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1.
Breast Cancer Res Treat ; 181(2): 391-401, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32323103

RESUMO

PURPOSE: AE37 and GP2 are HER2 derived peptide vaccines. AE37 primarily elicits a CD4+ response while GP2 elicits a CD8+ response against the HER2 antigen. These peptides were tested in a large randomized trial to assess their ability to prevent recurrence in HER2 expressing breast cancer patients. The primary analyses found no difference in 5-year overall disease-free survival (DFS) but possible benefit in subgroups. Here, we present the final landmark analysis. METHODS: In this 4-arm, prospective, randomized, single-blinded, multi-center phase II trial, disease-free node positive and high-risk node negative breast cancer patients enrolled after standard of care therapy. Six monthly inoculations of vaccine (VG) vs. control (CG) were given as the primary vaccine series with 4 boosters at 6-month intervals. Demographic, safety, immunologic, and DFS data were evaluated. RESULTS: 456 patients were enrolled; 154 patients in the VG and 147 in CG for AE37, 89 patients in the VG and 91 in CG for GP2. The AE37 arm had no difference in DFS as compared to CG, but pre-specified exploratory subgroup analyses showed a trend towards benefit in advanced stage (p = 0.132, HR 0.573 CI 0.275-1.193), HER2 under-expression (p = 0.181, HR 0.756 CI 0.499-1.145), and triple-negative breast cancer (p = 0.266, HR 0.443 CI 0.114-1.717). In patients with both HER2 under-expression and advanced stage, there was significant benefit in the VG (p = 0.039, HR 0.375 CI 0.142-0.988) as compared to CG. The GP2 arm had no significant difference in DFS as compared to CG, but on subgroup analysis, HER2 positive patients had no recurrences with a trend toward improved DFS (p = 0.052) in VG as compared to CG. CONCLUSIONS: This phase II trial reveals that AE37 and GP2 are safe and possibly associated with improved clinical outcomes of DFS in certain subgroups of breast cancer patients. With these findings, further evaluations are warranted of AE37 and GP2 vaccines given in combination and/or separately for specific subsets of breast cancer patients based on their disease biology.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Lobular/tratamento farmacológico , Recidiva Local de Neoplasia/prevenção & controle , Receptor ErbB-2/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Adulto , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/imunologia , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Fragmentos de Peptídeos , Prognóstico , Estudos Prospectivos , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Método Simples-Cego , Taxa de Sobrevida , Vacinas de Subunidades Antigênicas/imunologia
2.
Clin Immunol ; 195: 28-35, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30025819

RESUMO

Immunotherapy, using peptide-based cancer vaccines is being studied to assess its potential in breast cancer. Trials of HLA-restricted peptide vaccines have been difficult to enroll given HLA subtype restrictions. It is necessary to determine the prognostic significance of HLA-status in breast cancer if patients who are ineligible to receive a vaccine due to their HLA-status are used as controls. The impact of targeted tumor associated antigen expression, when it effects eligibility is also important. We examined control patients from two randomized phase II trials that tested HER2-peptide vaccines to determine the effect of HLA-A2 status and HER2 expression on disease-free survival. The analysis showed that HLA-A2-status does not affect disease-free survival, regardless of HER2 expression suggesting that HLA-A2 negative patients can be used as control patients. Additionally, HER2 over-expression was associated with a better disease-free survival in this population, underscoring the need for additional therapies in HER2 low-expressing breast cancer. ClinicalTrials.gov Identifier: NCT00524277.


Assuntos
Neoplasias da Mama/imunologia , Vacinas Anticâncer/imunologia , Antígeno HLA-A2/genética , Imunoterapia/métodos , Receptor ErbB-2/genética , Adulto , Idoso , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , Feminino , Seguimentos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Pessoa de Meia-Idade , Mutação/genética , Recidiva Local de Neoplasia , Receptor ErbB-2/imunologia , Projetos de Pesquisa , Risco , Análise de Sobrevida , Resultado do Tratamento , Vacinação , Vacinas de Subunidades Antigênicas
3.
J Immunother Cancer ; 4: 75, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27891225

RESUMO

BACKGROUND: Cancer vaccines aim at eliciting not only an immune response against specific tumor antigens, but also at enhancing a preexisting immunity against the tumor. In this context, we recently reported on the levels of preexisting immunity in prostate cancer patients vaccinated with the HER-2 hybrid peptide (AE37), during a phase I clinical trial. The purpose of the current study was to correlate between preexisting immunity to the native HER-2 peptide, AE36, and expression of HLA-A2 and -A24 molecules with the clinical outcome. Additionally, we investigated the ability of the AE37 vaccine to induce an antitumor immune response against other tumor associated antigens, not integrated in the vaccine formulation, with respect to the clinical response. METHODS: We analyzed prostate cancer patients who were vaccinated with the AE37 vaccine [Ii-Key-HER-2/neu(776-790) hybrid peptide vaccine (AE37), which is a MHC class II long peptide vaccine encompassing MHC class I epitopes, during a phase I clinical trial. Preexisting immunity to the native HER-2/neu(776-790) (AE36) peptide was assessed by IFNγ response or dermal reaction at the inoculation site. Antigen specificity against other tumor antigens was defined using multimer analysis. Progression free survival (PFS) was considered as the patients' clinical outcome. Two-tailed Wilcoxon signed rank test at 95 % confidence interval was used for statistical evaluation at different time points and Kaplan-Meier curves with log-rank (Mantel-Cox) test were used for the evaluation of PFS. RESULTS: Preexisting immunity to AE36, irrespectively of HLA expression, was correlated with longer PFS. Specific CD8+ T cell immunity against E75 and PSA146-151 (HLA-A2 restricted), as well as, PSA153-161 (HLA-A24 restricted) was detected at relatively high frequencies which were further enhanced during vaccinations. Specific immunity against PSA153-161 correlated with longer PFS in HLA-A24+ patients. However, HLA-A2+ patients with high preexisting or vaccine-induced immunity to E75, showed a trend for shorter PFS. CONCLUSIONS: Our data cast doubt on whether preexisting immunity or epitope spreading specific for HLA-class I-restricted peptides can actually predict a favorable clinical outcome. They also impose that preexisting immunity to long vaccine peptides, encompassing both HLA class II and I epitopes should be considered as an important prerequisite for the improvement of future immunotherapeutic protocols. Protocol ID Code: Generex-06-07 National Organization for Medicines (EOF) ID Code: IS-107-01-06 NEC Study Code: EED107/1/06 EudraCT Number: 2006-003299-37 Date of registration: 07/06/2006 Date of enrolment of the first participant to the trial: Nov 1st, 2007.


Assuntos
Vacinas Anticâncer/imunologia , Imunoterapia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/terapia , Adulto , Idoso , Antígenos de Neoplasias/imunologia , Biomarcadores Tumorais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Ensaios Clínicos Fase I como Assunto , Progressão da Doença , Epitopos de Linfócito T/imunologia , Antígeno HLA-A2/imunologia , Antígeno HLA-A24/imunologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Resultado do Tratamento
4.
Oncotarget ; 7(40): 66192-66201, 2016 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-27589688

RESUMO

GP2 is a HER2-derived, HLA-A2+ restricted peptide. Phase I studies showed GP2 administered with GM-CSF to be safe and immunogenic. Here we report the primary analysis of a prospective, randomized, multicenter phase II adjuvant trial conducted to determine the vaccine's efficacy. The trial enrolled HLA-A2+, clinically disease-free, node-positive and high-risk node-negative breast cancer patients with tumors expressing HER2 (immunohistochemistry[IHC] 1+-3+). Patients were randomized to GP2+GM-CSF versus GM-CSF alone. Disease-free survival (DFS) was analyzed in intention-to-treat (ITT) and per-treatment cohorts; pre-specified subgroup analyses were performed for patients with IHC 3+ or FISH+ disease. The trial enrolled 180 patients; 89 received GP2+GM-CSF and 91 received GM-CSF alone. The groups were well-matched for clinicopathologic characteristics. Toxicities have been minimal. The Kaplan-Meier estimated 5-year DFS rate in the ITT analyses was 88% (95% CI:78-94%) in vaccinated vs. 81% (95% CI:69-89%) (P = 0.43) in control patients after a 34 month median follow-up. In the per-treatment analysis, the estimated 5-year DFS rates were 94% (95% CI:83-98%) and 85% (73-92%) (P = 0.17). In IHC 3+/FISH+ patients, the estimated 5-year DFS rate was 94% (82-98%) in vaccinated patients (n = 51) vs. 89% (71-96%) in control patients (n = 50), (P = 0.86) in the ITT analyses and 100% vs. 89% (71-96%) in vaccinated vs. control patients in the per-treatment analyses (P = 0.08). While the overall ITT analysis did not demonstrate benefit to vaccination, this trial confirmed that the GP2 vaccine is safe and suggests that vaccination may have clinical activity, particularly in patients with HER2 overexpression who received the full vaccine series (ie per-treatment group).


Assuntos
Neoplasias da Mama/prevenção & controle , Vacinas Anticâncer/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Recidiva Local de Neoplasia/prevenção & controle , Fragmentos de Peptídeos/imunologia , Receptor ErbB-2/imunologia , Vacinas de Subunidades Antigênicas/uso terapêutico , Adulto , Idoso , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Prospectivos , Método Simples-Cego , Taxa de Sobrevida , Vacinação
5.
Oncoimmunology ; 5(7): e1178439, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27622033

RESUMO

Realizing the basis for generating long-lasting clinical responses in cancer patients after therapeutic vaccinations provides the means to further ameliorate clinical efficacy. Peptide cancer vaccines stimulating CD4(+) T helper cells are often promising for inducing immunological memory and persistent CD8(+) cytotoxic T cell responses. Recent reports from our clinical trial with the AE37 vaccine, which is a HER2 hybrid polypeptide, documented its efficacy to induce CD4(+) T cell immunity, which was associated with clinical improvements preferentially among HLA-DRB1*11(+) prostate cancer patients. Here, we performed in-depth investigation of the CD4(+) T cell response against the AE37 vaccine. We used the DR11/AE37 tetramer in combination with multicolor flow cytometry to identify and characterize AE37-specific CD4(+) T cells regarding memory and Tregs phenotype in HLA-DRB1*11(+) vaccinated patients. To verify vaccine-specific immunological memory in vivo, we also assessed AE37-specific CD4(+) T cells in defined CD4(+) memory subsets by cell sorting. Finally, vaccine-induced AE37-specific CD4(+) T cells were assessed regarding their functional profile. AE37-specific memory CD4(+) T cells could be detected in peptide-stimulated cultures from prostate cancer patients following vaccination even 4 y post-vaccination. The vast majority of vaccine-induced AE37-specific CD4(+) T cells exhibited a multifunctional, mostly Th1 cytokine signature, with the potential of granzyme B production. In contrast, we found relatively low frequencies of Tregs among AE37-specific CD4(+) T cells. This is the first report on the identification of vaccine-induced HER2-specific multifunctional long-lasting CD4(+) T cells in vaccinated prostate cancer patients.

6.
Cancer Immunol Immunother ; 64(9): 1123-36, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26026288

RESUMO

Recently, several types of immunotherapies have been shown to induce encouraging clinical results, though in a restricted number of patients. Consequently, there is a need to identify immune biomarkers to select patients who will benefit from such therapies. Such predictive biomarkers may be also used as surrogates for overall survival (OS). We have recently found correlations between immunologic parameters and clinical outcome in prostate cancer patients who had been vaccinated with a HER-2/neu hybrid polypeptide vaccine (AE37) and received one booster 6 months post-primary vaccinations. Herein, we aimed to expand these retrospective analyses by studying the predictive impact of HLA-A*24 and HLA-DRB1*11 alleles, which are expressed at high frequencies among responders in our vaccinated patients, for clinical and immunological responses to AE37 vaccination. Our data show an increased OS of patients expressing the HLA-DRB1*11 or HLA-A*24 alleles, or both. Vaccine-induced immunological responses, measured as interferon γ (IFN-γ) responses in vitro or delayed-type hypersensitivity reactions in vivo, were also higher in these patients and inversely correlated with suppressor elements. Preexisting (i.e., before vaccinations with AE37) levels of vaccine-specific IFN-γ immunity and plasma TGF-ß, among the HLA-A*24 and/or HLA-DRB1*11 positive patients, were strong indicators for immunological responses to AE37 treatment. These data suggest that HLA-DRB1*11 and HLA-A*24 are likely to be predictive factors for immunological and clinical responses to vaccination with AE37, though prospective validation in larger cohorts is needed.


Assuntos
Alelos , Vacinas Anticâncer/administração & dosagem , Antígeno HLA-A24/genética , Cadeias HLA-DRB1/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Vacinas Anticâncer/imunologia , Antígeno HLA-A24/biossíntese , Antígeno HLA-A24/imunologia , Cadeias HLA-DRB1/biossíntese , Cadeias HLA-DRB1/imunologia , Humanos , Masculino , Projetos Piloto , Prognóstico , Neoplasias da Próstata/sangue , Neoplasias da Próstata/imunologia , Receptor ErbB-2/biossíntese , Receptor ErbB-2/imunologia , Fator de Crescimento Transformador beta/sangue
7.
Cancer Immunol Immunother ; 64(4): 401-8, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25690791

RESUMO

Cancer vaccines as a modality of immune-based cancer treatment offer the promise of a non-toxic and efficacious therapeutic alternative for patients. Emerging data suggest that response to vaccination largely depends on the magnitude of the type I immune response generated, epitope spreading and immunogenic modulation of the tumor. Moreover, accumulating evidence suggests that cancer vaccines will likely induce better results in patients with low tumor burden and less aggressive disease. To induce long-lasting clinical responses, vaccines will need to be combined with immunoregulatory agents to overcome tumor-related immune suppression. Immunotherapy, as a treatment modality for prostate cancer, has received significant attention in the past few years. The most intriguing characteristics that make prostate cancer a preferred target for immune-based treatments are (1) its relative indolence which allows sufficient time for the immune system to develop meaningful antitumor responses; (2) prostate tumor-associated antigens are mainly tissue-lineage antigens, and thus, antitumor responses will preferentially target prostate cancer cells. But, also in the event of eradication of normal prostate epithelium as a result of immune attack, this will have no clinical consequences because the prostate gland is not a vital organ; (3) the use of prostate-specific antigen for early detection of recurrent disease allows for the initiation of vaccine immunotherapy while tumor burden is still minimal. Finally, for improving clinical outcome further to increasing vaccine potency, it is imperative to recognize prognostic and predictive biomarkers of clinical benefit that may guide to select the therapeutic strategies for patients most likely to gain benefit.


Assuntos
Vacinas Anticâncer/uso terapêutico , Imunoterapia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/terapia , Pesquisa Translacional Biomédica/tendências , Humanos , Masculino
8.
Expert Rev Mol Diagn ; 15(1): 49-59, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25345403

RESUMO

In order to be optimally efficacious, therapeutic cancer vaccines must induce robust tumor-specific CD8(+) cytotoxic T cells, which are responsible for tumor cell lysis. Unlike cytotoxic drugs, which act directly on the tumor, cancer vaccines demonstrate new kinetics involving the generation of specific cellular immune responses, which need to be translated into antitumor responses to delay tumor progression and improve survival. These delayed kinetics of action establish a new concept of benefit in the long term, which implies a slow down in tumor growth rates, than a marked reduction in tumor size. Therefore, there is a significant need to identify intermediate biomarkers so that clinical responses can be evaluated in a timely manner. Therapeutic vaccination as a modality for cancer treatment has received significant attention with multiple clinical trials demonstrating improvements in overall survival. Significant challenges to this modality remain, including increasing vaccine potency and minimizing treatment-related toxicities and identifying prognostic and predictive biomarkers of clinical benefit that may guide to select and optimize the therapeutic strategies for patients most likely to gain benefit.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias/sangue , Animais , Biomarcadores Tumorais/imunologia , Humanos , Linfócitos/imunologia , Neoplasias/diagnóstico , Neoplasias/imunologia , Prognóstico , Transcriptoma
9.
Cancer Immunol Immunother ; 63(11): 1141-50, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25052849

RESUMO

A fundamental challenge in administering immunotherapies for cancer is the establishment of biomarkers that can predict patients' responsiveness to treatment. In this study, our aim was to predict the immunologic and clinical responses of vaccination therapy with an Ii-key-modified HER-2/neu peptide (Ii-key/HER-2(776-790) or AE37), applied in our recent phase I study in patients with prostate cancer. To this end, we retrospectively analyzed our data derived from immunologic determinations before, during and after primary series of vaccinations with AE37, as well as after one AE37 booster injection. Using the obtained data, we then observed the relationship between the immunologic parameters and clinical outcome of patients. We found that preexisting levels of transforming growth factor beta (TGF-ß) had an inverse correlation with in vivo and in vitro immunologic responses to the AE37 vaccine which were measured as delayed-type hypersensitivity (DTH) and interferon gamma (IFN-γ) production in response to the native HER-2(776-790) (or AE36) peptide, respectively. Patients with preexistent IFN-γ immunity to AE36 developed positive DTH reactions after primary vaccinations and booster. Moreover, we could detect a direct correlation between IFN-γ production and DTH reactions in response to AE36 challenge in our vaccinated patients. DTH reactions were a stronger indicator for patients' overall survival (OS) than preexistent or vaccine-induced IFN-γ immunity. In contrast, we found that preexisting TGF-ß levels were correlated with shorter patients' OS. These retrospective analyses suggest that the above biomarkers at the time-points measured offer promise for evaluating immunologic and clinical responses to AE37-based vaccinations.


Assuntos
Biomarcadores Tumorais/metabolismo , Vacinas Anticâncer/uso terapêutico , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/terapia , Idoso , Idoso de 80 Anos ou mais , Seguimentos , Humanos , Interferon gama/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/metabolismo , Projetos de Pesquisa , Estudos Retrospectivos , Fator de Crescimento Transformador beta/metabolismo , Resultado do Tratamento
10.
Stem Cells Dev ; 23(20): 2501-12, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-24915579

RESUMO

Mesenchymal stem cells (MSCs) are a population of cells harboring in many tissues with the ability to differentiate toward many different lineages. Unraveling the molecular profile of MSCs is of great importance due to the fact that these cells are very often used in preclinical and clinical studies. We have previously reported the expression of insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) an oncofetal mRNA-binding protein-in different stem cell types such as bone marrow (BM)-MSC and umbilical cord blood (UCB)-hematopoietic stem cells. Here, we demonstrate that MSCs of adipose tissue, BM, and UC origin have a differential pattern of IGF2BP1 and ten-eleven-translocate 1/2 (TET1/2) expression that could correlate with their proliferation potential. Upon IGF2BP1 interference, a significant reduction of cell proliferation is observed, accompanied by reduced expression of c-MYC and GLI1 and increased p21. We also present, for the first time, evidence that IGF2BP1 is epigenetically regulated by TET1 and TET2 demethylases. Specifically, we show that TET1 directly binds to the promoter of IGF2BP1 gene and affects the hydroxymethylation status of its promoter. These results indicate that IGF2BP1 and TET1/2 contribute to the stemness of MSCs, at least regarding their proliferative potential.


Assuntos
Proliferação de Células/fisiologia , Proteínas de Ligação a DNA/biossíntese , Epigênese Genética/fisiologia , Regulação Enzimológica da Expressão Gênica/fisiologia , Células-Tronco Mesenquimais/metabolismo , Proteínas Proto-Oncogênicas/biossíntese , Proteínas de Ligação a RNA/biossíntese , Células Cultivadas , Proteínas de Ligação a DNA/genética , Dioxigenases , Feminino , Humanos , Masculino , Células-Tronco Mesenquimais/citologia , Oxigenases de Função Mista , Proteínas Proto-Oncogênicas/genética , Proteínas de Ligação a RNA/genética
11.
Methods Mol Biol ; 1139: 321-36, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24619690

RESUMO

A novel method for amplifying the activity of major histocompatibility complex (MHC) class II helper epitopes entails linking a 4-amino-acid moiety (LRMK) from the invariant chain (Ii) of MHC (referred to as Ii-Key) to the N-terminal end of the epitope peptide either directly or using a simple polymethylene spacer (-ava-). Ii-Key catalyzes binding of the linked epitope to the MHC class II molecule, thereby enhancing the overall potency of presentation. HER-2(776-790) (or AE36), which is derived from the intracellular domain of HER-2/neu, has been intensively used as an Ii-key/HER-2(776-790) (or AE37) fusion (hybrid) vaccine in clinical trials. This chapter describes procedures for the synthesis, reconstitution, sterility testing, and storage of both AE36 and AE37 for their use in clinical trials. Also provided is a detailed information about their in vivo administration and analysis of in-depth protocols for monitoring of immune activation upon vaccination with AE37.


Assuntos
Antígenos de Diferenciação de Linfócitos B/imunologia , Vacinas Anticâncer/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Receptor ErbB-2/imunologia , Vacinas de Subunidades Antigênicas/imunologia , Sequência de Aminoácidos , Antígenos de Diferenciação de Linfócitos B/administração & dosagem , Antígenos de Diferenciação de Linfócitos B/química , Antígenos de Diferenciação de Linfócitos B/genética , Neoplasias da Mama/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/química , Vacinas Anticâncer/genética , Proliferação de Células , Feminino , Antígenos de Histocompatibilidade Classe II/administração & dosagem , Antígenos de Histocompatibilidade Classe II/química , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Dados de Sequência Molecular , Neoplasias Ovarianas/imunologia , Estrutura Terciária de Proteína , Receptor ErbB-2/administração & dosagem , Receptor ErbB-2/química , Receptor ErbB-2/genética , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/química , Vacinas de Subunidades Antigênicas/genética
12.
Hum Vaccin Immunother ; 10(5): 1244-7, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24552987

RESUMO

One major achievement in cancer therapy is to select patients who will most likely benefit from a specific treatment. Predictive biomarkers play an important role in this respect being already useful in management of breast cancer and melanoma. For example, HER-2/neu (HER-2) overexpression selects for breast cancer patients to be treated with trastuzumab, and BRAFV600E mutations select for melanoma patients to be treated with vemurafenib. Identification of factors associated with T cell responsiveness to vaccination remains critical. Pre-existent immunity and circulating suppressor cells may regulate the levels of vaccine-specific T cell immunity after vaccination. The identification of immunologic endpoints to immunotherapy would thus considerably help guide the development of immunotherapy-based clinical trials. This commentary is based on a retrospective analysis we performed of data from prostate cancer patients vaccinated and boosted with the AE37 vaccine. The aim of these exploratory analyses was to identify factors useful in predicting which patients are more likely to respond to the treatment under study. The issue we are addressing here is to which extent common variables used pre- and/or following vaccinations with AE37 to assess the immune response status of the prostate cancer patients, may predict overall survival.


Assuntos
Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Neoplasias da Próstata/imunologia , Linfócitos T/imunologia , Biomarcadores/metabolismo , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/imunologia , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
13.
Expert Rev Vaccines ; 13(1): 131-44, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24224539

RESUMO

Harnessing the immune system to achieve therapeutic efficacy in cancer has been a milestone in immuno-oncology. Tumor-induced suppression works as an obstacle for the effectiveness of immunotherapies. Advances in our understanding of the interrelationship between cancer immunoediting and immunotherapy led to successful manipulation of anticancer immunity; this provided the platform for combining cancer vaccines with chemotherapies counteracting, to some extent, tumor-induced suppressive entities and demonstrating clinical efficacy. Targeting co-inhibitory and co-stimulatory receptors with immunostimulatory antibodies has also shown clinical promise and its combined use with vaccines is a promising new approach of immunotherapy for cancer. Recent evidence supporting vaccine administration in patients with early and less aggressive disease should be additionally placed to select the appropriate patient population and to identify earlier markers of clinical benefit and immunological parameters that correlate with survival. This review focuses on promising vaccination platforms and essential perspectives in the treatment of cancer.


Assuntos
Vacinas Anticâncer/imunologia , Vacinas Anticâncer/isolamento & purificação , Descoberta de Drogas/tendências , Imunoterapia/métodos , Neoplasias/terapia , Vacinas Anticâncer/administração & dosagem , Humanos
14.
Expert Opin Biol Ther ; 13(4): 517-26, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23289642

RESUMO

INTRODUCTION: There is now accumulating evidence to suggest that intratumoral adaptive immune responses predict patient prognosis. The presence of tumor-infiltrating lymphocytes has been correlated with patients' disease-free and overall survival. Recent exciting studies of human colorectal cancers (CRCs) have underlined the significance of including immunological biomarkers as prognostic markers. AREAS COVERED: This review covers recent literature which suggests that the type, density and location of immune cells within the colorectal tumors represent a better predictor of patient survival than the histopathological methods currently used to stage CRC. EXPERT OPINION: Remarkably, the quantity, quality and spatial distribution of immune cells within the tumor has a greater prognostic value than the standard tumor staging based on tumor burden, infiltration of draining and regional lymph nodes by tumor cells, and evidence of metastases. In addition, such an immune classification may also have a predictive value. Thus, by increasing the knowledge of the immune events inside the tumors and by better understanding the immune architecture of these tumors as well as the functional programs of their constituents, there will certainly be a more complete idea of how tumors evade from immunosurveillance. This knowledge will help to identify new targets for the development of therapeutic strategies.


Assuntos
Neoplasias Colorretais/classificação , Neoplasias Colorretais/imunologia , Animais , Neoplasias Colorretais/diagnóstico , Humanos , Linfócitos do Interstício Tumoral/imunologia , Estadiamento de Neoplasias/normas , Prognóstico , Linfócitos T/imunologia
17.
Oncoimmunology ; 1(2): 205-207, 2012 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-22720243

RESUMO

Repetitive infusions of ex vivo expanded NK cells induced antitumor T-cell responses in a metastatic lung cancer mouse model. These were further potentiated by Treg depletion. Thus the combination of NK cell-based immunotherapy with other treatment modalities in the direction of adaptive response enhancement might promote long lasting antitumor immunity.

18.
Expert Opin Biol Ther ; 11(11): 1543-50, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21895539

RESUMO

INTRODUCTION: Immunotherapy, including vaccines targeting the human EGFR2 (HER-2/neu) protein, is an active area of investigation in combatting breast cancer. Several vaccines are currently undergoing clinical trials, most of which are CD8(+) T-cell-eliciting vaccines. AE37 is a promising primarily CD4(+) T-cell-eliciting HER-2/neu breast cancer vaccine currently in clinical trials. AREAS COVERED: This article reviews preclinical investigations as well as findings from completed and ongoing Phase I and Phase II clinical trials of the AE37 vaccine. EXPERT OPINION: Clinical trials have shown the AE37 vaccine to be safe and capable of generating peptide-specific, durable immune responses. This has been shown in patients with any level of HER-2/neu expression. Early clinical findings suggest there may be benefit to AE37 vaccination in preventing breast cancer recurrence.


Assuntos
Neoplasias da Mama/terapia , Linfócitos T CD4-Positivos/imunologia , Vacinas Anticâncer/uso terapêutico , Linfócitos do Interstício Tumoral/imunologia , Animais , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Vacinas Anticâncer/efeitos adversos , Feminino , Humanos , Receptor ErbB-2/imunologia , Resultado do Tratamento
20.
Cancer Immunol Immunother ; 60(12): 1683-95, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21706285

RESUMO

We have previously reported a synergistic effect between hydrocortisone (HC) and IL-15 on promoting natural killer (NK) cell expansion and function. In the present study, we extend our findings to methylprednisolone (MeP) and dexamethasone (Dex), thus ascribing to glucocorticoids (GCs) a general feature as positive regulators of IL-15-mediated effects on NK cells. We demonstrate that each GC when combined with IL-15 in cultures of peripheral blood (PB)-derived CD56(+) cells induces increased expansion of CD56(+)CD3(-) cells displaying high cytolytic activity, IFN-γ production potential and activating receptor expression, including NKp30, NKp44, NKp46, 2B4, NKG2D and DNAM-1. Furthermore, GCs protected NK cells from IL-15-induced cell death. The combination of IL-15 with GCs favored the expansion of a relatively more immature CD16(low/neg) NK cell population, with high expression of NKG2A and CD94, and significantly lower expression of KIR (CD158a and CD158b) and CD57, compared to IL-15 alone. IL-15-expanded NK cells, in the presence or absence of GCs, did not express CD62L, CXCR1 or CCR7. However, the presence of GCs significantly increased the density of CXCR3 and induced strong CXCR4 expression on the surface of NK cells. Our data indicate that IL-15/GC-expanded NK cells, apart from their increased proliferation rate, retain their functional integrity and exhibit a migratory potential rendering them useful for adoptive transfer in NK cell-based cancer immunotherapy.


Assuntos
Proliferação de Células/efeitos dos fármacos , Glucocorticoides/farmacologia , Interleucina-15/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Adulto , Separação Celular , Células Cultivadas , Dexametasona/farmacologia , Citometria de Fluxo , Humanos , Imunofenotipagem , Células Matadoras Naturais/citologia , Metilprednisolona/farmacologia , Pessoa de Meia-Idade , Fenótipo
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