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1.
N Engl J Med ; 384(20): 1885-1898, 2021 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-33725432

RESUMEN

BACKGROUND: Assessment of the safety and efficacy of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in different populations is essential, as is investigation of the efficacy of the vaccines against emerging SARS-CoV-2 variants of concern, including the B.1.351 (501Y.V2) variant first identified in South Africa. METHODS: We conducted a multicenter, double-blind, randomized, controlled trial to assess the safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) in people not infected with the human immunodeficiency virus (HIV) in South Africa. Participants 18 to less than 65 years of age were assigned in a 1:1 ratio to receive two doses of vaccine containing 5×1010 viral particles or placebo (0.9% sodium chloride solution) 21 to 35 days apart. Serum samples obtained from 25 participants after the second dose were tested by pseudovirus and live-virus neutralization assays against the original D614G virus and the B.1.351 variant. The primary end points were safety and efficacy of the vaccine against laboratory-confirmed symptomatic coronavirus 2019 illness (Covid-19) more than 14 days after the second dose. RESULTS: Between June 24 and November 9, 2020, we enrolled 2026 HIV-negative adults (median age, 30 years); 1010 and 1011 participants received at least one dose of placebo or vaccine, respectively. Both the pseudovirus and the live-virus neutralization assays showed greater resistance to the B.1.351 variant in serum samples obtained from vaccine recipients than in samples from placebo recipients. In the primary end-point analysis, mild-to-moderate Covid-19 developed in 23 of 717 placebo recipients (3.2%) and in 19 of 750 vaccine recipients (2.5%), for an efficacy of 21.9% (95% confidence interval [CI], -49.9 to 59.8). Among the 42 participants with Covid-19, 39 cases (95.1% of 41 with sequencing data) were caused by the B.1.351 variant; vaccine efficacy against this variant, analyzed as a secondary end point, was 10.4% (95% CI, -76.8 to 54.8). The incidence of serious adverse events was balanced between the vaccine and placebo groups. CONCLUSIONS: A two-dose regimen of the ChAdOx1 nCoV-19 vaccine did not show protection against mild-to-moderate Covid-19 due to the B.1.351 variant. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT04444674; Pan African Clinical Trials Registry number, PACTR202006922165132).


Asunto(s)
Anticuerpos Neutralizantes/sangre , Vacunas contra la COVID-19/inmunología , COVID-19/prevención & control , Inmunogenicidad Vacunal , SARS-CoV-2 , Adenoviridae , Adolescente , Adulto , Anticuerpos Neutralizantes/fisiología , COVID-19/epidemiología , COVID-19/inmunología , Prueba Serológica para COVID-19 , Vacunas contra la COVID-19/administración & dosificación , Vacunas contra la COVID-19/efectos adversos , ChAdOx1 nCoV-19 , Método Doble Ciego , Humanos , Persona de Mediana Edad , Sudáfrica , Linfocitos T/fisiología , Insuficiencia del Tratamiento , Potencia de la Vacuna , Adulto Joven
2.
Mol Ther ; 25(8): 1917-1932, 2017 08 02.
Artículo en Inglés | MEDLINE | ID: mdl-28578991

RESUMEN

Vesicular stomatitis virus encoding the IFNß transgene (VSV-IFNß) is a mediator of potent oncolytic activity and is undergoing clinical evaluation for the treatment of solid tumors. Emerging preclinical and clinical data suggest treatment of tumors with oncolytic viruses may sensitize tumors to checkpoint inhibitors and increase the anti-tumor immune response. New generations of immuno-oncology molecules including T cell agonists are entering clinical development and could be hypothesized to enhance the activity of oncolytic viruses, including VSV-IFNß. Here, we show that VSV-IFNß exhibits multiple mechanisms of action, including direct cell killing, stimulation of an innate immune response, recruitment of CD8 T cells, and depletion of T regulatory cells. Moreover, VSV-IFNß promotes the establishment of a CD8 T cell response to endogenous tumor antigens. Our data demonstrate a significant enhancement of anti-tumor function for VSV-IFNß when combined with checkpoint inhibitors, but not OX40 agonists. While the addition of checkpoint inhibitors to VSV-IFNß generated robust tumor growth inhibition, it resulted in no increase in viral replication, transgene expression, or immunophenotypic changes beyond treatment with VSV-IFNß alone. We hypothesize that tumor-specific T cells generated by VSV-IFNß retain activity due to a lack of immune exhaustion when checkpoint inhibitors were used.


Asunto(s)
Terapia Genética , Vectores Genéticos/genética , Inmunoterapia , Neoplasias/genética , Neoplasias/inmunología , Viroterapia Oncolítica , Virus Oncolíticos/genética , Virus de la Estomatitis Vesicular Indiana/genética , Animales , Anticuerpos Monoclonales/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor , Terapia Combinada , Modelos Animales de Enfermedad , Expresión Génica , Terapia Genética/métodos , Humanos , Inmunomodulación , Inmunoterapia/métodos , Interferón beta/genética , Interferón beta/metabolismo , Interferones/genética , Interferones/metabolismo , Melanoma Experimental , Ratones , Neoplasias/patología , Neoplasias/terapia , Receptores OX40/agonistas , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Transducción Genética , Transgenes , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Replicación Viral , Ensayos Antitumor por Modelo de Xenoinjerto
3.
J Pathol ; 235(3): 478-89, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25348195

RESUMEN

Inflammation is associated with several diseases of the prostate including benign enlargement and cancer, but a causal relationship has not been established. Our objective was to characterize the prostate inflammatory microenvironment after infection with a human prostate-derived bacterial strain and to determine the effect of inflammation on prostate cancer progression. To this end, we mimicked typical human prostate infection with retrograde urethral instillation of CP1, a human prostatic isolate of Escherichia coli. CP1 bacteria were tropic for the accessory sex glands and induced acute inflammation in the prostate and seminal vesicles, with chronic inflammation lasting at least 1 year. Compared to controls, infection induced both acute and chronic inflammation with epithelial hyperplasia, stromal hyperplasia, and inflammatory cell infiltrates. In areas of inflammation, epithelial proliferation and hyperplasia often persist, despite decreased expression of androgen receptor (AR). Inflammatory cells in the prostates of CP1-infected mice were characterized at 8 weeks post-infection by flow cytometry, which showed an increase in macrophages and lymphocytes, particularly Th17 cells. Inflammation was additionally assessed in the context of carcinogenesis. Multiplex cytokine profiles of inflamed prostates showed that distinct inflammatory cytokines were expressed during prostate inflammation and cancer, with a subset of cytokines synergistically increased during concurrent inflammation and cancer. Furthermore, CP1 infection in the Hi-Myc mouse model of prostate cancer accelerated the development of invasive prostate adenocarcinoma, with 70% more mice developing cancer by 4.5 months of age. This study provides direct evidence that prostate inflammation accelerates prostate cancer progression and gives insight into the microenvironment changes induced by inflammation that may accelerate tumour initiation or progression.


Asunto(s)
Adenocarcinoma/patología , Progresión de la Enfermedad , Escherichia coli/fisiología , Próstata/microbiología , Próstata/patología , Neoplasias de la Próstata/patología , Microambiente Tumoral/fisiología , Adenocarcinoma/metabolismo , Adenocarcinoma/fisiopatología , Animales , Proliferación Celular , Citocinas/metabolismo , Modelos Animales de Enfermedad , Escherichia coli/aislamiento & purificación , Humanos , Hiperplasia , Masculino , Ratones , Ratones Endogámicos C57BL , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/fisiopatología , Prostatitis/metabolismo , Prostatitis/patología , Prostatitis/fisiopatología , Receptores Androgénicos/metabolismo , Células Th17/patología
4.
Mol Ther Oncol ; 32(1): 200758, 2024 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-38596304

RESUMEN

Oncolytic viruses are engineered to selectively kill tumor cells and have demonstrated promising results in early-phase clinical trials. To further modulate the innate and adaptive immune system, we generated AZD4820, a vaccinia virus engineered to express interleukin-12 (IL-12), a potent cytokine involved in the activation of natural killer (NK) and T cells and the reprogramming of the tumor immune microenvironment. Testing in cultured human tumor cell lines demonstrated broad in vitro oncolytic activity and IL-12 transgene expression. A surrogate virus expressing murine IL-12 demonstrated antitumor activity in both MC38 and CT26 mouse syngeneic tumor models that responded poorly to immune checkpoint inhibition. In both models, AZD4820 significantly upregulated interferon-gamma (IFN-γ) relative to control mice treated with oncolytic vaccinia virus (VACV)-luciferase. In the CT26 study, 6 of 10 mice had a complete response after treatment with AZD4820 murine surrogate, whereas control VACV-luciferase-treated mice had 0 of 10 complete responders. AZD4820 treatment combined with anti-PD-L1 blocking antibody augmented tumor-specific T cell immunity relative to monotherapies. These findings suggest that vaccinia virus delivery of IL-12, combined with immune checkpoint blockade, elicits antitumor immunity in tumors that respond poorly to immune checkpoint inhibitors.

5.
Clin Cancer Res ; 29(3): 560-570, 2023 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-36455147

RESUMEN

PURPOSE: Tumoral programmed cell death ligand-1 (PD-L1) expression is common in human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC). We assessed whether a DNA vaccine targeting HPV-16/18 E6/E7 with IL12 adjuvant (MEDI0457) combined with the PD-L1 inhibitor durvalumab could enhance HPV-specific T-cell response and improve outcomes in recurrent/metastatic HPV-16/18-associated HNSCC. PATIENTS AND METHODS: In this phase Ib/IIa study, immunotherapy-naïve patients with ≥1 previous platinum-containing regimen (neoadjuvant/adjuvant therapy or for recurrent/metastatic disease) received MEDI0457 7 mg intramuscularly with electroporation on weeks 1, 3, 7, and 12, then every 8 weeks, plus durvalumab 1,500 mg intravenously on weeks 4, 8, and 12, then every 4 weeks, until confirmed progression and/or unacceptable toxicity. Coprimary objectives were safety and objective response rate (ORR; H0: ORR ≤ 15%); secondary objectives included 16-week disease control rate (DCR-16), overall survival (OS), and progression-free survival (PFS). RESULTS: Of 35 treated patients, 29 were response evaluable (confirmed HPV-associated disease; received both agents). ORR was 27.6% [95% confidence interval (CI), 12.7-47.2; four complete responses, four partial responses]; responses were independent of PD-L1 tumor-cell expression (≥25% vs. <25%). DCR-16 was 44.8% (95% CI, 26.5-64.3). Median PFS was 3.5 months (95% CI, 1.9-9.0); median OS was 29.2 months (15.2-not calculable). Twenty-eight (80.0%) patients had treatment-related adverse events [grade 3: 5 (14.3%); no grade 4/5], resulting in discontinuation in 2 (5.7%) patients. HPV-16/18-specific T cells increased on treatment; 4 of 8 evaluable patients had a >2-fold increase in tumor-infiltrating CD8+ T cells. CONCLUSIONS: MEDI0457 plus durvalumab was well tolerated. While the primary efficacy endpoint was not reached, clinical benefit was encouraging.


Asunto(s)
Neoplasias de Cabeza y Cuello , Infecciones por Papillomavirus , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Virus del Papiloma Humano , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Infecciones por Papillomavirus/complicaciones , Papillomavirus Humano 16/genética , Antígeno B7-H1/genética , Papillomavirus Humano 18
6.
Prostate ; 72(5): 514-22, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21761425

RESUMEN

BACKGROUND: The CD8 T-cell response to prostate and other cancers is often functionally diminished or absent. This may occur via deletion of tumor-specific T cells, through acquisition of an anergic phenotype, or via active suppression mediated by another population of cells. METHODS: We used a double transgenic model in which mice express CD8 T cells specific for a prostate/prostate cancer antigen to study the response of CD8 T cells to evolving autochronous prostate tumors in TRAMP mice. CD8 T cells were analyzed for functionality by measuring IFN-γ production via flow cytometry and via an in vivo CTL killing assay. In addition, pathological scoring of the prostates of the double transgenic mice was compared to scoring of tumor burden prostates of ProTRAMP mice. RESULTS: Tumor-specific CD8 T cells were not grossly deleted in these animals, but evidenced a clearly non-functional phenotype. Interestingly, full lytic function was rapidly recovered upon removal from tumor-bearing mice. CONCLUSIONS: These data indicate a role for continuous antigen exposure in the maintenance of tumor-specific CD8 T-cell tolerance to prostate cancer.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Carcinoma Ductal/inmunología , Carcinoma de Células Pequeñas/inmunología , Neoplasia Intraepitelial Prostática/inmunología , Neoplasias de la Próstata/inmunología , Traslado Adoptivo , Animales , Linfocitos T CD8-positivos/trasplante , Carcinoma Ductal/patología , Carcinoma de Células Pequeñas/patología , Supervivencia Celular , Trasplante de Células , Modelos Animales de Enfermedad , Femenino , Interferón gamma/metabolismo , Masculino , Ratones , Ratones Transgénicos , Neoplasia Intraepitelial Prostática/patología , Neoplasias de la Próstata/patología
7.
Clin Cancer Res ; 28(12): 2567-2578, 2022 06 13.
Artículo en Inglés | MEDLINE | ID: mdl-35395080

RESUMEN

PURPOSE: PD-L1 is upregulated in glioblastoma and supports immunosuppression. We evaluated PD-L1 blockade with durvalumab among glioblastoma cohorts and investigated potential biomarkers. PATIENTS AND METHODS: MGMT unmethylated newly diagnosed patients received radiotherapy plus durvalumab (cohort A; n = 40). Bevacizumab-naïve, recurrent patients received durvalumab alone (cohort B; n = 31) or in combination with standard bevacizumab (cohort B2; n = 33) or low-dose bevacizumab (cohort B3; n = 33). Bevacizumab-refractory patients received durvalumab plus bevacizumab (cohort C; n = 22). Primary endpoints were: OS-12 (A), PFS-6 (B, B2, B3), and OS-6 (C). Exploratory biomarkers included: a systematic, quantitative, and phenotypic evaluation of circulating immune cells; tumor mutational burden (TMB); and tumor immune activation signature (IAS). RESULTS: No cohort achieved the primary efficacy endpoint. Outcome was comparable among recurrent, bevacizumab-naïve cohorts. No unexpected toxicities were observed. A widespread reduction of effector immune cell subsets was noted among recurrent patients compared with newly diagnosed patients that was partially due to dexamethasone use. A trend of increased CD8+Ki67+ T cells at day 15 was noted among patients who achieved the primary endpoint and were not on dexamethasone. Neither TMB nor IAS predicted outcome. CONCLUSIONS: Patients with recurrent glioblastoma have markedly lower baseline levels of multiple circulating immune cell subsets compared with newly diagnosed patients. An early increase in systemic Ki67+CD8+ cells may warrant further evaluation as a potential biomarker of therapeutic benefit among patients with glioblastoma undergoing checkpoint therapy. Dexamethasone decreased immune cell subsets. PD-L1 blockade and combination with standard or reduced dose bevacizumab was ineffective.


Asunto(s)
Dexametasona , Glioblastoma , Recurrencia Local de Neoplasia , Anticuerpos Monoclonales , Antígeno B7-H1/antagonistas & inhibidores , Bevacizumab/uso terapéutico , Biomarcadores de Tumor/análisis , Dexametasona/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/patología , Humanos , Antígeno Ki-67 , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología
8.
Mol Cancer Res ; 19(3): 498-506, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33257508

RESUMEN

Mutations that drive oncogenesis in cancer can generate neoantigens that may be recognized by the immune system. Identification of these neoantigens remains challenging due to the complexity of the MHC antigen and T-cell receptor interaction. Here, we describe the development of a systematic approach to efficiently identify and validate immunogenic neoantigens. Whole-exome sequencing of tissue from a patient with melanoma was used to identify nonsynonymous mutations, followed by MHC binding prediction and identification of tumor clonal architecture. The top 18 putative class I neoantigens were selected for immunogenicity testing via a novel in vitro pipeline in HLA-A201 healthy donor blood. Naïve CD8 T cells from donors were stimulated with allogeneic dendritic cells pulsed with peptide pools and then with individual peptides. The presence of antigen-specific T cells was determined via functional assays. We identified one putative neoantigen that expanded T cells specific to the mutant form of the peptide and validated this pipeline in a subset of patients with bladder tumors treated with durvalumab (n = 5). Within this cohort, the top predicted neoantigens from all patients were immunogenic in vitro. Finally, we looked at overall survival in the whole durvalumab-treated bladder cohort (N = 37) by stratifying patients by tertile measure of tumor mutation burden (TMB) or neoantigen load. Patients with higher neoantigen and TMB load tended to show better overall survival. IMPLICATIONS: This pipeline can enable accurate and rapid identification of personalized neoantigens that may help to identify patients who will survive longer on durvalumab.


Asunto(s)
Antígenos de Neoplasias/genética , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/tratamiento farmacológico , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología
9.
medRxiv ; 2021 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-34189538

RESUMEN

AZD1222 (ChAdOx1 nCoV-19), a replication-deficient simian adenovirus-vectored vaccine, has demonstrated safety, efficacy, and immunogenicity against coronavirus disease 2019 (COVID-19) in clinical trials and real-world studies. We characterized CD4+ and CD8+ T-cell responses induced by AZD1222 vaccination in peripheral blood mononuclear cells (PBMCs) from 280 unique vaccine recipients aged 18-85 years who enrolled in the phase 2/3 COV002 trial. Total spike-specific CD4+ T cell helper type 1 (Th1) and CD8+ T-cell responses were significantly increased in AZD1222-vaccinated adults of all ages following two doses of AZD1222. CD4+ Th2 responses following AZD1222 vaccination were not detected. Furthermore, AZD1222-specific Th1 and CD8+ T cells both displayed a high degree of polyfunctionality in all adult age groups. T-cell receptor (TCR) ß sequences from vaccinated participants mapped against TCR sequences known to react to SARS-CoV-2 revealed substantial breadth and depth across the SARS-CoV-2 spike protein for the AZD1222-induced CD4+ and CD8+ T-cell responses. Overall, AZD1222 vaccination induced a robust, polyfunctional Th1-dominated T-cell response, with broad CD4+ and CD8+ T-cell coverage across the SARS-CoV-2 spike protein. ONE SENTENCE SUMMARY: Polyfunctional CD4+ and CD8+ T-cell responses are elicited against the SARS-CoV-2 spike protein following vaccination with AZD1222.

10.
Sci Transl Med ; 13(620): eabj7211, 2021 Nov 17.
Artículo en Inglés | MEDLINE | ID: mdl-34591596

RESUMEN

AZD1222 (ChAdOx1 nCoV-19), a replication-deficient simian adenovirus­vectored vaccine, has demonstrated safety, efficacy, and immunogenicity against coronavirus disease 2019 in clinical trials and real-world studies. We characterized CD4+ and CD8+ T cell responses induced by AZD1222 vaccination in peripheral blood mononuclear cells from 296 unique vaccine recipients aged 18 to 85 years who enrolled in the phase 2/3 COV002 trial. Total spike protein­specific CD4+ T cell helper type 1 (TH1) and CD8+ T cell responses were increased in AZD1222-vaccinated adults of all ages after two doses of AZD1222. CD4+ TH2 responses after AZD1222 vaccination were not detected. Furthermore, AZD1222-specific TH1 and CD8+ T cells both displayed a high degree of polyfunctionality in all adult age groups. T cell receptor ß (TCRß) sequences from vaccinated participants mapped against TCR sequences known to react to SARS-CoV-2 revealed substantial breadth and depth across the SARS-CoV-2 spike protein for both AZD1222-induced CD4+ and CD8+ T cell responses. Overall, AZD1222 vaccination induced a polyfunctional TH1-dominated T cell response, with broad CD4+ and CD8+ T cell coverage across the SARS-CoV-2 spike protein.


Asunto(s)
COVID-19 , Glicoproteína de la Espiga del Coronavirus , Vacunas contra la COVID-19 , ChAdOx1 nCoV-19 , Humanos , Receptores de Antígenos de Linfocitos T , SARS-CoV-2 , Vacunación
11.
Mol Cancer Ther ; 20(9): 1723-1734, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34224361

RESUMEN

A recombinant Newcastle Disease Virus (NDV), encoding either a human (NDVhuGM-CSF, MEDI5395) or murine (NDVmuGM-CSF) GM-CSF transgene, combined broad oncolytic activity with the ability to significantly modulate genes related to immune functionality in human tumor cells. Replication in murine tumor lines was significantly diminished relative to human tumor cells. Nonetheless, intratumoral injection of NDVmuGM-CSF conferred antitumor effects in three syngeneic models in vivo; with efficacy further augmented by concomitant treatment with anti-PD-1/PD-L1 or T-cell agonists. Ex vivo immune profiling, including T-cell receptor sequencing, revealed profound immune-contexture changes consistent with priming and potentiation of adaptive immunity and tumor microenvironment (TME) reprogramming toward an immune-permissive state. CRISPR modifications rendered CT26 tumors significantly more permissive to NDV replication, and in this setting, NDVmuGM-CSF confers immune-mediated effects in the noninjected tumor in vivo Taken together, the data support the thesis that MEDI5395 primes and augments cell-mediated antitumor immunity and has significant utility as a combination partner with other immunomodulatory cancer treatments.


Asunto(s)
Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Inmunomodulación , Inmunoterapia/métodos , Virus de la Enfermedad de Newcastle/genética , Viroterapia Oncolítica/instrumentación , Microambiente Tumoral , Animales , Apoptosis , Proliferación Celular , Neoplasias del Colon/inmunología , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Neoplasias del Colon/terapia , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
12.
Oncotarget ; 8(43): 73469-73482, 2017 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-29088720

RESUMEN

Immunotherapy was significantly enhanced in a murine tumor model by combining a vaccine with a fusion protein designed to target the glucocorticoid-induced tumor necrosis factor (TNF) receptor related gene (GITR) on the surface of T cells. The recombinant poxvirus-based vaccine platform included Modified Vaccinia virus Ankara (rMVA) and fowlpox (rF) vectors as the driver immunogens both engineered to express the human carcinoembryonic antigen (CEA) and three murine costimulatory molecules B7.1, ICAM-1, LFA-3 (designated TRICOM). In previous studies, mice expressing human CEA as a transgene (CEA.Tg mice) vaccinated with rMVA/rF-CEA-TRICOM overcame CEA immune tolerance by inducing anti-CEA‒specific immunity and regression of CEA-expressing tumors. The murine GITR ligand fusion protein (mGITRL-FP) consisted of a mouse IgG2a Fc region, a yeast-derived coiled GCN4 pII and the extracellular GITR-binding domain of murine GITR ligand. The design maximized valency and the potential to agonize the GITR receptor. Combined treatment of the vaccine and mGITRL-FP mediated a more robust tumor regression, leading to sustained improvement in overall survival. The enhanced immunotherapeutic effect was linked to the generation of a strong CD8+ T cell antitumor immune response. A treatment schedule with mGITRL-FP administered prior to the priming rMVA-CEA-TRICOM vaccination was of paramount importance. The mechanism of action for the enhanced antitumor effects resided in the depletion of immune cells, particularly FoxP3+ regulatory T cells, that express high GITR levels following activation. The results provide evidence that targeting GITR with mGITRL-FP in concert with a cancer vaccine represents a potential novel approach to more effective immunotherapy.

13.
Oncoimmunology ; 5(8): e1208875, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-27622077

RESUMEN

MEDI9447 is a human monoclonal antibody that is specific for the ectoenzyme CD73 and currently undergoing Phase I clinical trials. Here we show that MEDI9447 is a potent inhibitor of CD73 ectonucleotidase activity, with wide ranging immune regulatory consequences. MEDI9447 results in relief from adenosine monophosphate (AMP)-mediated lymphocyte suppression in vitro and inhibition of mouse syngeneic tumor growth in vivo. In contrast with other cancer immunotherapy agents such as checkpoint inhibitors or T-cell agonists, MEDI9447 drives changes in both myeloid and lymphoid infiltrating leukocyte populations within the tumor microenvironment of mouse models. Changes include significant alterations in a number of tumor micro-environmental subpopulations including increases in CD8(+) effector cells and activated macrophages. Furthermore, these changes correlate directly with responder and non-responder subpopulations within animal studies using syngeneic tumors. Combination data showing additive activity between MEDI9447 and anti-PD-1 antibodies using human cells in vitro and mouse tumor models further demonstrate the potential value of relieving adenosine-mediated immunosuppression. Based on these data, a Phase I study to test the safety, tolerability, and clinical activity of MEDI9447 in cancer patients was initiated (NCT02503774).

14.
Clin Cancer Res ; 22(5): 1161-72, 2016 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-26490306

RESUMEN

PURPOSE: Immune responses to antigens originating in the central nervous system (CNS) are generally attenuated, as collateral damage can have devastating consequences. The significance of this finding for the efficacy of tumor-targeted immunotherapies is largely unknown. EXPERIMENTAL DESIGN: The B16 murine melanoma model was used to compare cytotoxic responses against established tumors in the CNS and in the periphery. Cytokine analysis of tissues from brain tumor-bearing mice detected elevated TGFß secretion from microglia and in the serum and TGFß signaling blockade reversed tolerance of tumor antigen-directed CD8 T cells. In addition, a treatment regimen using focal radiation therapy and recombinant Listeria monocytogenes was evaluated for immunologic activity and efficacy in this model. RESULTS: CNS melanomas were more tolerogenic than equivalently progressed tumors outside the CNS as antigen-specific CD8 T cells were deleted and exhibited impaired cytotoxicity. Tumor-bearing mice had elevated serum levels of TGFß; however, blocking TGFß signaling with a small-molecule inhibitor or a monoclonal antibody did not improve survival. Conversely, tumor antigen-specific vaccination in combination with focal radiation therapy reversed tolerance and improved survival. This treatment regimen was associated with increased polyfunctionality of CD8 T cells, elevated T effector to T regulatory cell ratios, and decreased TGFß secretion from microglia. CONCLUSIONS: These data suggest that CNS tumors may impair systemic antitumor immunity and consequently accelerate cancer progression locally as well as outside the CNS, whereas antitumor immunity may be restored by combining vaccination with radiation therapy. These findings are hypothesis-generating and warrant further study in contemporary melanoma models as well as human trials.


Asunto(s)
Neoplasias Encefálicas/terapia , Neoplasias del Sistema Nervioso Central/terapia , Tolerancia Inmunológica , Melanoma Experimental/terapia , Factor de Crecimiento Transformador beta/sangre , Animales , Antígenos de Neoplasias/administración & dosificación , Antígenos de Neoplasias/inmunología , Neoplasias Encefálicas/sangre , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/radioterapia , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de la radiación , Neoplasias del Sistema Nervioso Central/sangre , Neoplasias del Sistema Nervioso Central/inmunología , Neoplasias del Sistema Nervioso Central/radioterapia , Femenino , Humanos , Melanoma Experimental/sangre , Melanoma Experimental/inmunología , Melanoma Experimental/radioterapia , Ratones , Microglía/inmunología , Microglía/patología , Linfocitos T Citotóxicos/inmunología , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Vacunación
15.
PLoS One ; 9(11): e109080, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25372844

RESUMEN

Lymphocyte Activation Gene - 3 (LAG-3) is an immune checkpoint molecule that regulates both T-cell activation and homeostasis. However, the molecular mechanisms underlying LAG-3's function are generally unknown. Using a model in which LAG-3 blockade or absence reliably augmented homeostatic proliferation in vivo, we found that IL-2 and STAT5 are critical for LAG-3 function. Similarly, LAG-3 blockade was ineffective in the absence of regulatory T-cells (Treg), suggesting an important role for LAG-3 in either the responsiveness of conventional T-cells (Tconv) to regulation, or a relative defect in the ability of LAG-3 KO regulatory T-cells (Treg) to suppress the proliferation of Tconv. In this model, LAG-3 KO Treg suppressed proliferation in a manner fairly similar to wild-type (WT) Treg, but LAG-3 KO Tconv were relatively resistant to suppression. Further studies also identified a role for LAG-3 in the induction/expansion of Treg. Finally, we found that LAG-3 blockade (or knockout) led to a relative skewing of naïve CD4 T-cells toward a TH1 phenotype both in vitro and in in vivo. Together, these data suggest that LAG-3 expression on Tconv cells makes them more susceptible to Treg based suppression, and also regulates the development of a TH1 T-cell response.


Asunto(s)
Antígenos CD/metabolismo , Activación de Linfocitos , Linfocitos T Reguladores/inmunología , Animales , Antígenos CD/genética , Proliferación Celular , Interleucina-2/metabolismo , Ratones , Ratones Endogámicos C57BL , Factor de Transcripción STAT5/metabolismo , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/fisiología , Proteína del Gen 3 de Activación de Linfocitos
16.
PLoS One ; 9(7): e101764, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25013914

RESUMEN

BACKGROUND: Glioblastoma (GBM) is the most common malignant brain tumor in adults and is associated with a poor prognosis. Cytotoxic T lymphocyte antigen -4 (CTLA-4) blocking antibodies have demonstrated an ability to generate robust antitumor immune responses against a variety of solid tumors. 4-1BB (CD137) is expressed by activated T lymphocytes and served as a co-stimulatory signal, which promotes cytotoxic function. Here, we evaluate a combination immunotherapy regimen involving 4-1BB activation, CTLA-4 blockade, and focal radiation therapy in an immune-competent intracranial GBM model. METHODS: GL261-luciferace cells were stereotactically implanted in the striatum of C57BL/6 mice. Mice were treated with a triple therapy regimen consisted of 4-1BB agonist antibodies, CTLA-4 blocking antibodies, and focal radiation therapy using a small animal radiation research platform and mice were followed for survival. Numbers of brain-infiltrating lymphocytes were analyzed by FACS analysis. CD4 or CD8 depleting antibodies were administered to determine the relative contribution of T helper and cytotoxic T cells in this regimen. To evaluate the ability of this immunotherapy to generate an antigen-specific memory response, long-term survivors were re-challenged with GL261 glioma en B16 melanoma flank tumors. RESULTS: Mice treated with triple therapy had increased survival compared to mice treated with focal radiation therapy and immunotherapy with 4-1BB activation and CTLA-4 blockade. Animals treated with triple therapy exhibited at least 50% long-term tumor free survival. Treatment with triple therapy resulted in a higher density of CD4+ and CD8+ tumor infiltrating lymphocytes. Mechanistically, depletion of CD4+ T cells abrogated the antitumor efficacy of triple therapy, while depletion of CD8+ T cells had no effect on the treatment response. CONCLUSION: Combination therapy with 4-1BB activation and CTLA-4 blockade in the setting of focal radiation therapy improves survival in an orthotopic mouse model of glioma by a CD4+ T cell dependent mechanism and generates antigen-specific memory.


Asunto(s)
Antígeno CTLA-4/antagonistas & inhibidores , Glioma/tratamiento farmacológico , Glioma/radioterapia , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/agonistas , Animales , Anticuerpos/uso terapéutico , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Línea Celular Tumoral , Femenino , Glioma/inmunología , Ratones , Ratones Endogámicos C57BL
17.
PLoS One ; 7(3): e34547, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22479644

RESUMEN

Helios, an Ikaros family transcription factor, is preferentially expressed at the mRNA and protein level in regulatory T cells. Helios expression previously appeared to be restricted to thymic-derived Treg. Consistent with recent data, we show here that Helios expression is inducible in vitro under certain conditions. To understand phenotypic and functional differences between Helios(+) and Helios(-) Treg, we profiled cell-surface markers of FoxP3(+) Treg using unmanipulated splenocytes. We found that CD103 and GITR are expressed at high levels on a subset of Helios(+) Treg and that a Helios(+) Treg population could be significantly enriched by FACS sorting using these two markers. Quantitative real-time PCR (qPCR) analysis revealed increased TGF-ß message in Helios(+) Treg, consistent with the possibility that this population possesses enhanced regulatory potential. In tumor-bearing mice, we found that Helios(+) Treg were relatively over-represented in the tumor-mass, and BrdU studies showed that, in vivo, Helios(+) Treg proliferated more than Helios(-) Treg. We hypothesized that Helios-enriched Treg might exert increased suppressive effects. Using in vitro suppression assays, we show that Treg function correlates with the absolute number of Helios(+) cells in culture. Taken together, these data show that Helios(+) Treg represent a functional subset with associated CD103 and GITR expression.


Asunto(s)
Proteínas de Unión al ADN/genética , Linfocitos T Reguladores/metabolismo , Factores de Transcripción/genética , Animales , Antígenos CD/genética , Regulación Neoplásica de la Expresión Génica , Proteína Relacionada con TNFR Inducida por Glucocorticoide/genética , Cadenas alfa de Integrinas/genética , Ratones , Ratones Endogámicos BALB C , Neoplasias/genética , Fenotipo , Bazo/citología , Linfocitos T Reguladores/citología , Regulación hacia Arriba
18.
Mol Immunol ; 47(7-8): 1595-600, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20226531

RESUMEN

Relative upregulation of the Ikaros family transcription factor Helios in natural regulatory T cells (Tregs) has been reported by several groups. However, a role for Helios in regulatory T cells has not yet been described. Here, we show that Helios is upregulated in CD4(+)CD25(+) regulatory T cells. Chromatin-immunoprecipitation (ChIP) experiments indicated that Helios binds to the FoxP3 promoter. These data were further corroborated by experiments showing that knocking-down Helios with siRNA oligonucleotides results in down-regulation of FoxP3. Functionally, we found that suppression of Helios message in CD4(+)CD25(+) T cells significantly attenuates their suppressive function. Taken together, these data suggest that Helios may play an important role in regulatory T cell function and support the concept that Helios may be a novel target to manipulate Treg activity in a clinical setting.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Proteínas de Unión al ADN/inmunología , Factor de Transcripción Ikaros/inmunología , Factores de Transcripción/inmunología , Animales , Apoptosis , Linfocitos T CD4-Positivos/citología , Línea Celular , Proteínas de Unión al ADN/genética , Regulación hacia Abajo , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/inmunología , Humanos , Factor de Transcripción Ikaros/genética , Subunidad alfa del Receptor de Interleucina-2/inmunología , Ratones , Regiones Promotoras Genéticas , ARN Interferente Pequeño/genética , Factores de Transcripción/genética , Regulación hacia Arriba
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