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1.
J Immunol ; 205(11): 3218-3229, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33158953

RESUMO

Preclinical studies demonstrated that complement promotes tumor growth. Therefore, we sought to determine the best target for complement-based therapy among common human malignancies. High expression of 11 complement genes was linked to unfavorable prognosis in renal cell carcinoma. Complement protein expression or deposition was observed mainly in stroma, leukocytes, and tumor vasculature, corresponding to a role of complement in regulating the tumor microenvironment. Complement abundance in tumors correlated with a high nuclear grade. Complement genes clustered within an aggressive inflammatory subtype of renal cancer characterized by poor prognosis, markers of T cell dysfunction, and alternatively activated macrophages. Plasma levels of complement proteins correlated with response to immune checkpoint inhibitors. Corroborating human data, complement deficiencies and blockade reduced tumor growth by enhancing antitumor immunity and seemingly reducing angiogenesis in a mouse model of kidney cancer resistant to PD-1 blockade. Overall, this study implicates complement in the immune landscape of renal cell carcinoma, and notwithstanding cohort size and preclinical model limitations, the data suggest that tumors resistant to immune checkpoint inhibitors might be suitable targets for complement-based therapy.


Assuntos
Biomarcadores/sangue , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/imunologia , Proteínas do Sistema Complemento/imunologia , Neoplasias Renais/sangue , Neoplasias Renais/imunologia , Animais , Carcinoma de Células Renais/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Estudos de Coortes , Feminino , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inflamação/imunologia , Neoplasias Renais/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Pessoa de Meia-Idade , Neovascularização Patológica/imunologia , Prognóstico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
2.
J Immunol ; 204(4): 990-1000, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31900334

RESUMO

In the metastasis-targeted organs, angiogenesis is essential for the progression of dormant micrometastases to rapidly growing and clinically overt lesions. However, we observed changes suggesting angiogenic switching in the mouse lungs prior to arrival of tumor cells (i.e., in the premetastatic niche) in the models of breast carcinoma. This angiogenic switching appears to be caused by myeloid-derived suppressor cells recruited to the premetastatic lungs through complement C5a receptor 1 signaling. These myeloid cells are known to secrete several proangiogenic factors in tumors, including IL-1ß and matrix metalloproteinase-9, and we found upregulation of these genes in the premetastatic lungs. Blockade of C5a receptor 1 synergized with antiangiogenic Listeria monocytogenes-based vaccines to decrease the lung metastatic burden by reducing vascular density and improving antitumor immunity in the lungs. This was mediated even when growth of primary breast tumors was not affected by these treatments. This work provides initial evidence that angiogenesis contributes to the premetastatic niche in rapidly progressing cancers and that inhibiting this process through immunotherapy is beneficial for reducing or even preventing metastasis.


Assuntos
Vacinas Anticâncer/administração & dosagem , Neoplasias Pulmonares/terapia , Neoplasias Mamárias Experimentais/terapia , Células Supressoras Mieloides/imunologia , Neovascularização Patológica/terapia , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Linhagem Celular Tumoral , Terapia Combinada/métodos , Complemento C5a/imunologia , Complemento C5a/metabolismo , Feminino , Humanos , Imunoterapia/métodos , Listeria monocytogenes/imunologia , Pulmão/irrigação sanguínea , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/patologia , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Knockout , Células Supressoras Mieloides/metabolismo , Metástase Neoplásica/imunologia , Metástase Neoplásica/terapia , Neovascularização Patológica/imunologia , Receptor da Anafilatoxina C5a/antagonistas & inibidores , Receptor da Anafilatoxina C5a/genética , Receptor da Anafilatoxina C5a/metabolismo , Microambiente Tumoral/imunologia
3.
J Immunol ; 198(7): 2989-2999, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28228558

RESUMO

Relatively little is known about factors that initiate immunosuppression in tumors and act at the interface between tumor cells and host cells. In this article, we report novel immunosuppressive properties of the ribosomal protein S19 (RPS19), which is upregulated in human breast and ovarian cancer cells and released from apoptotic tumor cells, whereupon it interacts with the complement C5a receptor 1 expressed on tumor infiltrating myeloid-derived suppressor cells. This interaction promotes tumor growth by facilitating recruitment of these cells to tumors. RPS19 also induces the production of immunosuppressive cytokines, including TGF-ß, by myeloid-derived suppressor cells in tumor-draining lymph nodes, leading to T cell responses skewed toward Th2 phenotypes. RPS19 promotes generation of regulatory T cells while reducing infiltration of CD8+ T cells into tumors. Reducing RPS19 in tumor cells or blocking the C5a receptor 1-RPS19 interaction decreases RPS19-mediated immunosuppression, impairs tumor growth, and delays the development of tumors in a transgenic model of breast cancer. This work provides initial preclinical evidence for targeting RPS19 for anticancer therapy enhancing antitumor T cell responses.


Assuntos
Células Supressoras Mieloides/imunologia , Neoplasias Experimentais/imunologia , Receptor da Anafilatoxina C5a/imunologia , Proteínas Ribossômicas/imunologia , Animais , Western Blotting , Linhagem Celular Tumoral , Citometria de Fluxo , Humanos , Imunoprecipitação , Camundongos , Linfócitos T/imunologia
4.
Semin Immunol ; 22(3): 183-9, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20299242

RESUMO

This review covers the use of the facultative intracellular bacteria, Listeriamonocytogenes and Salmonella enterica serovar typhimurium as delivery systems for tumor-associated antigens in tumor immunotherapy. Because of their ability to infect and survive in antigen presenting cells, these bacteria have been harnessed to deliver tumor antigens to the immune system both as bacterially expressed proteins and encoded on eukaryotic plasmids. They do this in the context of strong innate immunity, which provides the required stimulus to the immune response to break tolerance against those tumor-associated antigens that bear homology to self. Here we describe differences in the properties of these bacteria as vaccine vectors, a summary of the major therapies they have been applied to and their advancement towards the clinic.


Assuntos
Antígenos de Neoplasias/genética , Vetores Genéticos , Imunoterapia/métodos , Listeria monocytogenes/genética , Neoplasias/imunologia , Salmonella enterica/genética , Inibidores da Angiogênese/genética , Animais , Antígenos de Neoplasias/imunologia , Humanos , Listeria monocytogenes/imunologia , Camundongos , Neoplasias/terapia , Proteínas Recombinantes/genética , Salmonella enterica/imunologia
5.
Cancer Immunol Immunother ; 61(5): 689-700, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22057675

RESUMO

The recent announcement of the first FDA-approved therapeutic vaccine for prostate cancer, Sipuleucel-T, is a watershed moment for the field of tumor immunotherapy. However, while Sipuleucel-T provides a powerful tool to clinicians for the most prevalent form of cancer in men, there remains an unmet need for a similar therapeutic strategy against breast cancer, the most prevalent cancer in women. While current breast cancer vaccines in development target several antigens, the most prevalent is the tumor-associated antigen, HER2. Initial results with HER2 vaccines appear promising in terms of efficacy; however, the lack of HER2 overexpression by a majority of breast tumors and the safety concerns associated with current HER2-targeted immunotherapy suggest that additional therapeutic strategies would be beneficial. Recently, several studies have identified ISG15 as a molecule highly expressed in numerous malignancies. ISG15 is a small ubiquitin-like protein regulated by type-I interferon and classically associated with viral defense. Elevated ISG15 expression in breast cancer is especially well documented and is independent of HER2, progesterone receptor, and estrogen receptor status. Additionally, high ISG15 expression in breast cancer correlates with an unfavorable prognosis and poor responses to traditional treatment strategies such as chemotherapy and radiation. To overcome these challenges, we employ a novel strategy to specifically target tumor-associated ISG15 expression with immunotherapy. We demonstrate that vaccination against ISG15 results in significant CD8-mediated reductions in both primary and metastatic mammary tumor burden. These results validate ISG15 as a tumor-associated antigen for cancer immunotherapy.


Assuntos
Antígenos de Neoplasias/imunologia , Citocinas/imunologia , Citocinas/farmacologia , Animais , Antígenos de Neoplasias/genética , Antígenos CD8/imunologia , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/farmacologia , Linhagem Celular Tumoral , Citocinas/genética , Feminino , Fibroblastos/imunologia , Imunoterapia/métodos , Interferon Tipo I/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Células NIH 3T3 , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Ratos , Receptor ErbB-2/genética , Receptor ErbB-2/imunologia , Ubiquitinas/genética , Ubiquitinas/imunologia , Ubiquitinas/farmacologia
6.
Mol Ther ; 19(9): 1727-36, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21587210

RESUMO

Vaccines that aim to expand tumor-specific CD8(+) T cells have yielded disappointing results in cancer patients although they showed efficacy in transplantable tumor mouse models. Using a system that more faithfully mimics a progressing cancer and its immunoinhibitory microenvironment, we here show that in transgenic mice, which gradually develop adenocarcinomas due to expression of HPV-16 E7 within their thyroid, a highly immunogenic vaccine expressing E7 only induces low E7-specific CD8(+) T-cell responses, which fail to affect the size of the tumors. In contrast, the same type of vaccine expressing E7 fused to herpes simplex virus (HSV)-1 glycoprotein D (gD), an antagonist of the coinhibitory B- and T-lymphocyte attenuator (BTLA)/CD160-herpes virus entry mediator (HVEM) pathways, stimulates potent E7-specific CD8(+) T-cell responses, which can be augmented by repeated vaccination, resulting in initial regression of even large tumor masses in all mice with sustained regression in more than half of them. These results indicate that active immunization concomitantly with blockade of the immunoinhibitory HVEM-BTLA/CD160 pathways through HSV-1 gD may result in sustained tumor regression.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/imunologia , Imunoterapia Ativa/métodos , Neoplasias/terapia , Proteínas E7 de Papillomavirus/imunologia , Animais , Animais Geneticamente Modificados , Biomarcadores , Linfócitos T CD8-Positivos/metabolismo , Regulação da Expressão Gênica , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neoplasias/imunologia , Neoplasias/metabolismo , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Membro 14 de Receptores do Fator de Necrose Tumoral/imunologia , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais , Glândula Tireoide/imunologia , Vacinação/métodos
7.
Cancer Immunol Immunother ; 60(7): 931-42, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21431419

RESUMO

The FDA approval of bevacizumab (Avastin®, Genentech/Roche), a monoclonal antibody raised against human VEGF-A, as second-line therapy for colon and lung carcinoma validated the approach of targeting human tumors with angiogenesis inhibitors. While the VEGF/VEGFR pathway is a viable target for anti-angiogenesis tumor therapy, additional targets involved in tumor neovascularization have been identified. One promising target present specifically on tumor vasculature is endoglin (CD105), a member of the TGF-ß receptor complex expressed on vascular endothelium and believed to play a role in angiogenesis. Monoclonal antibody therapy and preventive vaccination against CD105 has met with some success in controlling tumor growth. This report describes the in vivo proof-of-concept studies for two novel therapeutic vaccines, Lm-LLO-CD105A and Lm-LLO-CD105B, directed against CD105 as a strategy to target neovascularization of established tumors. Listeria-based vaccines directed against CD105 lead to therapeutic responses against primary and metastatic tumors in the 4T1-Luc and NT-2 mouse models of breast cancer. In a mouse model for autochthonous Her-2/neu-driven breast cancer, Lm-LLO-CD105A vaccination prevented tumor incidence in 20% of mice by week 58 after birth while all control mice developed tumors by week 40. In comparison with previous Listeria-based vaccines targeting tumor vasculature, Lm-LLO-CD105A and Lm-LLO-CD105B demonstrated equivalent or superior efficacy against two transplantable mouse models of breast cancer. Support is provided for epitope spreading to endogenous tumor antigens and reduction in tumor vascularity after vaccination with Listeria-based CD105 vaccines. Reported here, these CD105 therapeutic vaccines are highly effective in stimulating anti-angiogenesis and anti-tumor immune responses leading to therapeutic efficacy against primary and metastatic breast cancer.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Imunoterapia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Listeria/imunologia , Neoplasias Mamárias Experimentais/irrigação sanguínea , Neoplasias Mamárias Experimentais/prevenção & controle , Neovascularização Patológica/prevenção & controle , Sequência de Aminoácidos , Animais , Endoglina , Feminino , Humanos , Listeria/genética , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Dados de Sequência Molecular , Neovascularização Patológica/imunologia , Ratos , Receptores de Fatores de Crescimento Transformadores beta , Taxa de Sobrevida
8.
J Immunol ; 182(9): 5537-46, 2009 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-19380802

RESUMO

Thirty years after angiogenesis was shown to play an enabling role in cancer, modern medicine is still trying to develop novel compounds and therapeutics to target the tumor vasculature. However, most therapeutics require multiple rounds of administration and can have toxic side effects. In this study, we use anti-angiogenesis immunotherapy to target cells actively involved in forming new blood vessels that support the growth and spread of breast cancer. Targeting a central cell type involved in angiogenesis, endothelial cells, we immunized against host vascular endothelial growth factor receptor 2 to fight the growth of Her-2/neu(+) breast tumors. Using the bacterial vector, Listeria monocytogenes (Lm), we fused polypeptides from the mouse vascular endothelial growth factor receptor 2 molecule (fetal liver kinase-1) to the microbial adjuvant, listeriolysin-O, and used Lm to deliver the Ags and elicit potent antitumor CTL responses. Lm-listeriolysin-O-fetal liver kinase-1 was able to eradicate some established breast tumors, reduce microvascular density in the remaining tumors, protect against tumor rechallenge and experimental metastases, and induce epitope spreading to various regions of the tumor-associated Ag Her-2/neu. Tumor eradication was found to be dependent on epitope spreading to HER-2/neu and was not solely due to the reduction of tumor vasculature. However, vaccine efficacy did not affect normal wound healing nor have toxic side effects on pregnancy. We show that an anti-angiogenesis vaccine can overcome tolerance to the host vasculature driving epitope spreading to an endogenous tumor protein and drive active tumor regression.


Assuntos
Inibidores da Angiogênese/imunologia , Vacinas Anticâncer/imunologia , Listeria monocytogenes/imunologia , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/prevenção & controle , Neovascularização Patológica/prevenção & controle , Receptor ErbB-2/biossíntese , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/imunologia , Sequência de Aminoácidos , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/genética , Animais , Toxinas Bacterianas/administração & dosagem , Toxinas Bacterianas/genética , Toxinas Bacterianas/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/genética , Linhagem Celular Tumoral , Feminino , Inibidores do Crescimento/administração & dosagem , Inibidores do Crescimento/genética , Inibidores do Crescimento/imunologia , Proteínas de Choque Térmico/administração & dosagem , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/imunologia , Proteínas Hemolisinas/administração & dosagem , Proteínas Hemolisinas/genética , Proteínas Hemolisinas/imunologia , Listeria monocytogenes/genética , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/prevenção & controle , Neoplasias Mamárias Experimentais/irrigação sanguínea , Neoplasias Mamárias Experimentais/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Dados de Sequência Molecular , Neovascularização Patológica/imunologia , Neovascularização Patológica/fisiopatologia , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
9.
Front Immunol ; 12: 642316, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936058

RESUMO

The promise of tumor immunotherapy to significantly improve survival in patients who are refractory to long-standing therapies, such as chemotherapy and radiation, is now being realized. While immune checkpoint inhibitors that target PD-1 and CTLA-4 are leading the charge in clinical efficacy, there are a number of other promising tumor immunotherapies in advanced development such as Listeria-based vaccines. Due to its unique life cycle and ability to induce robust CTL responses, attenuated strains of Listeria monocytogenes (Lm) have been utilized as vaccine vectors targeting both infectious disease and cancer. In fact, preclinical studies in a multitude of cancer types have found Listeria-based vaccines to be highly effective at activating anti-tumor immunity and eradicating tumors. Several clinical trials have now recently reported their results, demonstrating promising efficacy against some cancers, and unique challenges. Development of the Lm-based immunotherapies continues with discovery of improved methods of attenuation, novel uses, and more effective combinatorial regimens. In this review, we provide a brief background of Listeria monocytogenes as a vaccine vector, discuss recent clinical experience with Listeria-based immunotherapies, and detail the advancements in development of improved Listeria-based vaccine platforms and in their utilization.


Assuntos
Vacinas Anticâncer/imunologia , Imunoterapia/métodos , Listeria monocytogenes , Neoplasias/terapia , Animais , Vetores Genéticos , Humanos
10.
Cancer Immunol Immunother ; 59(7): 1049-1058, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20213121

RESUMO

Tumor immunotherapy is currently at the cusp of becoming an important aspect of comprehensive cancer treatment in the clinic. However, the need for improved adjuvants to augment immune responses against tumor antigens is always present. In this paper, we characterize the Listeria monocytogenes-derived actin-nucleating protein, ActA, as a novel adjuvant for use in tumor immunotherapy. ActA is a virulence factor that is expressed on the cell surface of L. monocytogenes and facilitates the production of actin tails that propel Listeria throughout the cytosol of an infected host cell. It is believed that this ActA-dependent cytosolic motility allows Listeria to evade adaptive host cell defenses and facilitates its invasion into a proximal uninfected host cell. However, there is evidence that ActA fused to a tumor antigen and delivered by L. monocytogenes can perform a beneficial function in tumor immunotherapy as an adjuvant. Our investigation of this adjuvant activity demonstrates that ActA, either fused to or administered as a mixture with a tumor antigen, can augment anti-tumor immune responses, break immune tolerance and facilitate tumor eradication, which suggests that ActA is not only an effective adjuvant in tumor immunotherapy but can also be applied in a number of therapeutic settings.


Assuntos
Proteínas de Bactérias/imunologia , Imunoterapia/métodos , Proteínas de Membrana/imunologia , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/terapia , Adjuvantes Imunológicos/administração & dosagem , Animais , Antígenos de Neoplasias/imunologia , Proteínas de Bactérias/administração & dosagem , Proteínas de Bactérias/genética , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Proteínas de Membrana/administração & dosagem , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Metástase Neoplásica , Neoplasias Experimentais/patologia , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/imunologia , Resultado do Tratamento , Carga Tumoral
11.
Clin Cancer Res ; 15(3): 924-32, 2009 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-19188163

RESUMO

PURPOSE: The aim of this study was to efficiently design a novel vaccine for human Her-2/neu-positive (hHer-2/neu) breast cancer using the live, attenuated bacterial vector Listeria monocytogenes. EXPERIMENTAL DESIGN: Three recombinant L. monocytogenes-based vaccines were generated that could express and secrete extracellular and intracellular fragments of the hHer-2/neu protein. In addition, we generated a fourth construct fusing selected portions of each individual fragment that contained most of the human leukocyte antigen (HLA) epitopes as a combination vaccine (L. monocytogenes-hHer-2/neu chimera). RESULTS: Each individual vaccine was able to either fully regress or slow tumor growth in a mouse model for Her-2/neu-positive tumors. All three vaccines could elicit immune responses directed toward human leukocyte antigen-A2 epitopes of hHer-2/neu. The L. monocytogenes-hHer-2/neu chimera was able to mimic responses generated by the three separate vaccines and prevent spontaneous outgrowth of tumors in an autochthonous model for Her-2/neu-positive breast cancer, induce tumor regression in transplantable models, and prevent seeding of experimental lung metastases in a murine model for metastatic breast cancer. CONCLUSION: This novel L. monocytogenes-hHer-2/neu chimera vaccine proves to be just as effective as the individual vaccines but combines the strength of all three in a single vaccination. These encouraging results support future clinical trials using this chimera vaccine and may be applicable to other cancer types expressing the Her-2/neu molecule such as colorectal and pancreatic cancer.


Assuntos
Neoplasias da Mama/terapia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/uso terapêutico , Genes erbB-2 , Antígeno HLA-A2/imunologia , Listeria monocytogenes/imunologia , Vacinas Sintéticas/uso terapêutico , Sequência de Aminoácidos , Animais , Antígenos de Neoplasias/imunologia , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Vacinas Anticâncer/imunologia , Vetores Genéticos , Humanos , Camundongos , Dados de Sequência Molecular , Transplante de Neoplasias , Fragmentos de Peptídeos/imunologia
12.
Adv Appl Microbiol ; 66: 1-27, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19203646

RESUMO

Listeria monocytogenes is a facultative intracellular gram-positive bacterium that naturally infects professional antigen presenting cells (APC) to target antigens to both class I and class II antigen processing pathways. This infection process results in the stimulation of strong innate and adaptive immune responses, which make it an ideal candidate for a vaccine vector to deliver heterologous antigens. This ability of L. monocytogenes has been exploited by several researchers over the past decade to specifically deliver tumor-associated antigens that are poorly immunogenic such as self-antigens. This review describes the preclinical studies that have elucidated the multiple immune responses elicited by this bacterium that direct its ability to influence tumor growth.


Assuntos
Vacinas Anticâncer/uso terapêutico , Listeria monocytogenes/imunologia , Listeriose/imunologia , Neoplasias/terapia , Vacinas Sintéticas/uso terapêutico , Células Apresentadoras de Antígenos/imunologia , Vacinas Anticâncer/imunologia , Humanos , Listeria monocytogenes/genética , Listeria monocytogenes/patogenicidade , Listeriose/microbiologia , Neoplasias/imunologia , Linfócitos T Reguladores/imunologia , Vacinas Sintéticas/imunologia , Virulência , Fatores de Virulência/genética , Fatores de Virulência/imunologia
13.
Cancer Res ; 67(5): 1887-92, 2007 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-17332314

RESUMO

Immunoediting of tumor-associated antigens occurs in response to immune pressure. We show that the mutation of residues within epitopes of HER-2/neu leads to the outgrowth of autochthonous tumors after immunizing HER-2/neu transgenic mice with Listeria monocytogenes therapeutic vaccines expressing fragments of HER-2/neu. Three of these vaccines target the extracellular domain (LmLLO-EC1, LmLLO-EC2, and LmLLO-EC3), and two of these vaccines target the intracellular domain (Lm-LLO-IC1 and Lm-LLO-IC2). Mutations occurred in the regions of the HER-2/neu molecule targeted by the Listeria strain expressing that region, which suggests that the rate of generation of escape mutants was a significant factor in the efficacy of each vaccine. A longer delay in the onset of tumors after immunotherapy occurred with the vaccine that targeted the kinase domain. We verified that the mutations in this domain occurred within novel CD8(+) T-cell epitopes, and that the mutation of these residues abrogated CTL responses to these epitopes. The long delay in the onset of tumors after immunotherapy targeting the kinase domain may be because this region of HER-2/neu cannot undergo extensive mutations without impairing its ability to signal cell growth.


Assuntos
Vacinas Anticâncer/uso terapêutico , Epitopos , Neoplasias Mamárias Animais/imunologia , Neoplasias Mamárias Animais/terapia , Receptor ErbB-2/imunologia , Células 3T3 , Animais , Antígenos de Neoplasias/química , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Epitopos de Linfócito T , Feminino , Neoplasias Mamárias Animais/genética , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Mutação , Estrutura Terciária de Proteína , Proteínas Tirosina Quinases/genética , Receptor ErbB-2/química , Receptor ErbB-2/genética
14.
Immunol Res ; 42(1-3): 233-45, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-19018479

RESUMO

Our laboratory is interested in how immunogenicity may be modulated in vivo in order to better design more effective immunotherapeutics against cancer. Our main approach is to use a facultative intracellular bacterium, Listeria monocytogenes, which has the unusual ability to live and grow in the cytoplasm of the cell and is thus an excellent vector for targeting passenger antigens to the major histocompatibility complex (MHC) class I pathway of antigen processing with the generation of authentic CTL epitopes. We have used this approach to target tumor antigens expressed on breast, melanoma and cervical cancer. We are also exploring the role of Listerial virulence factors in potentiating adaptive immune responses by activating innate immunity. Specifically, we are using these proteins as adjuvants for B cell lymphomas.


Assuntos
Vacinas Anticâncer/imunologia , Imunoterapia/métodos , Listeria monocytogenes/imunologia , Fatores de Virulência/imunologia , Animais , Toxinas Bacterianas/imunologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/prevenção & controle , Neoplasias da Mama/terapia , Vacinas Anticâncer/uso terapêutico , Feminino , Proteínas de Choque Térmico/imunologia , Proteínas Hemolisinas/imunologia , Humanos , Linfoma não Hodgkin/imunologia , Linfoma não Hodgkin/prevenção & controle , Linfoma não Hodgkin/terapia
15.
Cancer Res ; 66(15): 7748-57, 2006 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-16885378

RESUMO

The HER-2/neu oncogene has >25 HLA epitopes, yet only one FVB/N mouse CD8(+) T-cell epitope has been mapped to date. This epitope has been termed the immunodominant epitope for the FVB/N mouse, but we propose that the vaccination strategy determines the dominance of epitopes. Using a series of overlapping peptides, we have mapped another CD8(+) T-cell epitope that emerges in the FVB/N mouse following vaccination with Listeria monocytogenes-based vaccines that express fragments of HER-2/neu. Following the identification of this novel H-2K(q)-restricted epitope, we sought to compare the T-cell response to this epitope with the previously identified PDSLRDLSVF epitope. This newly identified epitope and the previously identified epitope lie within fragments contained in different vaccines, the PDSLRDLSVF epitope in Lm-LLO-EC2 and the newly identified PYNYLSTEV epitope in Lm-LLO-EC1; thus, it has been possible to compare the responses of these epitopes independent of any competing response between the epitopes. CTL analysis of individual peptide-pulsed target cells and intracellular cytokine stain for IFN-gamma produced by splenocytes from Lm-LLO-EC1 compared with Lm-LLO-EC2 vaccinated FVB/N mice shows that there is no difference between the responses generated to either of these epitopes. We also show that the avidity of the CD8(+) T cells for either of these epitopes is similar based on the concentration of peptide necessary to mediate similar levels of lysis of target cells. In addition, HER-2/neu DNA vaccination followed by CTL analysis further showed that both of these peptides can emerge as epitopes.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/imunologia , Epitopos de Linfócito T/imunologia , Genes erbB-2/imunologia , Neoplasias Mamárias Experimentais/imunologia , Vacinas de DNA/imunologia , Sequência de Aminoácidos , Animais , Afinidade de Anticorpos , Vacinas Anticâncer/genética , Epitopos de Linfócito T/genética , Feminino , Genes erbB-2/genética , Listeria monocytogenes/imunologia , Neoplasias Mamárias Experimentais/genética , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Células NIH 3T3 , Ratos , Baço/imunologia , Linfócitos T Citotóxicos/imunologia , Vacinas de DNA/genética
16.
Cancer Immun ; 7: 2, 2007 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-17279610

RESUMO

We have created a transgenic mouse with tissue-specific expression of the human papilloma virus (HPV) 16 E6 and E7 oncoproteins in the thyroid as a model of HPV transformed cancer. The expression of the transgenes results in the formation of palpable thyroid tumors. E7 is not expressed in other tissues but is expressed in medullary thymic epithelial cells, which have been implicated in the control of negative selection. We show that Listeria-based vaccines against E7 can induce the regression of solid implanted tumors in the transgenic mice, although at a lower frequency than in wild type (WT) mice. E7-specific CD8+ T cells induced in transgenic mice are of both lower avidity and lower frequency when compared to the WT mice. In this model, Listeria-based vaccines against E7 appear to be overcoming central tolerance by expanding low avidity CD8+ T cells specific for E7 that are not deleted during thymopoesis and can eliminate solid tumors.


Assuntos
Vacinas Bacterianas/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer , Listeria/imunologia , Alphapapillomavirus , Animais , Afinidade de Anticorpos , Linhagem Celular , Genes ras , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Oncogênicas Virais/genética , Proteínas E7 de Papillomavirus/imunologia , Fenótipo
17.
Cancer Res ; 64(24): 8821-5, 2004 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-15604239

RESUMO

Previous work in our laboratory has established that the fusion of tumor-associated antigens to a truncated form of the Listeria monocytogenes virulence factor listeriolysin O (LLO) enhances the immunogenicity and antitumor efficacy of the tumor antigen when delivered by Listeria or by vaccinia. LLO contains a PEST sequence at the NH(2) terminus. These sequences, which are found in eukaryotic proteins with a short cellular half-life, target proteins for degradation in the ubiquitin-proteosome pathway. To investigate whether the enhanced immunogenicity conferred by LLO is due to the PEST sequence, we constructed new Listeria recombinants that expressed the HPV-16 E7 antigen fused to LLO, which either contained or had been deleted of this sequence. We then compared the antitumor efficacy of this set of vectors and found that Listeria expressing the fusion protein LLO-E7 or PEST-E7 were effective at regressing established macroscopic HPV-16 immortalized tumors in syngeneic mice. In contrast, Listeria recombinants expressing E7 alone or E7 fused to LLO from which the PEST sequence had been genetically removed could only slow tumor growth. Because CD8(+) T cell epitopes are generated in the ubiquitin-proteosome pathway, we also investigated the ability of the vaccines to induce E7-specific CD8(+) T cells in the spleen and to generate E7-specific tumor-infiltrating lymphocytes. A strong correlation was observed between CD8(+) T-cell induction and tumor homing and the antitumor efficacy of the Listeria-E7 vaccines. These findings suggest a strategy for the augmentation of tumor antigen-based immunotherapeutic strategies that may be broadly applicable.


Assuntos
Toxinas Bacterianas/imunologia , Vacinas Anticâncer/imunologia , Proteínas de Choque Térmico/imunologia , Listeria monocytogenes/imunologia , Proteínas Oncogênicas Virais/imunologia , Vacinas contra Papillomavirus , Sequência de Aminoácidos , Animais , Toxinas Bacterianas/genética , Vacinas Bacterianas/genética , Vacinas Bacterianas/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/genética , Linhagem Celular Tumoral , Epitopos , Epitopos de Linfócito T/imunologia , Proteínas de Choque Térmico/genética , Proteínas Hemolisinas , Listeria monocytogenes/genética , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/terapia , Neoplasias Experimentais/virologia , Proteínas Oncogênicas Virais/genética , Proteínas E7 de Papillomavirus , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Baço/citologia , Baço/imunologia , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia
18.
Clin Cancer Res ; 22(17): 4380-90, 2016 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26994144

RESUMO

PURPOSE: Recombinant Listeria vaccines induce tumor-specific T-cell responses that eliminate established tumors and prevent metastatic disease in murine cancer models. We used dogs with HER2/neu(+) appendicular osteosarcoma, a well-recognized spontaneous model for pediatric osteosarcoma, to determine whether a highly attenuated, recombinant Listeria monocytogenes expressing a chimeric human HER2/neu fusion protein (ADXS31-164) could safely induce HER2/neu-specific immunity and prevent metastatic disease. EXPERIMENTAL DESIGN: Eighteen dogs that underwent limb amputation or salvage surgery and adjuvant chemotherapy were enrolled in a phase I dose escalation clinical trial and received either 2 × 10(8), 5 × 10(8), 1 × 10(9), or 3.3 × 10(9) CFU of ADXS31-164 intravenously every 3 weeks for 3 administrations. RESULTS: Only low-grade, transient toxicities were observed. ADXS31-164 broke peripheral tolerance and induced antigen-specific IFNγ responses against the intracellular domain of HER2/neu in 15 of 18 dogs within 6 months of treatment. Furthermore, ADXS31-164 reduced the incidence of metastatic disease and significantly increased duration of survival time and 1-, 2-, and 3-year survival rates when compared with a historical control group with HER2/neu(+) appendicular osteosarcoma treated with amputation and chemotherapy alone. CONCLUSIONS: These findings demonstrate that ADXS31-164 administered in the setting of minimal residual disease can induce HER2/neu-specific immunity and may reduce the incidence of metastatic disease and prolong overall survival in a clinically relevant, spontaneous, large animal model of cancer. These findings, therefore, have important translational relevance for children with osteosarcoma and adults with other HER2/neu(+) cancers. Clin Cancer Res; 22(17); 4380-90. ©2016 AACR.


Assuntos
Neoplasias Ósseas/veterinária , Vacinas Anticâncer/imunologia , Doenças do Cão/imunologia , Doenças do Cão/terapia , Imunoterapia , Listeria/imunologia , Osteossarcoma/veterinária , Receptor ErbB-2/antagonistas & inibidores , Animais , Biomarcadores , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Progressão da Doença , Doenças do Cão/diagnóstico , Doenças do Cão/mortalidade , Cães , Imunidade Celular , Esquemas de Imunização , Imunoterapia/métodos , Interferon gama , Receptor ErbB-2/imunologia , Resultado do Tratamento , Vacinação , Vacinas Sintéticas
19.
Clin Transl Med ; 5(Suppl 1): 26, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27558513

RESUMO

TABLE OF CONTENTS: A1 One health advances and successes in comparative medicine and translational researchCheryl StroudA2 Dendritic cell-targeted gorilla adenoviral vector for cancer vaccination for canine melanomaIgor Dmitriev, Elena Kashentseva, Jeffrey N. Bryan, David T. CurielA3 Viroimmunotherapy for malignant melanoma in the companion dog modelJeffrey N. Bryan, David Curiel, Igor Dmitriev, Elena Kashentseva, Hans Rindt, Carol Reinero, Carolyn J. HenryA4 Of mice and men (and dogs!): development of a commercially licensed xenogeneic DNA vaccine for companion animals with malignant melanomaPhilip J. BergmanA5 Successful immunotherapy with a recombinant HER2-expressing Listeria monocytogenes in dogs with spontaneous osteosarcoma paves the way for advances in pediatric osteosarcomaNicola J. Mason, Josephine S. Gnanandarajah, Julie B. Engiles, Falon Gray, Danielle Laughlin, Anita Gaurnier-Hausser, Anu Wallecha, Margie Huebner, Yvonne PatersonA6 Human clinical development of ADXS-HER2Daniel O'ConnorA7 Leveraging use of data for both human and veterinary benefitLaura S. TremlA8 Biologic replacement of the knee: innovations and early clinical resultsJames P. StannardA9 Mizzou BioJoint Center: a translational success storyJames L. CookA10 University and industry translational partnership: from the lab to commercializationMarc JacobsA11 Beyond docking: an evolutionarily guided OneHealth approach to drug discoveryGerald J. Wyckoff, Lee Likins, Ubadah Sabbagh, Andrew SkaffA12 Challenges and opportunities for data applications in animal health: from precision medicine to precision husbandryAmado S. GuloyA13 A cloud-based programmable platform for healthHarlen D. HaysA14 Comparative oncology: One Health in actionAmy K. LeBlancA15 Companion animal diseases bridge the translational gap for human neurodegenerative diseaseJoan R. Coates, Martin L. Katz, Leslie A. Lyons, Gayle C. Johnson, Gary S. Johnson, Dennis P. O'BrienA16 Duchenne muscular dystrophy gene therapyDongsheng DuanA17 Polycystic kidney disease: cellular mechanisms to emerging therapiesJames P. CalvetA18 The domestic cat as a large animal model for polycystic kidney diseaseLeslie A. Lyons, Barbara GandolfiA19 The support of basic and clinical research by the Polycystic Kidney Disease FoundationDavid A. BaronA20 Using naturally occurring large animal models of human disease to enable clinical translation: treatment of arthritis using autologous stromal vascular fraction in dogsMark L. WeissA21 Regulatory requirements regarding clinical use of human cells, tissues, and tissue-based productsDebra A. WebsterA22 Regenerative medicine approaches to Type 1 diabetes treatmentFrancis N. KaranuA23 The zoobiquity of canine diabetes mellitus, man's best friend is a friend indeed-islet transplantationEdward J. RobbA24 One Medicine: a development model for cellular therapy of diabetesRobert J. Harman.

20.
Curr Opin Mol Ther ; 7(3): 256-63, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15977424

RESUMO

Stressgen is developing HspE7, a recombinant fusion protein comprising the human papillomavirus (HPV) E7 antigen and the heat shock protein Hsp65 from Mycobacterium bovis, as a potential therapy for conditions associated with HPV infection. This therapy is currently undergoing phase III clinical trials.


Assuntos
Proteínas de Bactérias/uso terapêutico , Chaperoninas/uso terapêutico , Proteínas Oncogênicas Virais/uso terapêutico , Infecções por Papillomavirus/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Animais , Proteínas de Bactérias/genética , Chaperonina 60 , Chaperoninas/genética , Ensaios Clínicos Fase III como Assunto , Humanos , Proteínas Oncogênicas Virais/genética , Proteínas E7 de Papillomavirus , Proteínas Recombinantes de Fusão/genética
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