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1.
Cell Rep Med ; 2(3): 100209, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33763654

RESUMO

Therapeutic vaccination regimens inducing clinically effective tumor-specific CD8+ T lymphocyte (CTL) responses are an unmet medical need. We engineer two distantly related arenaviruses, Pichinde virus and lymphocytic choriomeningitis virus, for therapeutic cancer vaccination. In mice, life-replicating vector formats of these two viruses delivering a self-antigen in a heterologous prime-boost regimen induce tumor-specific CTL responses up to 50% of the circulating CD8 T cell pool. This CTL attack eliminates established solid tumors in a significant proportion of animals, accompanied by protection against tumor rechallenge. The magnitude of CTL responses is alarmin driven and requires combining two genealogically distantly related arenaviruses. Vector-neutralizing antibodies do not inhibit booster immunizations by the same vector or by closely related vectors. Rather, CTL immunodominance hierarchies favor vector backbone-targeted responses at the expense of self-reactive CTLs. These findings establish an arenavirus-based immunotherapy regimen that allows reshuffling of immunodominance hierarchies and breaking self-directed tolerance for efficient tumor control.


Assuntos
Vacinas Anticâncer/administração & dosagem , Imunoterapia/métodos , Vírus da Coriomeningite Linfocítica/imunologia , Mastocitoma/terapia , Vírus Pichinde/imunologia , Linfócitos T Citotóxicos/imunologia , Alarminas/genética , Alarminas/imunologia , Animais , Anticorpos Neutralizantes/farmacologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Feminino , Expressão Gênica , Engenharia Genética/métodos , Vetores Genéticos/classificação , Vetores Genéticos/imunologia , Cobaias , Imunização Secundária , Vírus da Coriomeningite Linfocítica/classificação , Vírus da Coriomeningite Linfocítica/genética , Mastocitoma/genética , Mastocitoma/imunologia , Mastocitoma/mortalidade , Camundongos , Camundongos Endogâmicos C57BL , Filogenia , Vírus Pichinde/classificação , Vírus Pichinde/genética , Tolerância a Antígenos Próprios , Análise de Sobrevida , Vacinação/métodos
2.
J Exp Med ; 214(2): 359-380, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28031480

RESUMO

Aberrant proliferation, symmetric self-renewal, increased survival, and defective differentiation of malignant blasts are key oncogenic drivers in acute myeloid leukemia (AML). Stem cell gene signatures predict poor prognosis in AML patients; however, with few exceptions, these deregulated molecular pathways cannot be targeted therapeutically. In this study, we demonstrate that the TNF superfamily ligand-receptor pair CD70/CD27 is expressed on AML blasts and AML stem/progenitor cells. CD70/CD27 signaling in AML cells activates stem cell gene expression programs, including the Wnt pathway, and promotes symmetric cell divisions and proliferation. Soluble CD27, reflecting the extent of CD70/CD27 interactions in vivo, was significantly elevated in the sera of newly diagnosed AML patients and is a strong independent negative prognostic biomarker for overall survival. Blocking the CD70/CD27 interaction by mAb induced asymmetric cell divisions and differentiation in AML blasts and AML stem/progenitor cells, inhibited cell growth and colony formation, and significantly prolonged survival in murine AML xenografts. Importantly, hematopoietic stem/progenitor cells from healthy BM donors express neither CD70 nor CD27 and were unaffected by blocking mAb treatment. Therefore, targeting CD70/CD27 signaling represents a promising therapeutic strategy for AML.


Assuntos
Crise Blástica/etiologia , Ligante CD27/fisiologia , Leucemia Mieloide Aguda/patologia , Transdução de Sinais/fisiologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/fisiologia , Idoso , Animais , Anticorpos Monoclonais/uso terapêutico , Ligante CD27/antagonistas & inibidores , Quinases do Centro Germinativo , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Camundongos , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/fisiologia , Fator 2 Associado a Receptor de TNF/fisiologia , Células Tumorais Cultivadas , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/antagonistas & inibidores , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/sangue , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Via de Sinalização Wnt/fisiologia
3.
Cancer Res ; 75(15): 3020-31, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-26116496

RESUMO

Vaccines that can coordinately induce multi-epitope T cell-mediated immunity, T helper functions, and immunologic memory may offer effective tools for cancer immunotherapy. Here, we report the development of a new class of recombinant protein cancer vaccines that deliver different CD8(+) and CD4(+) T-cell epitopes presented by MHC class I and class II alleles, respectively. In these vaccines, the recombinant protein is fused with Z12, a novel cell-penetrating peptide that promotes efficient protein loading into the antigen-processing machinery of dendritic cells. Z12 elicited an integrated and multi-epitopic immune response with persistent effector T cells. Therapy with Z12-formulated vaccines prolonged survival in three robust tumor models, with the longest survival in an orthotopic model of aggressive brain cancer. Analysis of the tumor sites showed antigen-specific T-cell accumulation with favorable modulation of the balance of the immune infiltrate. Taken together, the results offered a preclinical proof of concept for the use of Z12-formulated vaccines as a versatile platform for the development of effective cancer vaccines.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/farmacologia , Peptídeos Penetradores de Células/imunologia , Animais , Apresentação de Antígeno/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Citosol/efeitos dos fármacos , Citosol/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Epitopos de Linfócito T/imunologia , Feminino , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Imunidade Celular , Imunização/métodos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neoplasias Experimentais/terapia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Vacinas Sintéticas/imunologia , Vacinas Sintéticas/farmacologia
4.
Oncoimmunology ; 2(9): e25772, 2013 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-24244904

RESUMO

Tumor infiltration by effector cells is essential for the efficacy of T cell-based immunotherapeutic approaches against brain malignancies. We found that tumor-associated antigen (TAA)-specific CD8+ T cells are optimally recruited to neoplastic lesions when co-administered with TH1 polarized CD4+ T cells that are also TAA-specific. However, in vitro TH1 polarization is not required for the long-term therapeutic efficacy of the combined transfer of CD4+ and CD8+ T cells.

5.
PLoS One ; 8(5): e63933, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23717511

RESUMO

The feasibility of cancer immunotherapy mediated by T lymphocytes is now a clinical reality. Indeed, many tumour associated antigens have been identified for cytotoxic CD8 T cells, which are believed to be key mediators of tumour rejection. However, for aggressive malignancies in specialised anatomic sites such as the brain, a limiting factor is suboptimal tumour infiltration by CD8 T cells. Here we take advantage of recent advances in T cell biology to differentially polarise CD4 T cells in order to explore their capacity to enhance immunotherapy. We used an adoptive cell therapy approach to work with clonal T cell populations of defined specificity. Th1 CD4 T cells preferentially homed to and accumulated within intracranial tumours compared with Th2 CD4 T cells. Moreover, tumour-antigen specific Th1 CD4 T cells enhanced CD8 T cell recruitment and function within the brain tumour bed. Survival of mice bearing intracranial tumours was significantly prolonged when CD4 and CD8 T cells were co-transferred. These results should encourage further definition of tumour antigens recognised by CD4 T cells, and exploitation of both CD4 and CD8 T cell subsets to optimise T cell therapy of cancer.


Assuntos
Neoplasias Encefálicas/terapia , Linfócitos T CD8-Positivos/imunologia , Imunoterapia Adotiva , Células Th1/imunologia , Células Th2/imunologia , Animais , Neoplasias Encefálicas/imunologia , Linfócitos T CD8-Positivos/metabolismo , Polaridade Celular , Citocinas/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transplante de Neoplasias , Receptores de Retorno de Linfócitos/metabolismo , Células Th1/metabolismo , Células Th2/metabolismo
6.
Cancer Res ; 70(12): 4829-39, 2010 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-20501837

RESUMO

Immune infiltration of advanced human gliomas has been shown, but it is doubtful whether these immune cells affect tumor progression. It could be hypothesized that this infiltrate reflects recently recruited immune cells that are immediately overwhelmed by a high tumor burden. Alternatively, if there is earlier immune detection and infiltration of the tumor, the question arises as to when antitumor competency is lost. To address these issues, we analyzed a transgenic mouse model of spontaneous astrocytoma (GFAP-V(12)HA-ras mice), which allows the study of immune interactions with developing glioma, even at early asymptomatic stages. T cells, including a significant proportion of Tregs, are already present in the brain before symptoms develop, followed later by macrophages, natural killer cells, and dendritic cells. The effector potential of CD8 T-cells is defective, with the absence of granzyme B expression and low expression of IFN-gamma, tumor necrosis factor, and interleukin 2. Overall, our results show an early defective endogenous immune response to gliomas, and local accumulation of immunosuppressive cells at the tumor site. Thus, the antiglioma response is not simply overwhelmed at advanced stages of tumor growth, but is counterbalanced by an inhibitory microenvironment from the outset. Nevertheless, we determined that effector molecule expression (granzyme B, IFN-gamma) by brain-infiltrating CD8 T-cells could be enhanced, despite this unfavorable milieu, by strong immune stimuli. This potential to modulate the strong imbalance in local antiglioma immunity is encouraging for the development and optimization of future glioma immunotherapies.


Assuntos
Astrocitoma/imunologia , Neoplasias Encefálicas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos T Reguladores/imunologia , Animais , Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Linfócitos T CD8-Positivos/imunologia , Movimento Celular , Citometria de Fluxo , Proteína Glial Fibrilar Ácida/metabolismo , Granzimas/metabolismo , Humanos , Técnicas Imunoenzimáticas , Terapia de Imunossupressão , Ativação Linfocitária , Camundongos , Camundongos Transgênicos , Proteínas Proto-Oncogênicas p21(ras)/fisiologia
7.
PLoS One ; 4(9): e6811, 2009 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-19738910

RESUMO

BACKGROUND: Class II MHC molecules (MHC II) are cell surface receptors displaying short protein fragments for the surveillance by CD4+ T cells. Antigens therefore have to be loaded onto this receptor in order to induce productive immune responses. On the cell surface, most MHC II molecules are either occupied by ligands or their binding cleft has been blocked by the acquisition of a non-receptive state. Direct loading with antigens, as required during peptide vaccinations, is therefore hindered. PRINCIPAL FINDINGS: Here we show, that the in vivo response of CD4+ T cells can be improved, when the antigens are administered together with 'MHC-loading enhancer' (MLE). MLE are small catalytic compounds able to open up the MHC binding site by triggering ligand-release and stabilizing the receptive state. Their enhancing effect on the immune response was demonstrated here with an antigen from the influenza virus and tumour associated antigens (TAA) derived from the NY-ESO-1 protein. The application of these antigens in combination with adamantane ethanol (AdEtOH), an MLE compound active on human HLA-DR molecules, significantly increased the frequency of antigen-specific CD4+ T cells in mice transgenic for the human MHC II molecule. Notably, the effect was evident only with the MLE-susceptible HLA-DR molecule and not with murine MHC II molecules non-susceptible for the catalytic effect of the MLE. CONCLUSION: MLE can specifically increase the potency of a vaccine by facilitating the efficient transfer of the antigen onto the MHC molecule. They may therefore open a new way to improve vaccination efficacy and tumour-immunotherapy.


Assuntos
Antígenos de Histocompatibilidade Classe II/imunologia , Imunoterapia/métodos , Neoplasias/terapia , Animais , Linfócitos T CD4-Positivos , Vacinas Anticâncer/química , Linhagem Celular Tumoral , Proliferação de Células , Separação Celular , Ilhas de CpG , Antígenos de Histocompatibilidade Classe II/química , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Vacinas de Subunidades Antigênicas
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