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1.
Am J Clin Oncol ; 38(1): 90-7, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25616204

RESUMEN

A clear contribution of the immune system to eradication of tumors has been supported by recent developments in the field of immunotherapy. Durable clinical responses obtained after treatment with immunomodulatory agents such as ipilimumab (Yervoy) and anti-PD-1 antibody (BMS-936558), have established that harnessing the immune response against chemoresistant tumors can result in their complete eradication. However, only a subset of patients benefit from these therapeutic approaches. Accumulating evidence suggests that tumors with a preexisting active immune microenvironment might have a better response to immunotherapy. In a number of preclinical and clinical studies, many cytotoxic agents elicit changes within tumors and their microenvironment that may make these malignant cells more sensitive to an efficient immune cell attack. Therefore, it is plausible that combining immunotherapy with standard anticancer therapies such as chemotherapy or radiotherapy will provide synergistic antitumor effects. Despite a large collection of preclinical data, the immune mechanisms that might contribute to the efficacy of conventional cytotoxic therapies and their combinations with immunotherapeutic approaches have not yet been extensively studied in the clinical setting and warrant further investigation. This review will focus on current knowledge of the immunomodulatory effects of one such cytotoxic treatment, radiotherapy, and explore different pathways by which its combination with immunomodulatory antibodies might contribute toward more efficacious antitumor immunity.


Asunto(s)
Inmunoterapia/métodos , Neoplasias/radioterapia , Radioterapia/métodos , Microambiente Tumoral/efectos de la radiación , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Terapia Combinada , Humanos , Ipilimumab , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Nivolumab , Microambiente Tumoral/inmunología
2.
J Transl Med ; 11: 75, 2013 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-23521917

RESUMEN

BACKGROUND: Treatment with ipilimumab, a fully human anti-CTLA-4 antibody approved for the treatment of advanced melanoma, is associated with some immune-related adverse events (irAEs) such as colitis (gastrointestinal irAE, or GI irAE) and skin rash, which are managed by treatment guidelines. Nevertheless, predictive biomarkers that can help identify patients more likely to develop these irAEs could enhance the management of these toxicities. METHODS: To identify candidate predictive biomarkers associated with GI irAEs, gene expression profiling was performed on whole blood samples from 162 advanced melanoma patients at baseline, 3 and 11 weeks after the start of ipilimumab treatment in two phase II clinical trials (CA184004 and CA184007). Overall, 49 patients developed Grade 2 or higher (grade 2+) GI irAEs during the course of treatment. A repeated measures analysis of variance (ANOVA) was used to evaluate the differences in mean expression levels between the GI irAE and No-GI irAE groups of patients at the three time points. RESULTS: In baseline samples, 27 probe sets showed differential mean expression (≥ 1.5 fold, P ≤ 0.05) between the GI irAE and No-GI irAE groups. Most of these probe sets belonged to three functional categories: immune system, cell cycle, and intracellular trafficking. Changes in gene expression over time were also characterized. In the GI irAE group, 58 and 247 probe sets had a ≥ 1.5 fold change in expression from baseline to 3 and 11 weeks after first ipilimumab dose, respectively. In particular, on-treatment expression increases of CD177 and CEACAM1, two neutrophil-activation markers, were closely associated with GI irAEs, suggesting a possible role of neutrophils in ipilimumab-associated GI irAEs. In addition, the expression of several immunoglobulin genes increased over time, with greater increases in patients with grade 2+ GI irAEs. CONCLUSIONS: Gene expression profiling of peripheral blood, sampled before or early in the course of treatment with ipilimumab, resulted in the identification of a set of potential biomarkers that were associated with occurrence of GI irAEs. However, because of the low sensitivity of these biomarkers, they cannot be used alone to predict which patients will develop GI irAEs. Further investigation of these biomarkers in a larger patient cohort is warranted.


Asunto(s)
Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Biomarcadores de Tumor/sangre , Tracto Gastrointestinal/patología , Perfilación de la Expresión Génica , Sistema Inmunológico/metabolismo , Melanoma/genética , Proteínas Ligadas a GPI/metabolismo , Tracto Gastrointestinal/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Sistema Inmunológico/efectos de los fármacos , Inmunoglobulinas/genética , Inmunoglobulinas/metabolismo , Ipilimumab , Isoantígenos/metabolismo , Recuento de Leucocitos , Melanoma/sangre , Melanoma/tratamiento farmacológico , Neutrófilos/metabolismo , Curva ROC , Receptores de Superficie Celular/metabolismo , Reproducibilidad de los Resultados , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética
3.
Clin Vaccine Immunol ; 20(1): 77-84, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23136118

RESUMEN

There is a constant need for improved adjuvants to augment the induction of immune responses against tumor-associated antigens (TAA) during immunotherapy. Previous studies have established that listeriolysin O (LLO), a cholesterol-dependent cytolysin derived from Listeria monocytogenes, exhibits multifaceted effects to boost the stimulation of immune responses to a variety of antigens. However, the direct ability of LLO as an adjuvant and whether it acts as a pathogen-associated molecular pattern (PAMP) have not been demonstrated. In this paper, we show that a detoxified, nonhemolytic form of LLO (dtLLO) is an effective adjuvant in tumor immunotherapy and may activate innate and cellular immune responses by acting as a PAMP. Our investigation of the adjuvant activity demonstrates that dtLLO, either fused to or administered as a mixture with a human papillomavirus type 16 (HPV-16) E7 recombinant protein, can augment antitumor immune responses and facilitate tumor eradication. Further mechanistic studies using bone marrow-derived dendritic cells suggest that dtLLO acts as a PAMP by stimulating production of proinflammatory cytokines and inducing maturation of antigen-presenting cells (APC). We propose that dtLLO is an effective adjuvant for tumor immunotherapy, and likely for other therapeutic settings.


Asunto(s)
Adyuvantes Inmunológicos/farmacología , Toxinas Bacterianas/farmacología , Vacunas contra el Cáncer/administración & dosificación , Proteínas de Choque Térmico/farmacología , Proteínas Hemolisinas/farmacología , Inmunoterapia/métodos , Listeria monocytogenes/química , Adyuvantes Inmunológicos/aislamiento & purificación , Animales , Células Presentadoras de Antígenos/efectos de los fármacos , Células Presentadoras de Antígenos/inmunología , Toxinas Bacterianas/aislamiento & purificación , Vacunas contra el Cáncer/inmunología , Citocinas/metabolismo , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Proteínas de Choque Térmico/aislamiento & purificación , Proteínas Hemolisinas/aislamiento & purificación , Ratones , Ratones Endogámicos C57BL , Proteínas E7 de Papillomavirus/inmunología
4.
Cancer Immunol Immunother ; 61(5): 733-7, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22382362

RESUMEN

Ipilimumab, a fully human monoclonal antibody against cytotoxic T lymphocyte antigen-4, has demonstrated significant improvement in overall survival in previously treated advanced melanoma patients. The BRAF inhibitor, vemurafenib, has shown up to 78% objective response rates in melanoma patients harboring the BRAF-V600E mutation but not in patients lacking the mutation. As an immune potentiator, the mechanism of action of ipilimumab may not be dependent of the activity of the BRAF pathway. To test this, we investigated whether the clinical activity of ipilimumab would be affected by the BRAF-V600E mutation status of the tumors. Thus, this retrospective analysis was carried using a set of tumor biopsies from a completed phase II clinical trial. CA184004 was a randomized, double-blind, multicenter trial of 82 previously treated or untreated patients with unresectable stage III/IV melanoma. Patients received ipilimumab 3 or 10 mg/kg every 3 weeks for four doses followed by maintenance dosing in eligible patients. The BRAF-V600E mutation status for 80 patients was determined in tumor biopsies by PCR-based assays. Data on disease control were available for 69 patients with evaluated BRAF-V600E mutation status. Rates of objective responses and stable disease in patients with BRAF-V600E mutation positive tumors (30%) were comparable to those in patients with the wild-type gene (~33%). Eleven patients displayed Durable Disease Control (DDC) of which 55% had BRAF-V600E mutation positive tumors and 45% did not. In the 48 patients showing no DDC, the mutation frequency was 50%. In this study, no association between BRAF-V600E mutation status of melanoma tumors and DDC after treatment with ipilimumab was detected.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/genética , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Anticuerpos Monoclonales/inmunología , Ensayos Clínicos Fase II como Asunto , Método Doble Ciego , Humanos , Ipilimumab , Estudios Retrospectivos , Resultado del Tratamiento
5.
Cancer Immunol Immunother ; 61(7): 1019-31, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22146893

RESUMEN

PURPOSE: Ipilimumab, a fully human monoclonal antibody specific to CTLA-4, has been shown to improve overall survival in metastatic melanoma patients. As a consequence of CTLA-4 blockade, ipilimumab treatment is associated with proliferation and activation of peripheral T cells. To better understand various tumor-associated components that may influence the clinical outcome of ipilimumab treatment, gene expression profiles of tumors from patients treated with ipilimumab were characterized. EXPERIMENTAL DESIGN: Gene expression profiling was performed on tumor biopsies collected from 45 melanoma patients before and 3 weeks after the start of treatment in a phase II clinical trial. RESULTS: Analysis of pre-treatment tumors indicated that patients with high baseline expression levels of immune-related genes were more likely to respond favorably to ipilimumab. Furthermore, ipilimumab appeared to induce two major changes in tumors from patients who exhibited clinical activity: genes involved in immune response showed increased expression, whereas expression of genes for melanoma-specific antigens and genes involved in cell proliferation decreased. These changes were associated with the total lymphocyte infiltrate in tumors, and there was a suggestion of association with prolonged overall survival in these patients. Many IFN-γ-inducible genes and Th1-associated markers showed increased expression after ipilimumab treatment, suggesting an accumulation of this particular type of T cell at the tumor sites, which might play an important role in mediating the antitumor activity of ipilimumab. CONCLUSIONS: These results support the proposed mechanism of action of ipilimumab, suggesting that cell-mediated immune responses play an important role in the antitumor activity of ipilimumab.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Anticuerpos Monoclonales/inmunología , Antineoplásicos/inmunología , Biopsia , Expresión Génica/efectos de los fármacos , Perfilación de la Expresión Génica , Humanos , Ipilimumab , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma/genética , Melanoma/inmunología , Melanoma/patología , Metástasis de la Neoplasia , Estadificación de Neoplasias , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Análisis de Supervivencia , Microambiente Tumoral/inmunología
6.
Semin Oncol ; 37(5): 533-46, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21074069

RESUMEN

Identification of cytotoxic T-lymphocyte antigen-4 (CTLA-4) as a key negative regulator of T-cell activity led to development of the fully human, monoclonal antibody ipilimumab to block CTLA-4 and potentiate antitumor T-cell responses. Animal studies first provided insight into the ability of an anti-CTLA-4 antibody to cause tumor regression, particularly in combination regimens. Early clinical studies defined ipilimumab pharmacokinetics and possibilities for combinability. Phase II trials of ipilimumab in advanced melanoma showed objective responses, but a greater number of patients had disease stabilization. In a phase III trial, ipilimumab was the first agent to demonstrate an improvement in overall survival in patients with previously treated, advanced melanoma. The adverse event profile associated with ipilimumab was primarily immune-related. Adverse events can be severe and life-threatening, but most were reversible using treatment guidelines. Ipilimumab monotherapy exhibits conventional and new patterns of activity in advanced melanoma, with a delayed separation of Kaplan-Meier survival curves. The observation of some new response patterns with ipilimumab, which are not captured by standard response criteria, led to novel criteria for the evaluation of immunotherapy in solid tumors. Overall, lessons from the development of ipilimumab contributed to a new clinical paradigm for cancer immunotherapy evolved by the Cancer Immunotherapy Consortium.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antígenos CD/inmunología , Antineoplásicos/uso terapéutico , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/inmunología , Antineoplásicos/efectos adversos , Antineoplásicos/inmunología , Biomarcadores , Antígeno CTLA-4 , Evaluación de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Enfermedades del Sistema Inmune/inducido químicamente , Enfermedades del Sistema Inmune/terapia , Ipilimumab , Melanoma/inmunología , Monitorización Inmunológica , Guías de Práctica Clínica como Asunto , Neoplasias Cutáneas/inmunología , Análisis de Supervivencia
7.
J Immunother ; 33(6): 609-17, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20551836

RESUMEN

The p53 gene product is overexpressed in approximately 50% of cancers, making it an ideal target for cancer immunotherapy. We previously demonstrated that a modified vaccinia Ankara (MVA) vaccine expressing human p53 (MVA-p53) was moderately active when given as a homologous prime/boost in a human p53 knock in (Hupki) mouse model. We needed to improve upon the inefficient homologous boosting approach, because development of neutralizing immunity to the vaccine viral vector backbone suppresses its immunogenicity. To enhance specificity, we examined the combination of 2 different vaccine vectors provided in sequence as a heterologous prime/boost. Hupki mice were evaluated as a human p53 tolerant model to explore the capacity of heterologous p53 immunization to reject human p53-expressing tumors. We employed attenuated recombinant Listeria monocytogenes expressing human p53 (LmddA-LLO-p53) in addition to MVA-p53. Heterologous p53 immunization resulted in a significant increase in p53-specific CD8 and CD4 T cells compared with homologous single vector p53 immunization. Heterologous p53 immunization induced protection against tumor growth but had only a modest effect on established tumors. To enhance the immune response we used synthetic double-strand RNA (polyinsosinic:polycytidylic acid) and unmethylated CpG-containing oligodeoxynucleotide to activate the innate immune system via Toll-like receptors. Treatment of established tumor-bearing Hupki mice with polyinsosinic:polycytidylic acid and CpG-oligodeoxynucleotide in combination with heterologous p53 immunization resulted in enhanced tumor rejection relative to treatment with either agent alone. These results suggest that heterologous prime/boost immunization and Toll-like receptor stimulation increases the efficacy of a cancer vaccine, targeting a tolerized tumor antigen.


Asunto(s)
Adenocarcinoma/inmunología , Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Oligodesoxirribonucleótidos/inmunología , ARN Bicatenario/inmunología , Proteína p53 Supresora de Tumor/inmunología , Adenocarcinoma/patología , Animales , Vacunas contra el Cáncer , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Vectores Genéticos/inmunología , Rechazo de Injerto , Humanos , Inmunización Secundaria , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/patología , Receptores Toll-Like/inmunología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo
8.
Cancer Immunol Immunother ; 59(7): 1049-1058, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20213121

RESUMEN

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.


Asunto(s)
Proteínas Bacterianas/inmunología , Inmunoterapia/métodos , Proteínas de la Membrana/inmunología , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/terapia , Adyuvantes Inmunológicos/administración & dosificación , Animales , Antígenos de Neoplasias/inmunología , Proteínas Bacterianas/administración & dosificación , Proteínas Bacterianas/genética , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/inmunología , Línea Celular Tumoral , Femenino , Humanos , Masculino , Proteínas de la Membrana/administración & dosificación , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Metástasis de la Neoplasia , Neoplasias Experimentales/patología , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/inmunología , Resultado del Tratamiento , Carga Tumoral
9.
Bioeng Bugs ; 1(4): 235-43, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-21327055

RESUMEN

Live, attenuated strains of many bacteria that synthesize and secrete foreign antigens are being developed as vaccines for a number of infectious diseases and cancer. Bacterial-based vaccines provide a number of advantages over other antigen delivery strategies including low cost of production, the absence of animal products, genetic stability and safety. In addition, bacterial vaccines delivering a tumor-associated antigen (TAA) stimulate innate immunity and also activate both arms of the adaptive immune system by which they exert efficacious anti-tumor effects. Listeria monocytogenes and several strains of Salmonella have been most extensively studied for this purpose. A number of attenuated strains have been generated and used to deliver antigens associated with infectious diseases and cancer. Although both bacteria are intracellular, the immune responses invoked by Listeria and Salmonella are different due to their sub-cellular locations. Upon entering antigen-presenting cells by phagocytosis, Listeria is capable of escaping from the phagosomal compartment and thus has direct access to the cell cytosol. Proteins delivered by this vector behave as endogenous antigens, are presented on the cell surface in the context of MHC class I molecules, and generate strong cell-mediated immune responses. In contrast, proteins delivered by Salmonella, which lacks a phagosomal escape mechanism, are treated as exogenous antigens and presented by MHC class II molecules resulting predominantly in Th2 type immune responses. This fundamental disparity between the life cycles of the two vectors accounts for their differential application as antigen delivery vehicles. The present paper includes a review of the most recent advances in the development of these two bacterial vectors for treatment of cancer. Similarities and differences between the two vectors are discussed.


Asunto(s)
Listeria/inmunología , Neoplasias/inmunología , Salmonella/inmunología , Animales , Células Presentadoras de Antígenos/inmunología , Vacunas contra el Cáncer/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Listeria/metabolismo , Modelos Biológicos , Salmonella/metabolismo
10.
Clin Cancer Res ; 15(3): 924-32, 2009 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-19188163

RESUMEN

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.


Asunto(s)
Neoplasias de la Mama/terapia , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/uso terapéutico , Genes erbB-2 , Antígeno HLA-A2/inmunología , Listeria monocytogenes/inmunología , Vacunas Sintéticas/uso terapéutico , Secuencia de Aminoácidos , Animales , Antígenos de Neoplasias/inmunología , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Vacunas contra el Cáncer/inmunología , Vectores Genéticos , Humanos , Ratones , Datos de Secuencia Molecular , Trasplante de Neoplasias , Fragmentos de Péptidos/inmunología
11.
Adv Appl Microbiol ; 66: 1-27, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19203646

RESUMEN

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.


Asunto(s)
Vacunas contra el Cáncer/uso terapéutico , Listeria monocytogenes/inmunología , Listeriosis/inmunología , Neoplasias/terapia , Vacunas Sintéticas/uso terapéutico , Células Presentadoras de Antígenos/inmunología , Vacunas contra el Cáncer/inmunología , Humanos , Listeria monocytogenes/genética , Listeria monocytogenes/patogenicidad , Listeriosis/microbiología , Neoplasias/inmunología , Linfocitos T Reguladores/inmunología , Vacunas Sintéticas/inmunología , Virulencia , Factores de Virulencia/genética , Factores de Virulencia/inmunología
12.
Clin Vaccine Immunol ; 16(1): 96-103, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19020110

RESUMEN

Listeria monocytogenes has been exploited previously as a vaccine vector for the delivery of heterologous proteins such as tumor-specific antigens for active cancer immunotherapy. However, for effective use of live vector in clinics, safety is a major concern. In the present study, we describe an irreversibly attenuated and highly immunogenic L. monocytogenes platform, the L. monocytogenes dal-, dat-, and actA-deleted strain that expresses the human prostate-specific antigen (PSA) using an antibiotic resistance marker-free plasmid (the dal dat DeltaactA 142 strain expressing PSA). Despite limited in vivo survival, the dal dat DeltaactA 142 strain was able to elicit efficient immune responses required for tumor clearance. Our results showed that immunization of mice with the dal dat DeltaactA 142 strain caused the regression of the tumors established by the prostate adenocarcinoma cell line expressing PSA. An evaluation of immunologic potency indicated that the dal dat DeltaactA 142 strain elicits a high frequency of PSA-specific immune responses. Interestingly, immunization with the dal dat DeltaactA 142 strain induced significant infiltration of PSA-specific T cells in the intratumoral milieu. Collectively, our data suggest that the dal dat DeltaactA 142 strain is a safe and potent vector for clinical use and that this platform may be further exploited as a potential candidate to express other single or multiple antigens for cancer immunotherapy.


Asunto(s)
Vacunas contra el Cáncer/inmunología , Inmunoterapia/métodos , Listeria monocytogenes/inmunología , Neoplasias/terapia , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Adenocarcinoma/prevención & control , Animales , Vacunas contra el Cáncer/genética , Eliminación de Gen , Genes Bacterianos , Listeria monocytogenes/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Plásmidos , Antígeno Prostático Específico/genética , Antígeno Prostático Específico/inmunología , Análisis de Supervivencia , Vacunas Atenuadas/genética , Vacunas Atenuadas/inmunología
13.
Cancer Immunol Immunother ; 57(9): 1301-13, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18273616

RESUMEN

Prostate specific antigen (PSA) is a likely immunotherapeutic target antigen for prostate cancer, the second leading cause of cancer-related death in American men. Previously, we demonstrated that attenuated strains of Listeria monocytogenes (Lm) can be used as effective vaccine vectors for delivery of tumor antigens causing regression of established tumors accompanied by strong immune responses toward these antigens in murine models of cancer. In the present study, we have developed and characterized a recombinant live attenuated L. monocytogenes/PSA (Lm-LLO-PSA) vaccine with potential use for the treatment of pCa. Human PSA gene was cloned into and expressed by an attenuated Lm strain. This recombinant bacterial vaccine, Lm-LLO-PSA was tested for stability, virulence, immunogenicity and anti-tumor effects in a murine model for pCa. Immunization with Lm-LLO-PSA was shown to lower the number of tumor infiltrating T regulatory cells and cause complete regression of over 80% of tumors formed by an implanted genetically modified mouse prostate adenocarcinoma cell line, which expressed human PSA. Lm-LLO-PSA was immunogenic in C57BL/6 mice and splenocytes from mice immunized with Lm-LLO-PSA showed significantly higher number of IFN-gamma secreting cells over that of the naïve animals in response to a PSA H2Db-specific peptide, as measured by both, ELISpot and intracellular cytokine staining. In addition, using a CTL assay we show that the T cells specific for PSA were able to recognize and lyse PSA-peptide pulsed target cells in vitro. In a comparison study with two other PSA-based vaccines (a pDNA and a vaccinia vaccine), Lm-LLO-PSA was shown to be more efficacious in regressing established tumors when used in a homologues prime/boost regimen. Together, these results indicate that Lm-LLO-PSA is a potential candidate for pCa immunotherapy and should be further developed.


Asunto(s)
Vacunas contra el Cáncer , Listeria monocytogenes/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/terapia , Animales , Antígenos de Neoplasias/química , Antineoplásicos/farmacología , Toxinas Bacterianas/química , Proteínas de Choque Térmico/química , Proteínas Hemolisinas/química , Humanos , Sistema Inmunológico , Inmunoterapia/métodos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Virulencia
14.
J Immunol Methods ; 305(2): 128-34, 2005 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-16181634

RESUMEN

Interferon-gamma (IFN-gamma) secreting T-cells play an important role in immunodeficiency virus (HIV) disease pathogenesis. A common technique to determine the efficacy of the HIV vaccines in murine models is to compare the number of IFN-gamma secreting T-cells induced by HIV vaccine to a control group. The measurement of IFN-gamma secreting T-cells relies on an ELISPOT assay. This assay is carried out in triplicate wells from the same mouse on the same ELISPOT plate. The numbers of spot forming cells (SFC) from these wells are correlated counts. Traditionally, simple statistical methods, such as ANOVA or Kruskall-Wallis tests, are performed on means by mouse. These approaches ignore the fact that the data are correlated counts. Count data are usually assumed to follow the Poisson distribution. However, some count data exhibit overdispersion that can affect the test statistics. The negative binomial distribution is an alternative to the Poisson distribution in the presence of overdispersion. Hence, negative binomial regression is a more suitable approach for overdispersed count data. In this study, we used a negative binomial regression to determine that IL-12 was a good adjuvant. The results of the study using a negative binomial regression are discussed.


Asunto(s)
Vacunas contra el SIDA/inmunología , Adyuvantes Inmunológicos/farmacología , Epítopos de Linfocito T/inmunología , Infecciones por VIH/inmunología , Interferón gamma/inmunología , Interleucina-12/inmunología , Linfocitos T/inmunología , Animales , Distribución Binomial , Interpretación Estadística de Datos , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , VIH/inmunología , Infecciones por VIH/prevención & control , Epítopos Inmunodominantes/inmunología , Interferón gamma/metabolismo , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Linfocitos T/metabolismo , Vacunas de ADN/inmunología
15.
Cancer Res ; 64(24): 8821-5, 2004 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-15604239

RESUMEN

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.


Asunto(s)
Toxinas Bacterianas/inmunología , Vacunas contra el Cáncer/inmunología , Proteínas de Choque Térmico/inmunología , Listeria monocytogenes/inmunología , Proteínas Oncogénicas Virales/inmunología , Vacunas contra Papillomavirus , Secuencia de Aminoácidos , Animales , Toxinas Bacterianas/genética , Vacunas Bacterianas/genética , Vacunas Bacterianas/inmunología , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/genética , Línea Celular Tumoral , Epítopos , Epítopos de Linfocito T/inmunología , Proteínas de Choque Térmico/genética , Proteínas Hemolisinas , Listeria monocytogenes/genética , Linfocitos Infiltrantes de Tumor/inmunología , Ratones , Ratones Endogámicos C57BL , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/terapia , Neoplasias Experimentales/virología , Proteínas Oncogénicas Virales/genética , Proteínas E7 de Papillomavirus , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , Bazo/citología , Bazo/inmunología , Vacunas Sintéticas/genética , Vacunas Sintéticas/inmunología
16.
Vaccine ; 22(3-4): 520-7, 2004 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-14670335

RESUMEN

An effective vaccine for treating human papillomavirus (HPV)-associated malignancies such as cervical cancer should elicit strong T cell-mediated immunity (CMI) against the E6 and/or E7 proteins necessary for the malignant state. We have developed Venezuelan equine encephalitis (VEE) virus replicon particle (VRP) vaccines encoding the HPV16 E6 and E7 genes and tested their immunogenicity and antitumor efficacy. The E6 and E7 genes were fused to create one open reading frame and mutated at four or at five amino acid positions to inactivate their oncogenic potential. VRP encoding mutant or wild type E6 and E7 proteins elicited comparable cytotoxic T lymphocyte (CTL) responses to an immunodominant E7(49-57) epitope and generated comparable antitumor responses in several HPV16 E6(+)E7(+) tumor challenge models: protection from either C3 or TC-1 tumor challenge was observed in 100% of VRP-vaccinated mice. Eradication of C3 tumors was observed in approximately 90% of mice following therapeutic VRP vaccination. Eradication of HLF16 tumors lacking the E7(49-57) epitope was observed in 90% of human leukocyte antigen (HLA)-A(*)0201 transgenic mice following therapeutic VRP vaccination. Finally, the predicted inactivation of E6 and E7 oncogenic potential was confirmed by demonstrating normal levels of both p53 and retinoblastoma proteins in human mammary epithelial cells (MEC) infected with VRP expressing mutant E6 and E7 genes. These promising results support the continued development of mutant E6 and E7 VRP as safe and effective candidates for clinical evaluation against HPV-associated disease.


Asunto(s)
Virus de la Encefalitis Equina Venezolana/inmunología , Genes Virales/inmunología , Proteínas Oncogénicas Virales/genética , Proteínas Oncogénicas Virales/inmunología , Papiloma/prevención & control , Papiloma/virología , Papillomaviridae/inmunología , Replicón/inmunología , Proteínas Represoras , Animales , Supervivencia Celular/efectos de los fármacos , Femenino , Genes p53/genética , Inmunización , Ratones , Ratones Endogámicos C57BL , Mutagénesis/genética , Trasplante de Neoplasias , Proteínas E7 de Papillomavirus , Fenotipo
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