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1.
Vaccines (Basel) ; 8(1)2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-32013270

RESUMO

: Background: Recurrent respiratory papillomatosis (RRP) is a rare disorder characterized by the generation of papillomas of the aerodigestive tract, usually associated with human papilloma virus (HPV) subtypes 6, 11. INO-3106 is a DNA plasmid-based immunotherapy targeting E6 and E7 proteins of HPV6, in order to create a robust immune T cell response. METHODS: Testing of INO-3016 in animal models confirmed immunogenicity of the DNA-based therapy. A single-site open-label Phase 1 study was initiated for patients with HPV6-positive RRP. Patients were dosed with INO-3106 with or without INO-9012, a DNA plasmid immunotherapy that encodes IL-12, delivered intramuscularly (IM) in combination with electroporation (EP) with the CELLECTRA® device. Patients received an escalating dose of INO-3106, 3 mg once and then 6 mg for three additional doses, each dose three weeks apart, with the third and fourth doses co-administered with INO-9012. The primary objective of the study was to evaluate the safety and tolerability of INO-3106 with and without INO-9012. The secondary objective was to determine cellular immune responses to INO-3106 with and without INO-9012. Exploratory objectives included preliminary clinical efficacy to the therapy. RESULTS: Three patients were enrolled in this study, of which two had RRP. Study therapy was well-tolerated, with no related serious adverse events and all related adverse events (AEs) were low-grade. Injection site pain was the most common related AE reported. Immunogenicity was evidenced by multiple immune assays showing engagement and expansion of an HPV6-specific cellular response, including cytotoxic T cells. Preliminary efficacy was demonstrated in patients with RRP in the form of reduction in need for surgical intervention for papilloma growth. Prior to intervention, both patients required surgical intervention approximately every 180 days. One patient demonstrated a greater than three-fold increase in surgery avoidance (584 days) and the other patient remains completely surgery-free as of the last contact at 915 days, a greater than 5-fold increase in surgery interval. CONCLUSION: INO-3106 with and without INO-9012 was well tolerated, immunogenic and demonstrated preliminary efficacy in patients with HPV6-associated RRP aerodigestive lesions. Further clinical study is indicated.

2.
J Infect Dis ; 220(3): 400-410, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-30891607

RESUMO

BACKGROUND: Nonlive vaccine approaches that are simple to deliver and stable at room temperature or 2-8°C could be advantageous in controlling future Ebola virus (EBOV) outbreaks. Using an immunopotent DNA vaccine that generates protection from lethal EBOV challenge in small animals and nonhuman primates, we performed a clinical study to evaluate both intramuscular (IM) and novel intradermal (ID) DNA delivery. METHODS: Two DNA vaccine candidates (INO-4201 and INO-4202) targeting the EBOV glycoprotein (GP) were evaluated for safety, tolerability, and immunogenicity in a phase 1 clinical trial. The candidates were evaluated alone, together, or in combination with plasmid-encoded human cytokine interleukin-12 followed by in vivo electroporation using either the CELLECTRA® IM or ID delivery devices. RESULTS: The safety profile of all 5 regimens was shown to be benign, with the ID route being better tolerated. Antibodies to EBOV GP were generated by all 5 regimens with the fastest and steepest rise observed in the ID group. Cellular immune responses were generated with every regimen. CONCLUSIONS: ID delivery of INO-4201 was well tolerated and resulted in 100% seroreactivity after 2 doses and elicited interferon-γ T-cell responses in over 70% of subjects, providing a new approach for EBOV prevention in diverse populations. Clinical Trials Registration. NCT02464670.


Assuntos
Vacinas contra Ebola/efeitos adversos , Vacinas contra Ebola/imunologia , Imunidade Celular/imunologia , Imunidade Humoral/imunologia , Vacinas de DNA/efeitos adversos , Vacinas de DNA/imunologia , Adolescente , Adulto , Anticorpos Antivirais/imunologia , Ebolavirus/imunologia , Eletroporação/métodos , Feminino , Glicoproteínas/imunologia , Voluntários Saudáveis , Doença pelo Vírus Ebola/imunologia , Humanos , Injeções Intradérmicas/métodos , Interleucina-12/imunologia , Masculino , Pessoa de Meia-Idade , Temperatura , Vacinação/métodos , Adulto Jovem
3.
Clin Cancer Res ; 25(1): 110-124, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30242022

RESUMO

PURPOSE: Clinical responses with programmed death (PD-1) receptor-directed antibodies occur in about 20% of patients with advanced head and neck squamous cell cancer (HNSCCa). Viral neoantigens, such as the E6/E7 proteins of HPV16/18, are attractive targets for therapeutic immunization and offer an immune activation strategy that may be complementary to PD-1 inhibition. PATIENTS AND METHODS: We report phase Ib/II safety, tolerability, and immunogenicity results of immunotherapy with MEDI0457 (DNA immunotherapy targeting HPV16/18 E6/E7 with IL12 encoding plasmids) delivered by electroporation with CELLECTRA constant current device. Twenty-two patients with locally advanced, p16+ HNSCCa received MEDI0457. RESULTS: MEDI0457 was associated with mild injection site reactions, but no treatment-related grade 3-5 adverse events (AE) were noted. Eighteen of 21 evaluable patients showed elevated antigen-specific T-cell activity by IFNγ ELISpot, and persistent cellular responses surpassing 100 spot-forming units (SFUs)/106 peripheral blood mononuclear cells (PBMCs) were noted out to 1 year. Induction of HPV-specific CD8+ T cells was observed. MEDI0457 shifted the CD8+/FoxP3+ ratio in 4 of 5 post immunotherapy tumor samples and increased the number of perforin+ immune infiltrates in all 5 patients. One patient developed metastatic disease and was treated with anti-PD-1 therapy with a rapid and durable complete response. Flow-cytometric analyses revealed induction of HPV16-specific PD-1+ CD8+ T cells that were not found prior to MEDI0547 (0% vs. 1.8%). CONCLUSIONS: These data demonstrate that MEDI0457 can generate durable HPV16/18 antigen-specific peripheral and tumor immune responses. This approach may be used as a complementary strategy to PD-1/PD-L1 inhibition in HPV-associated HNSCCa to improve therapeutic outcomes.


Assuntos
Neoplasias de Cabeça e Pescoço/terapia , Imunoterapia , Infecções por Papillomavirus/terapia , Vacinas contra Papillomavirus/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Idoso , Antígenos Virais de Tumores/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/imunologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/virologia , Papillomavirus Humano 16/patogenicidade , Papillomavirus Humano 18/patogenicidade , Humanos , Imunidade Inata/efeitos dos fármacos , Interferon gama/genética , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Proteínas Oncogênicas Virais/antagonistas & inibidores , Proteínas Oncogênicas Virais/imunologia , Proteínas E7 de Papillomavirus/antagonistas & inibidores , Proteínas E7 de Papillomavirus/imunologia , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Receptor de Morte Celular Programada 1/imunologia , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/imunologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia
4.
Clin Cancer Res ; 24(2): 276-294, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29084917

RESUMO

Purpose: As previously reported, treatment of high-grade cervical dysplasia with VGX-3100 resulted in complete histopathologic regression (CR) concomitant with elimination of HPV16/18 infection in 40.0% of VGX-3100-treated patients compared with only 14.3% in placebo recipients in a randomized phase IIb study. Here, we identify clinical and immunologic characteristics that either predicted or correlated with therapeutic benefit from VGX-3100 to identify parameters that might guide clinical decision-making for this disease.Experimental Design: We analyzed samples taken from cervical swabs, whole blood, and tissue biopsies/resections to determine correlates and predictors of treatment success.Results: At study entry, the presence of preexisting immunosuppressive factors such as FoxP3 and PD-L1 in cervical lesions showed no association with treatment outcome. The combination of HPV typing and cervical cytology following dosing was predictive for both histologic regression and elimination of detectable virus at the efficacy assessment 22 weeks later (negative predictive value 94%). Patients treated with VGX-3100 who had lesion regression had a statistically significant >2-fold increase in CD137+perforin+CD8+ T cells specific for the HPV genotype causing disease. Increases in cervical mucosal CD137+ and CD103+ infiltrates were observed only in treated patients. Perforin+ cell infiltrates were significantly increased >2-fold in cervical tissue only in treated patients who had histologic CR.Conclusions: Quantitative measures associated with an effector immune response to VGX-3100 antigens were associated with lesion regression. Consequently, these analyses indicate that certain immunologic responses associate with successful resolution of HPV-induced premalignancy, with particular emphasis on the upregulation of perforin in the immunotherapy-induced immune response. Clin Cancer Res; 24(2); 276-94. ©2017 AACR.


Assuntos
Papillomavirus Humano 16 , Papillomavirus Humano 18 , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Displasia do Colo do Útero/diagnóstico , Displasia do Colo do Útero/etiologia , Biomarcadores , Biópsia , Linfócitos T CD8-Positivos , Progressão da Doença , Feminino , Genótipo , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Humanos , Imuno-Histoquímica , Imunoterapia , Hibridização In Situ , Infecções por Papillomavirus/imunologia , Vacinas contra Papillomavirus/administração & dosagem , Vacinas contra Papillomavirus/imunologia , Prognóstico , Resultado do Tratamento , Displasia do Colo do Útero/terapia , Vacinas de DNA/administração & dosagem , Vacinas de DNA/imunologia
5.
Cancer Immunol Immunother ; 66(12): 1609-1617, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28856392

RESUMO

The ability of some tumors to exclude effector T cells represents a major challenge to immunotherapy. T cell exclusion is particularly evident in pancreatic ductal adenocarcinoma (PDAC), a disease where blockade of the immune checkpoint molecule CTLA-4 has not produced significant clinical activity. In PDAC, effector T cells are often scarce within tumor tissue and confined to peritumoral lymph nodes and lymphoid aggregates. We hypothesized that CTLA-4 blockade, despite a lack of clinical efficacy seen thus far in PDAC, might still alter T cell immunobiology, which would have therapeutic implications. Using clinically relevant genetic models of PDAC, we found that regulatory T cells (Tregs), which constitutively express CTLA-4, accumulate early during tumor development but are largely confined to peritumoral lymph nodes during disease progression. Tregs were observed to regulate CD4+, but not CD8+, T cell infiltration into tumors through a CTLA-4/CD80 dependent mechanism. Disrupting CTLA-4 interaction with CD80 was sufficient to induce CD4 T cell infiltration into tumors. These data have important implications for T cell immunotherapy in PDAC and demonstrate a novel role for CTLA-4/CD80 interactions in regulating T cell exclusion. In addition, our findings suggest distinct mechanisms govern CD4+ and CD8+ T cell infiltration in PDAC.


Assuntos
Antígeno B7-1/imunologia , Antígeno CTLA-4/imunologia , Neoplasias Pancreáticas/imunologia , Linfócitos T Reguladores/imunologia , Animais , Anticorpos/imunologia , Anticorpos/farmacologia , Antígeno CTLA-4/antagonistas & inibidores , Humanos , Subunidade alfa de Receptor de Interleucina-2/imunologia , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Transdução de Sinais , Neoplasias Pancreáticas
6.
Gastroenterology ; 149(1): 201-10, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25888329

RESUMO

BACKGROUND & AIMS: Immunotherapies that induce T-cell responses have shown efficacy against some solid malignancies in patients and mice, but these have little effect on pancreatic ductal adenocarcinoma (PDAC). We investigated whether the ability of PDAC to evade T-cell responses induced by immunotherapies results from the low level of immunogenicity of tumor cells, the tumor's immunosuppressive mechanisms, or both. METHODS: Kras(G12D/+);Trp53(R172H/+);Pdx-1-Cre (KPC) mice, which develop spontaneous PDAC, or their littermates (controls) were given subcutaneous injections of a syngeneic KPC-derived PDAC cell line. Mice were then given gemcitabine and an agonist of CD40 to induce tumor-specific immunity mediated by T cells. Some mice were also given clodronate-encapsulated liposomes to deplete macrophages. Tumor growth was monitored. Tumor and spleen tissues were collected and analyzed by histology, flow cytometry, and immunohistochemistry. RESULTS: Gemcitabine in combination with a CD40 agonist induced T-cell-dependent regression of subcutaneous PDAC in KPC and control mice. In KPC mice given gemcitabine and a CD40 agonist, CD4(+) and CD8(+) T cells infiltrated subcutaneous tumors, but only CD4(+) T cells infiltrated spontaneous pancreatic tumors (not CD8(+) T cells). In mice depleted of Ly6C(low) F4/80(+) extratumoral macrophages, the combination of gemcitabine and a CD40 agonist stimulated infiltration of spontaneous tumors by CD8(+) T cells and induced tumor regression, mediated by CD8(+) T cells. CONCLUSIONS: Ly6C(low) F4/80(+) macrophages that reside outside of the tumor microenvironment regulate infiltration of T cells into PDAC and establish a site of immune privilege. Strategies to reverse the immune privilege of PDAC, which is regulated by extratumoral macrophages, might increase the efficacy of T-cell immunotherapy for patients with PDAC.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Imunoterapia/métodos , Macrófagos/citologia , Macrófagos/imunologia , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Antimetabólitos Antineoplásicos/farmacologia , Antígenos CD40/agonistas , Linfócitos T CD8-Positivos/efeitos dos fármacos , Carcinoma Ductal Pancreático/imunologia , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Modelos Animais de Doenças , Imuno-Histoquímica , Macrófagos/efeitos dos fármacos , Camundongos , Neoplasias Pancreáticas/imunologia , Gencitabina , Neoplasias Pancreáticas
7.
Immunity ; 27(1): 100-10, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17658278

RESUMO

Notch signaling plays multiple roles to direct diverse decisions regarding cell fate during T cell development. During helper T (Th) cell differentiation, Notch is involved in generating optimal Th2 cell responses. Here, we present data investigating how Notch mediates Th2 cell differentiation. Notch showed a CD4(+) T cell intrinsic role in promoting IL-4 expression that required GATA-3. In the absence of Notch signals, Gata3 expression was markedly diminished. Introduction of an activated allele of Notch1 into CD4(+) T cells led to the specific and direct upregulation of a developmentally regulated Gata3 transcript that included the exon 1a sequences. Furthermore, Notch acted in parallel with GATA-3 to synergistically activate IL-4 expression. Together, these data implicate Gata3 as a direct transcriptional Notch target that acts in concert with Notch signaling to generate optimal Th2 cell responses.


Assuntos
Diferenciação Celular/imunologia , Fator de Transcrição GATA3/metabolismo , Receptores Notch/fisiologia , Células Th2/citologia , Células Th2/metabolismo , Animais , Células Cultivadas , Regulação para Baixo/imunologia , Fator de Transcrição GATA3/antagonistas & inibidores , Fator de Transcrição GATA3/biossíntese , Fator de Transcrição GATA3/genética , Regulação da Expressão Gênica/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Transdução de Sinais/imunologia , Células Th2/imunologia
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