differences in immunologic response.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer , Genes MHC da Classe II , Genes MHC Classe I , Melanoma/química , Melanoma/terapia , Adulto , Idoso , Antígenos de Neoplasias , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Ensaios Clínicos como Assunto , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interferon gama/metabolismo , Interleucina-2/uso terapêutico , Leucócitos Mononucleares/metabolismo , Antígeno MART-1 , Masculino , Glicoproteínas de Membrana/química , Pessoa de Meia-Idade , Proteínas de Neoplasias/química , Proteínas de Neoplasias/fisiologia , Peptídeos/química , Receptores de Interleucina-2/biossíntese , Resultado do Tratamento , Antígeno gp100 de MelanomaRESUMO
Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a critical immunoregulatory molecule (expressed on activated T cells and a subset of regulatory T cells) capable of down-regulating T cell activation. Blockade of CTLA-4 has been shown in animal models to improve the effectiveness of cancer immunotherapy. We thus treated 14 patients with metastatic melanoma by using serial i.v. administration of a fully human anti-CTLA-4 antibody (MDX-010) in conjunction with s.c. vaccination with two modified HLA-A*0201-restricted peptides from the gp100 melanoma-associated antigen, gp100:209-217(210M) and gp100:280-288(288V). This blockade of CTLA-4 induced grade III/IV autoimmune manifestations in six patients (43%), including dermatitis, enterocolitis, hepatitis, and hypophysitis, and mediated objective cancer regression in three patients (21%; two complete and one partial responses). This study establishes CTLA-4 as an important molecule regulating tolerance to "self" antigens in humans and suggests a role for CTLA-4 blockade in breaking tolerance to human cancer antigens for cancer immunotherapy.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Antineoplásicos/uso terapêutico , Antígenos de Diferenciação/imunologia , Antígenos de Neoplasias/imunologia , Doenças Autoimunes/etiologia , Imunoterapia , Melanoma/terapia , Glicoproteínas de Membrana/imunologia , Proteínas de Neoplasias/imunologia , Fragmentos de Peptídeos/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Vacinação , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Anticorpos Antineoplásicos/efeitos adversos , Anticorpos Antineoplásicos/imunologia , Antígenos CD , Antígenos de Diferenciação/fisiologia , Antígenos de Neoplasias/administração & dosagem , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Antígeno CTLA-4 , Colite/etiologia , Colite/imunologia , Colite/patologia , Dermatite/etiologia , Dermatite/imunologia , Dermatite/patologia , Feminino , Antígeno HLA-A2/imunologia , Hepatite Autoimune/etiologia , Hepatite Autoimune/imunologia , Hepatite Autoimune/patologia , Humanos , Tolerância Imunológica/imunologia , Injeções Intravenosas , Injeções Subcutâneas , Ativação Linfocitária , Masculino , Melanoma/imunologia , Glicoproteínas de Membrana/química , Pessoa de Meia-Idade , Metástase Neoplásica , Proteínas de Neoplasias/química , Fragmentos de Peptídeos/administração & dosagem , Peptídeos , Terapia de Salvação , Vitiligo/etiologia , Vitiligo/imunologia , Vitiligo/patologia , Antígeno gp100 de MelanomaRESUMO
Immunization with plasmid DNA represents a theoretically attractive method for increasing T cell responses against cancer antigens. We administered plasmid DNA encoding the gp100 melanoma-melanocyte differentiation antigen to 22 patients with metastatic melanoma and evaluated immunologic and clinical responses. Patients were randomized to receive plasmid DNA either intradermally (n = 10) or intramuscularly (n = 12). One patient (4.5%) exhibited a partial response of several subcentimeter cutaneous nodules. All other patients had progressive disease. Of 13 patients with cells available before and after immunization, no patient exhibited evidence of the development of anti-gp100 cell responses using in vitro boost assays. The same assays were capable of demonstrating immunologic precursors after immunization with fowl poxvirus encoding gp100 or with gp100 peptides. We were thus unable to demonstrate significant clinical or immunologic responses to plasmid DNA encoding the "self" nonmutated gp100 tumor antigen.
Assuntos
Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Melanoma/tratamento farmacológico , Glicoproteínas de Membrana/imunologia , Proteínas de Neoplasias/imunologia , Plasmídeos , Adulto , Idoso , Vacinas Anticâncer/administração & dosagem , Feminino , Humanos , Injeções Intradérmicas , Injeções Intramusculares , Injeções Subcutâneas , Leucócitos Mononucleares/imunologia , Masculino , Melanoma/imunologia , Melanoma/patologia , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Metástase Neoplásica , Proteínas de Neoplasias/genética , Plasmídeos/administração & dosagem , Falha de Tratamento , Vacinas de DNA/administração & dosagem , Vacinas de DNA/imunologia , Vacinas de DNA/uso terapêutico , Antígeno gp100 de MelanomaRESUMO
PURPOSE: Successful therapeutic interventions to prevent disease progression in patients with nonmetastatic osteosarcoma have included surgery with adjuvant chemotherapy. Presurgical chemotherapy has been advocated for these patients because of putative improvement in event-free survival (EFS). The advantages of presurgical chemotherapy include early administration of systemic chemotherapy, shrinkage of primary tumor, and pathologic identification of risk groups. The theoretic disadvantage is that it exposes a large tumor burden to marginally effective chemotherapy. The contribution of chemotherapy and surgery timing has not been tested rigorously. PATIENTS AND METHODS: Between 1986 and 1993, we conducted a prospective trial in patients with nonmetastatic osteosarcoma who were assigned randomly to immediate surgery or presurgical chemotherapy. Except for the timing of surgery (week 0 or 10), patients received 44 weeks of identical combination chemotherapy that included high-dose methotrexate with leucovorin rescue, doxorubicin, cisplatin, bleomycin, cyclophosphamide, and dactinomycin. RESULTS: One hundred six patients were enrolled onto this study. Six were excluded from analysis. Of the remaining 100 patients, 45 were randomly assigned to immediate chemotherapy, and 55 were randomly assigned to immediate surgery. Sixty-seven patients remain disease-free. At 5 years, the projected EFS +/- SE is 65% +/- 6% (69% +/- 8% for immediate surgery and 61% +/- 8% for presurgical chemotherapy; P =.8). The treatment arms had similar incidence of limb salvage (55% for immediate surgery and 50% for presurgical chemotherapy). CONCLUSION: Chemotherapy was effective in both treatment groups. There was no advantage in EFS for patients given presurgical chemotherapy.