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6.
Cancer Immunol Immunother ; 59(3): 397-408, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19756595

RESUMO

PURPOSE: Studies comparing two or more vaccine platforms have historically evaluated each platform based on its ability to induce an immune response and may conclude that one vaccine is more efficacious than the other(s), leading to a recommendation for development of the more effective vaccine for clinical studies. Alternatively, these studies have documented the advantages of a diversified prime and boost regimen due to amplification of the antigen-specific T-cell population. We hypothesize here that two vaccine platforms targeting the same antigen might induce shared and distinct antigen-specific T-cell populations, and examined the possibility that two distinct vaccines could be used concomitantly. EXPERIMENTAL DESIGN: Using recombinant poxvirus and yeast vaccines, we compared the T-cell populations induced by these two platforms in terms of serum cytokine response, T-cell gene expression, T-cell receptor phenotype, antigen-specific cytokine expression, T-cell avidity, and T-cell antigen-specific tumor cell lysis. RESULTS: These studies demonstrate for the first time that vaccination with a recombinant poxvirus platform (rV/F-CEA/TRICOM) or a heat-killed yeast vaccine platform (yeast-CEA) elicits T-cell populations with both shared and unique phenotypic and functional characteristics. Furthermore, both the antigen and the vector play a role in the induction of distinct T-cell populations. CONCLUSIONS: In this study, we demonstrate that concurrent administration of two vaccines targeting the same antigen induces a more diverse T-cell population that leads to enhanced antitumor efficacy. These studies provide the rationale for future clinical studies investigating concurrent administration of vaccine platforms targeting a single antigen to enhance the antigen-specific immune response.


Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Linfócitos T/imunologia , Vacinação , Animais , Antígenos/imunologia , Antígeno Carcinoembrionário/imunologia , Linhagem Celular , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Citocinas/sangue , Feminino , Vetores Genéticos , Imunização Secundária , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Poxviridae/imunologia , Saccharomyces cerevisiae/imunologia
7.
Clin Cancer Res ; 14(13): 4316-25, 2008 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-18594015

RESUMO

PURPOSE: Saccharomyces cerevisiae, a nonpathogenic yeast, has been used previously as a vehicle to elicit immune responses to foreign antigens, and tumor-associated antigens, and has been shown to reduce tumor burden in mice. Studies were designed to determine if vaccination of human carcinoembryonic antigen (CEA)-transgenic (CEA-Tg) mice (where CEA is a self-antigen) with a recombinant S. cerevisiae construct expressing human CEA (yeast-CEA) elicits CEA-specific T-cell responses and antitumor activity. EXPERIMENTAL DESIGN: CEA-Tg mice were vaccinated with yeast-CEA, and CD4(+) and CD8(+) T-cell responses were assessed after one and multiple administrations or vaccinations at multiple sites per administration. Antitumor activity was determined by tumor growth and overall survival in both pulmonary metastasis and s.c. pancreatic tumor models. RESULTS: These studies demonstrate that recombinant yeast can break tolerance and that (a) yeast-CEA constructs elicit both CEA-specific CD4(+) and CD8(+) T-cell responses; (b) repeated yeast-CEA administration causes increased antigen-specific T-cell responses after each vaccination; (c) vaccination with yeast-CEA at multiple sites induces a greater T-cell response than the same dose given at a single site; and (d) tumor-bearing mice vaccinated with yeast-CEA show a reduction in tumor burden and increased overall survival compared to mock-treated or control yeast-vaccinated mice in both pulmonary metastasis and s.c. pancreatic tumor models. CONCLUSIONS: Vaccination with a heat-killed recombinant yeast expressing the tumor-associated antigen CEA induces CEA-specific immune responses, reduces tumor burden, and extends overall survival in CEA-Tg mice. These studies thus form the rationale for the incorporation of recombinant yeast-CEA and other recombinant yeast constructs in cancer immunotherapy protocols.


Assuntos
Antígenos de Neoplasias/química , Antineoplásicos/farmacologia , Antígeno Carcinoembrionário/química , Regulação da Expressão Gênica , Imunoterapia/métodos , Saccharomyces cerevisiae/metabolismo , Vacinas de DNA/química , Animais , Antígenos de Neoplasias/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Vacinas Anticâncer , Antígeno Carcinoembrionário/metabolismo , Proliferação de Células , Feminino , Humanos , Linfócitos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/química , Vacinas de DNA/metabolismo
8.
Mol Pharmacol ; 73(6): 1632-42, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18326051

RESUMO

Squamous cell carcinoma of the head and neck (SCCHN) is a leading cause of cancer deaths worldwide. Epidermal growth factor receptor (EGFR), an upstream mediator of signal transducer and activator of transcription (STAT)-3 is overexpressed in a variety of cancers, including SCCHN. Therapies such as monoclonal antibodies and tyrosine kinase inhibitors targeting EGFR have demonstrated limited antitumor efficacy, which may be explained, in part, by persistent STAT3 activation despite EGFR inhibition. STAT3 activation induces expression of target genes in SCCHN, including Bcl-X(L), a mediator of antiapoptotic activity. Bcl-X(L) is commonly overexpressed in SCCHN where it correlates with chemoresistance, making it a potential therapeutic target. Targeting the EGFR-STAT3-Bcl-X(L) pathway at several levels, including the upstream receptor, the intracellular transcription factor, and the downstream target gene, has not been investigated previously. Using erlotinib, an EGFR-specific reversible tyrosine kinase inhibitor in combination with a STAT3 transcription factor decoy, we found enhanced antitumor effects in vitro and in vivo. The combination of the STAT3 decoy and gossypol, a small molecule targeting Bcl-X(L), also yielded enhanced inhibition of cell proliferation. The triple combination of erlotinib, STAT3 decoy, and gossypol further enhanced cell growth inhibition and apoptosis in vitro, and it down-regulated signaling molecules further downstream of the EGFR-STAT3 signaling pathway, such as cyclin D1. These results suggest that combined targeting of several components of an oncogenic signaling pathway may be an effective therapeutic strategy for SCCHN.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Receptores ErbB/metabolismo , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Fator de Transcrição STAT3/metabolismo , Proteína bcl-X/metabolismo , Animais , Antineoplásicos/administração & dosagem , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib , Feminino , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Camundongos , Quinazolinas/administração & dosagem , Fator de Transcrição STAT3/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Proteína bcl-X/antagonistas & inibidores
9.
Neoplasia ; 9(10): 801-11, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17971900

RESUMO

Head and neck squamous cell carcinomas (HNSCC) are frequently characterized by chemotherapy and radiation resistance, and by overexpression of Bcl-XL, an antiapoptotic member of the Bcl-2 protein family. In this report we examined whether cell-permeable peptides derived from the BH3 domains of proapoptotic Bax, Bad, or Bak could be used to target Bcl-XL and/or Bcl-2 in HNSCC cells, and induce apoptotic death in these cells. To render the peptides cell permeable, Antennapedia (Ant) or polyarginine (R8) peptide transduction domains were fused to the amino termini. Fluorescence microscopy of peptide-treated HNSCC cells revealed that the BH3 peptides colocalized with mitochondria, the site of Bcl-XL and Bcl-2 expression. By contrast, a mutant peptide (BaxE BH3) which cannot bind Bcl-XL or Bcl-2 was diffusely localized throughout the cytoplasm. Treatment of three HNSCC cell lines (1483, UM-22A, UM-22B) with the wild-type BH3 peptides resulted in loss of viability and induction of apoptosis, as assessed by MTS assays and annexin V staining. In general, Ant-conjugated peptides were more potent than R8-conjugated peptides, and Bad BH3 peptide was typically more potent than Bax BH3 or Bak BH3. Treatment of purified HNSCC mitochondria with BH3 peptides resulted in robust release of cytochrome c. Thus, the relative apoptosis resistance of HNSCC cells is not due to a deficit in this step of the intrinsic, mitochondrial-mediated apoptosis pathway. We conclude that cell-permeable BH3 peptides can be used to target Bcl-XL and/or Bcl-2 in HNSCC, and targeting of these proteins may have therapeutic value in the treatment of this disease.


Assuntos
Apoptose/fisiologia , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Peptídeos/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sequência de Aminoácidos , Proteína do Homeodomínio de Antennapedia/química , Proteína do Homeodomínio de Antennapedia/metabolismo , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/química , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Citometria de Fluxo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Immunoblotting , Microscopia de Fluorescência , Mitocôndrias/metabolismo , Dados de Sequência Molecular , Peptídeos/química
10.
J Cell Biochem ; 102(2): 311-9, 2007 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-17661350

RESUMO

The epidermal growth factor receptor (EGFR) and signal transducers and activators of transcription (STATs) are commonly expressed and activated in many malignancies. EGFR is an upstream activator of several pathways involved in tumor progression, and STATs activate selected genes involved in oncogenesis. There are several different mechanisms by which STAT proteins can mediate intracellular EGFR signaling, including direct activation of STATs by EGFR binding and indirect activation of STATs through Src-mediated EGFR signaling. EGFR likely activates STAT in a manner distinctive from other mechanisms of STAT activation; STAT5 can be phosphorylated in an EGF-dependent manner at unique sites, conferring novel functions. Cumulative evidence suggests that targeting EGFR signaling pathways at several levels may demonstrate synergistic therapeutic effects compared with targeting the upstream receptor alone. Thus, methods to inhibit EGFR in conjunction with oncogenic STATs may represent a novel therapeutic strategy for cancers characterized by upregulation of EGFR signaling.


Assuntos
Receptores ErbB/fisiologia , Neoplasias/metabolismo , Fatores de Transcrição STAT/fisiologia , Animais , Receptores ErbB/antagonistas & inibidores , Humanos , Neoplasias/terapia , Fosforilação , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais
11.
Mol Pharmacol ; 71(5): 1435-43, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17325127

RESUMO

We previously developed a transcription factor decoy targeting signal transducer and activator of transcription 3 (STAT3) and reported antitumor activity in both in vitro and in vivo models of squamous cell carcinoma of the head and neck (SCCHN). Based on the known existence of STAT1-STAT3 heterodimers, the high sequence homology between STAT1 and STAT3, as well as expression of both STAT1 and STAT3 in SCCHN, we examined whether the STAT3 decoy interferes with STAT1 signaling. SCCHN cell lines with different STAT1 expression levels (but similar STAT3 levels) were used. Both cell lines were sensitive to the growth-inhibitory effects of the STAT3 decoy compared with a mutant control decoy. Intact STAT1 signaling was demonstrated by interferon-gamma (IFN-gamma)-mediated induction of STAT1 phosphorylation (Tyr701) and interferon-regulatory factor-1 (IRF-1) expression. Treatment with the STAT3 decoy (but not a mutant control decoy) resulted in inhibition of IRF-1 protein expression in both cell lines, indicating specific inhibition of STAT1 signaling by the STAT3 decoy. Because STAT1 is a potential tumor suppressor, we also investigated whether STAT1 signaling mitigated the therapeutic efficacy of the STAT3 decoy. In both PCI-15B and UM-22B cells, STAT1 siRNA treatment resulted in decreased STAT1 expression, without altering the antitumor activity of the STAT3 decoy. Likewise, the antitumor effects of the STAT3 decoy were not altered by STAT1 activation upon IFN-gamma treatment. These results suggest that the therapeutic mechanisms of STAT3 blockade using a transcription factor decoy are independent of STAT1 activation.


Assuntos
Oligonucleotídeos/farmacologia , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Camundongos , Transdução de Sinais/efeitos dos fármacos
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