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1.
Recent Results Cancer Res ; 214: 153-167, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31473852

RESUMO

After more than a century of efforts to establish cancer immunotherapy in clinical practice, the advent of checkpoint inhibition (CPI) therapy was a critical breakthrough toward this direction (Hodi et al. in Cell Rep 13(2):412-424, 2010; Wolchok et al. in N Engl J Med 369(2):122-133, 2013; Herbst et al. in Nature 515(7528):563-567, 2014; Tumeh et al. in Nature 515(7528):568-571, 2014). Further, CPIs shifted the focus from long studied shared tumor-associated antigens to mutated ones. As cancer is caused by mutations in somatic cells, the concept to utilize these correlates of 'foreignness' to enable recognition and lysis of the cancer cell by T cell immunity seems an obvious thing to do.


Assuntos
Vacinas Anticâncer , Epitopos/imunologia , Imunoterapia , Neoplasias/terapia , Antígenos de Neoplasias/imunologia , Humanos
2.
Gan To Kagaku Ryoho ; 46(9): 1367-1371, 2019 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-31530772

RESUMO

Recent advances in cancer immunotherapies, such as immune checkpoint inhibitors(ICIs), have shown some durable clinical responses in patients with various types of advanced cancers. The development of the next-generation sequencing technologies can result in a comprehensive characterization of the human cancer genomes. Personalized immunotherapy and precision cancer medicine might enable the next generation of rational cancer immunotherapy. Conventional cancer vaccines are designed to target tumor-associated antigens(TAAs), which are overexpressed in cancers. However, since TAAs are also expressed in normal tissues, cancer vaccine against TAAs can potentially initiate central and peripheral tolerance responses, which results in low vaccination efficiency. Cancer neoantigens derived from somatic mutations in tumor tissue represent highly immunogenic and can escape from central thymic tolerance. They are suggested to provide tumor specific targets for personalized cancer vaccines. Therefore, neoantigen-based cancer vaccine, which can induce tumor-specific cytotoxic T lymphocytes( CTLs), should be developed. The efficacy of current immunotherapies also remains limited due to the immunosuppressive tumor microenvironment, which leads to CTLs exhaustion or anergy and the escape of tumor cells from immune attack. The combination of neoantigen-based cancer vaccine and ICIs should be a potential therapeutic approach. In this paper, we provide a brief overview of the recent advances in the development of neoantigen-based cancer vaccines.


Assuntos
Vacinas Anticâncer , Neoplasias , Antígenos de Neoplasias , Humanos , Imunoterapia , Medicina de Precisão , Microambiente Tumoral
3.
Cancer Immunol Immunother ; 68(10): 1635-1648, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31549214

RESUMO

Pancreatic cancer has been termed a 'recalcitrant cancer' due to its relative resistance to chemotherapy and immunotherapy. This resistance is thought to be due in part to the dense fibrotic tumor microenvironment and lack of tumor infiltrating CD8 + T cells. The gastrointestinal peptide, gastrin, has been shown to stimulate growth of pancreatic cancer by both a paracrine and autocrine mechanism. Interruption of gastrin at the CCK receptor may reduce tumor-associated fibrosis and alter tumor immune cells. Polyclonal Ab Stimulator (PAS) is a vaccine that targets gastrin and has been shown to prolong survival of patients with pancreatic cancer. Here, we report that PAS vaccination monotherapy elicits both a humoral and cellular immune response when used in immune competent mice-bearing pancreatic tumors and that PAS monotherapy produced a marked T-cell activation and influx of CD8 + lymphocytes into pancreatic tumors. Isolated peripheral lymphocytes elicited cytokine release upon re-stimulation with gastrin in vitro demonstrating specificity of immune activation for the target peptide. Combination therapy with PAS and PD-1 Ab activated CD4 -/CD8 - TEMRA cells important in T-cell-mediated tumor death and memory. Tumors of mice treated with PAS (250 µg) or PAS (100 and 250 µg) in combination with a PD-1 Ab were significantly smaller compared to tumors from PBS or PD-1 Ab-treated mice. When PAS was given in combination with PD-1 Ab, tumors had less fibrosis, fewer inhibitory Treg lymphocytes, and fewer tumor-associated macrophages. These findings reveal a novel approach to improve treatment strategies for pancreatic cancer.


Assuntos
Vacinas Anticâncer/imunologia , Gastrinas/imunologia , Neoplasias Pancreáticas/terapia , Receptor de Morte Celular Programada 1/imunologia , Microambiente Tumoral , Vacinação , Animais , Linhagem Celular Tumoral , Memória Imunológica , Ativação Linfocitária , Linfócitos do Interstício Tumoral/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Linfócitos T/imunologia
4.
Adv Exp Med Biol ; 1155: 543-553, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468430

RESUMO

Taurine transporter (TauT) has been identified as a target gene of p53 tumor suppressor. TauT is also found to be overexpressed in variety type of human cancers, such as leukemia. This study showed that expression of TauT was upregulated by c-Myc and c-Jun oncogenes. To explore whether blocking of TauT inhibits tumor development, the RNA interference (RNAi) and immune targeting approaches were tested in tumor cells in vitro and in p53 mutant mice in vivo. Knockdown of TauT expression by RNAi resulted in cell cycle G2 arrest and suppressed human breast cancer MCF-7 cells proliferation determined by colonies production and cell migration assays. Knockdown of TauT also rendered MCF-7 cells more susceptible to chemotherapeutic drug-induced apoptosis. An antibody specifically against TauT blocked taurine uptake and induced cell cycle G2 arrest leading to cell death of variety type of tumor cells without affecting the viability of normal mammalian cells. TauT peptide vaccination significantly increased median lifespan (1.5-fold) of the p53 null mice and rescued p53+/- mice by extending the median lifespan from 315 days to 621 days. Furthermore, single dose treatment of tumor-bearing (thymic lymphoma) p53 null mice with TauT peptide reduced tumor size by about 50% and significantly prolonged survival of these mice from average 7 days (after observing the thymic lymphoma) to 21 days. This finding demonstrates that a novel TauT peptide vaccine can delay, inhibit, and/or treat p53 mutation related spontaneous tumorigenesis in vivo. Therefore, TauT peptide may be used as a universal cancer vaccine to prevent and/or treat patients with p53 mutation-mediated cancers.


Assuntos
Vacinas Anticâncer , Imunoterapia , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras , Interferência de RNA , Proteína Supressora de Tumor p53/genética , Animais , Anticorpos Monoclonais/farmacologia , Pontos de Checagem do Ciclo Celular , Técnicas de Silenciamento de Genes , Genes jun , Genes myc , Humanos , Células MCF-7 , Camundongos , Camundongos Knockout , Terapia de Alvo Molecular , Mutação , Taurina , Vacinas de Subunidades
5.
Cancer Sci ; 110(10): 3049-3060, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31390678

RESUMO

Heat shock protein 105 (HSP105) is overexpressed in many cancers, including colorectal cancer (CRC) and esophageal cancer (EC). We carried out a phase I clinical trial of HLA-A24- and HLA-A2-restricted HSP105 peptide vaccines in patients with CRC or EC. In this additional study of the trial, we examined the immunological efficacy of the novel vaccine. Thirty patients with advanced CRC or EC underwent HSP105 peptide vaccination. Immunological responses were evaluated by ex vivo and in vitro γ-interferon enzyme-linked immunospot assays and their correlation with patients' prognosis was analyzed. The HSP105 peptide vaccines induced peptide-specific CTLs in 15 of 30 patients. Among HLA-A24 patients (n = 15), 7 showed induction of CTLs only ex vivo, whereas among HLA-A2 patients (n = 15), 4 showed the induction ex vivo and 6 in vitro. Heat shock protein 105-specific CTL induction correlated with suppression of cancer progression and was revealed as a potential predictive biomarker for progression-free survival (P = .008; hazard ratio = 3.03; 95% confidence interval, 1.34-6.85) and overall survival (P = .025; hazard ratio = 2.72; 95% confidence interval, 1.13-6.52). Production of cytokines by HSP105 peptide-specific CTLs was observed at the injection sites (skin) and tumor tissues, suggesting that HSP105-specific CTLs not only accumulated at vaccination sites but also infiltrated tumors. Furthermore, we established 2 HSP105 peptide-specific CTL clones, which showed HSP105-specific cytokine secretion and cytotoxicity. Our results suggest that the HSP105 peptide vaccine could induce immunological effects in cancer patients and improve their prognosis.


Assuntos
Vacinas Anticâncer/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Esofágicas/tratamento farmacológico , Proteínas de Choque Térmico HSP110/química , Proteínas de Choque Térmico HSP110/metabolismo , Adulto , Idoso , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Neoplasias Colorretais/imunologia , Citocinas/metabolismo , Intervalo Livre de Doença , Neoplasias Esofágicas/imunologia , Feminino , Antígeno HLA-A2/metabolismo , Antígeno HLA-A24/metabolismo , Células Hep G2 , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Linfócitos T Citotóxicos/imunologia , Resultado do Tratamento , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/imunologia
6.
BMC Complement Altern Med ; 19(1): 163, 2019 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-31277636

RESUMO

BACKGROUND: Therapeutic vaccines against cervical cancer remain ineffective. Previously, we demonstrated that blocking the signalling of a cytokine, interleukin 10, at the time of immunisation elicited significantly higher numbers of antigen specific T cells and inhibited tumour growth in mice. RESULTS: In the current paper, we demonstrate, in a HPV16 E6/E7 transformed TC-1 tumour mouse model, that despite increased antigen specific T cell numbers, blocking IL-10 signalling at the time of immunisation does not increase the survival time of the TC-1 tumour bearing mice compared to mice receiving the same immunisation with no IL-10 signalling blockade. Moreover, the function of tumour infiltrating T cells isolated 3 weeks post TC-1 transplantation is more suppressed than those isolated 2 weeks after tumour inoculation. We demonstrate that synthesized caerin peptides, derived from amphibian skin secretions, 1) were able to inhibit TC-1 tumour growth both in vitro and in vivo; 2) are environmentally stable; and 3) promote the secretion of pro-inflammatory interlukine-6 by TC-1 cells. Notably caerin peptides were able to increase the survival time of TC-1 tumour bearing mice after therapeutic vaccination with a HPV16E7 peptide-based vaccine containing IL-10 inhibitor, via recruiting increased levels of T cells to the tumour site. CONCLUSION: Caerin peptides increase the efficacy of a therapeutic vaccine by recruiting more T cells to the tumour site.


Assuntos
Proteínas de Anfíbios/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Vacinas Anticâncer/uso terapêutico , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Proteínas de Anfíbios/uso terapêutico , Animais , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Vacinas Anticâncer/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HeLa , Humanos , Interleucina-10/antagonistas & inibidores , Interleucina-6/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Neoplasias Experimentais/tratamento farmacológico , Linfócitos T/metabolismo
7.
Clin Cancer Res ; 25(18): 5435-5437, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31315885

RESUMO

No immunotherapy strategy is yet offering consistent results against pancreatic ductal adenocarcinoma. A randomized clinical trial testing repeated immunization with a Listeria monocytogenes-based vaccine encoding for mesothelin in combination with a GM-CSF-transfected allogeneic pancreatic cell vaccine reports no survival benefit for the vaccinated patients.See related article by Le et al., p. 5493.


Assuntos
Vacinas Anticâncer , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Imunoterapia , Nozes , Vacinação
8.
Zhonghua Zhong Liu Za Zhi ; 41(7): 501-507, 2019 Jul 23.
Artigo em Chinês | MEDLINE | ID: mdl-31357836

RESUMO

Objective: To investigate the feasibility of myeloid and plasmacytoid dendritic cell combined vaccines loaded with heat-treated Lewis lung cancer cell lysates for treatment of lung cancer in mice. Methods: Bone marrow cells were induced by the recombinant mouse fms-like tyrosine kinase receptor 3 ligand (rmFlt3-L) in vitro, myeloid dendritic cells (mDC) and plasmacytoid dendritic cells (pDC) were separated by magnetic beads. The mDC, pDC, and mDC∶pDC=1∶1 were stimulated with heat-treated Lewis lung cancer cell lysates, respectively. The effects of each group on stimulating of lymphocyte proliferation and inducing of T cell to kill tumor cells in vitro were compared. The alternations of the immunophenotypes of CD80, CD86, CD40 and major histocompatibility complex Ⅱ (MHC-Ⅱ) were detected by flow cytometry. The secretion of cytokines including interlukin-12 (IL-12), interlukin-6 (IL-6), and tumor necrosis factor α (TNF-α) were detected by enzyme-linked immunosorbent assay (ELISA). Results: The lymphocyte proliferation in mice stimulated with mDC+ pDC group loaded with heat-treated Lewis lung cancer cell lysates was 10.80±0.66, significantly higher than 8.63±0.65 of mDC group and 7.10±0.46 pDC group under the same culture conditions, respectively (P<0.05). When the ratio of effector cells: target cells (E∶T) was 10∶1, the killing rate of the mDC+ pDC group loaded with heat-treated tumor cell lysate was 31.68%±2.93%, significantly higher than 17.44%±0.97% of mDC group and 10.29%±1.33% of pDC group, respectively (P<0.05). When the ratio of E∶T was 20∶1, the killing rate of the mDC+ pDC group loaded with heat-treated tumor cell lysate was 54.77%±3.28%, significantly higher than 35.25%±1.51% of mDC group and 15.52%±0.73% of pDC group, respectively (P<0.05). When the ratio of E∶T was 40∶1, the killing rate of the mDC+ pDC group loaded with heat-treated tumor cell lysate was 73.01%±0.91%, significantly higher than 51.36%±0.58% of mDC group and 22.65%±1.28% of pDC group, respectively (P<0.05). With the rate of E∶T increased, the killing rate also increased. The mean fluorescence intensities of surface molecules including CD80, CD86, CD40 and MHC-Ⅱ of mDC: pDC=1 group pulsed with heat-treated Lewis lung cancer cell lysates were higher than those of mDC group and pDC group. The IL-6 cytokine concentrations of mDC+ pDC group, mDC group and pDC group loaded with heat-treated Lewis lung cancer cell lysates were (586.67±52.52) pg/ml, (323.33±67.14) pg/ml and (166.67±16.07) pg/ml, respectively. The concentrations of IL-12 in each group were (2 568.75±119.24) pg/ml, (2 156.25±120.55) pg/ml and (672.92±31.46) pg/ml, respectively. The concentrations of TNF-α in each group were (789.33±48.08) pg/ml, (584.89±116.49) pg/ml and (291.56±40.73) pg/ml, respectively. The concentrations of IL-6, IL-12 and TNF-α secreted by mDC+ pDC group were much higher than those of mDC group and pDC group under the same culture conditions (P<0.05). Conclusions: The mDCs and pDCs combined vaccines pulsed with heat-treated Lewis lung cancer cell lysates have synergistic effects on inducing of T lymphocyte proliferation and killing tumor cells in vitro. This synergistic anti-tumor effect is related with up-regulation of co-stimulatory molecules and increased secretion of cytokines.


Assuntos
Vacinas Anticâncer/administração & dosagem , Células Dendríticas/imunologia , Neoplasias Pulmonares/prevenção & controle , Ativação Linfocitária , Animais , Camundongos , Vacinas Combinadas
9.
Cancer Immunol Immunother ; 68(8): 1359-1368, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31332464

RESUMO

Immune checkpoint inhibitors targeting coinhibitory pathways in T cells possess efficacy in combating cancer. In addition to PD-1/PD-L1 and CTLA-4 antibodies which are already established in tumor immunotherapy, immune checkpoints such as LAG-3 or BTLA are emerging, which may have the potential to enhance T-cell responses alone or in combination with PD-1 blockers. CD4+ T cells play a central role in the immune system and contribute to productive immune responses in multiple ways. The effects of immune checkpoint inhibitors on this cell subset may thus critically influence therapeutic outcomes. Here, we have used in vitro responses to tetanus toxoid (TT) as a model system to study the effects of immune checkpoint inhibitors on CD4+ T-cell responses. CFSE-labeled PBMCs of 65 donors were stimulated with TT in the presence of blocking antibodies to PD-L1, CTLA-4, LAG-3, or BTLA for 7 days. We found that the PD-L1 antibody greatly enhanced cytokine production and antigen-specific CD4+ T-cell proliferation, whereas blocking antibodies to BTLA or LAG-3 did not augment responses to TT. Surprisingly, the presence of the therapeutic CTLA-4 antibody ipilimumab resulted in a significant reduction of CD4+ T-cell proliferation and cytokine production. Stimulation experiments with an IgG4 variant of ipilimumab indicated that the inhibitory effect of ipilimumab was dependent on its IgG1 isotype. Our results indicate that the therapeutic CTLA-4 antibody ipilimumab can impair CD4+ effector T-cell responses and that this activity is mediated by its Fc part and CD16-expressing cells.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Linfócitos T CD4-Positivos/imunologia , Vacinas Anticâncer/imunologia , Imunoterapia/métodos , Ipilimumab/farmacologia , Neoplasias/terapia , Anticorpos Monoclonais/uso terapêutico , Antígenos CD/imunologia , Antineoplásicos/uso terapêutico , Antígeno B7-H1/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Antígeno CTLA-4/imunologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Humanos , Fragmentos Fc das Imunoglobulinas/metabolismo , Ipilimumab/uso terapêutico , Ativação Linfocitária/efeitos dos fármacos , Neoplasias/imunologia , Receptores Imunológicos/imunologia , Toxoide Tetânico/imunologia
10.
Cancer Treat Rev ; 78: 8-16, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31302573

RESUMO

Human papillomavirus (HPV)-associated intraepithelial neoplasia or cancers are ideal candidates for cancer immunotherapy since HPV oncoproteins, such as E6 and E7 proteins of high-risk HPVs, could be utilized as foreign antigens. In HPV-associated cancers as well as nonviral cancers, the cancer cells may evade host immunity through the expression of immune checkpoint molecules, downregulation of human leukocyte antigen, and activation of immune regulatory cells. Because of these immune suppressive mechanisms, HPV therapeutic vaccines have shown little efficacy against HPV-associated cancers, although they have shown efficacy in treating HPV-associated intraepithelial neoplasias. Recently, checkpoint blockade emerged as a promising new treatment for solid cancers; however, these therapies have shown only modest efficacy against HPV-associated cancers. Here we reviewed literature analyzing a combinatory therapy using an immune checkpoint inhibitor and an HPV therapeutic vaccine for treating HPV-associated cancers to compensate for shortfalls of each monotherapy. Complimentary modes of T cell activation would be deployed; as vaccines would directly stimulate the T cells, while checkpoint inhibitors would do so by releasing inhibition. Some promising studies using animal models and early human clinical trials raised a possibility that such combinations may be efficacious in regressing HPV-associated cancers. Epitope spreading (the phenomenon in which non-targeted antigens become new targets of immune response) may play a critical role mechanistically. Currently ongoing studies will shed light as to whether such combination therapy would indeed be a promising new treatment paradigm. Current and future studies must also determine the adverse effect profile of such a combination treatment.


Assuntos
Vacinas Anticâncer/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Neoplasias/prevenção & controle , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/uso terapêutico , Animais , Humanos , Neoplasias/epidemiologia , Neoplasias/virologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia
11.
Cancer Immunol Immunother ; 68(8): 1245-1261, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31222486

RESUMO

The efficacy of cancer immunotherapy, including treatment with immune-checkpoint inhibitors, often is limited by ineffective presentation of antigenic peptides that elicit T-cell-mediated anti-tumor cytotoxic responses. Manipulation of antigen presentation pathways is an emerging approach for enhancing the immunogenicity of tumors in immunotherapy settings. ER aminopeptidase 1 (ERAP1) is an intracellular enzyme that trims peptides as part of the system that generates peptides for binding to MHC class I molecules (MHC-I). We hypothesized that pharmacological inhibition of ERAP1 in cells could regulate the cellular immunopeptidome. To test this hypothesis, we treated A375 melanoma cells with a recently developed potent ERAP1 inhibitor and analyzed the presented MHC-I peptide repertoire by isolating MHC-I, eluting bound peptides, and identifying them using capillary chromatography and tandem mass spectrometry (LC-MS/MS). Although the inhibitor did not reduce cell-surface MHC-I expression, it induced qualitative and quantitative changes in the presented peptidomes. Specifically, inhibitor treatment altered presentation of about half of the total 3204 identified peptides, including about one third of the peptides predicted to bind tightly to MHC-I. Inhibitor treatment altered the length distribution of eluted peptides without change in the basic binding motifs. Surprisingly, inhibitor treatment enhanced the average predicted MHC-I binding affinity, by reducing presentation of sub-optimal long peptides and increasing presentation of many high-affinity 9-12mers, suggesting that baseline ERAP1 activity in this cell line is destructive for many potential epitopes. Our results suggest that chemical inhibition of ERAP1 may be a viable approach for manipulating the immunopeptidome of cancer.


Assuntos
Aminopeptidases/metabolismo , Antígenos de Neoplasias/metabolismo , Antineoplásicos/farmacologia , Vacinas Anticâncer/imunologia , Epitopos de Linfócito T/metabolismo , Imunoterapia/métodos , Melanoma/tratamento farmacológico , Antígenos de Histocompatibilidade Menor/metabolismo , Peptídeos/metabolismo , Inibidores de Proteases/farmacologia , Linfócitos T Citotóxicos/imunologia , Aminopeptidases/antagonistas & inibidores , Apresentação do Antígeno , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Antígenos HLA/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Imunogenicidade da Vacina , Ativação Linfocitária , Terapia de Alvo Molecular , Peptídeos/genética , Peptídeos/imunologia , Ligação Proteica
12.
Cancer Immunol Immunother ; 68(8): 1273-1286, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31243491

RESUMO

Therapeutic cancer vaccines have met limited clinical success. In the setting of cancer, the immune system is either tolerized and/or has a limited tumor-specific T cell repertoire. In this study, we explore whether intratumoral (IT) vaccination with an HPV vaccine can elicit quantitative and qualitative differences in immune response as compared to intramuscular (IM) vaccination to overcome immune resistance in established tumors. We report that IT administration of an HPV-16 E7 peptide vaccine formulated with polyinosinic-polycytidylic acid [poly(I:C)] generated an enhanced antitumor effect relative to IM delivery. The elicited anti-tumor effect with IT vaccination was consistent among the vaccinated groups and across various C57BL/6 substrains. IT vaccination resulted in an increased frequency of PD-1hi TILs, which represented both vaccine-targeted and non-vaccine-targeted tumor-specific CD8+ T cells. Overall, the CD8+/Treg ratio was increased within the tumor microenvironment using IT vaccination. We also assessed transcriptional changes in several immune-related genes in the tumor microenvironment of the various treated groups, and our data suggest that IT vaccination leads to upregulation of a broad complement of immunomodulatory genes, including upregulation of interferon gamma (IFNγ) and antigen presentation and processing machine (APM) components. IT vaccine delivery is superior to traditional IM vaccination routes with the potential to improve tumor immunogenicity, which has potential clinical application in the setting of accessible lesions such as head and neck squamous cell carcinomas (HNSCCs).


Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeça e Pescoço/terapia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Experimentais/imunologia , Proteínas E7 de Papillomavirus/imunologia , Vacinas contra Papillomavirus/imunologia , Linfócitos T Reguladores/imunologia , Animais , Apresentação do Antígeno/genética , Vacinas Anticâncer/imunologia , Carcinoma de Células Escamosas/imunologia , Células Cultivadas , Citotoxicidade Imunológica , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/imunologia , Humanos , Imunidade Celular/genética , Injeções Intramusculares , Interferon gama/genética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Poli I-C/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Vacinação
13.
Mol Biol (Mosk) ; 53(3): 367-379, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31184601

RESUMO

The paper discusses the techniques which are currently implemented for vaccine production based on virus-like particles (VLPs). The factors which determine the characteristics of VLP monomers assembly are provided in detail. Analysis of the literature demonstrates that the development of the techniques of VLP production and immobilization of target antigens on their surface have led to the development of universal platforms which make it possible for virtually any known antigen to be exposed on the particle surface in a highly concentrated form. As a result, the focus of attention has shifted from the approaches to VLP production to the development of a precise interface between the organism's immune system and the peptides inducing a strong immune response to pathogens or the organism's own pathological cells. Immunome-specified methods for vaccine design and the prospects of immunoprophylaxis are discussed. Certain examples of vaccines against viral diseases and cancers are considered.


Assuntos
Vacinas de Partículas Semelhantes a Vírus/provisão & distribução , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/provisão & distribução , Humanos , Vacinas de Partículas Semelhantes a Vírus/imunologia , Vacinas Virais/imunologia , Vacinas Virais/provisão & distribução
14.
Cancer Immunol Immunother ; 68(7): 1143-1155, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31177328

RESUMO

Enhancement of endogenous immunity to tumor-associated self-antigens and neoantigens is the goal of preventive vaccination. Toward this goal, we compared the efficacy of the following HER2 DNA vaccine constructs: vaccines encoding wild-type HER2, hybrid HER2 vaccines consisting of human HER2 and rat Neu, HER2 vaccines with single residue substitutions and a novel human HER2 DNA vaccine, ph(es)E2TM. ph(es)E2TM was designed to contain five evolution-selected substitutions: M198V, Q398R, F425L, H473R and A622T that occur frequently in 12 primate HER2 sequences. These ph(es)E2TM substitutions score 0 to 1 in blocks substitutions matrix (BLOSUM), indicating minimal biochemical alterations. h(es)E2TM recombinant protein is recognized by a panel of anti-HER2 mAbs, demonstrating the preservation of HER2 protein structure. Compared to native human HER2, electrovaccination of HER2 transgenic mice with ph(es)E2TM induced a threefold increase in HER2-binding antibody (Ab) and elevated levels of IFNγ-producing T cells. ph(es)E2TM, but not pE2TM immune serum, recognized HER2 peptide p95 355LPESFDGDPASNTAP369, suggesting a broadening of epitope recognition induced by the minimally modified HER2 vaccine. ph(es)E2TM vaccination reduced tumor growth more effectively than wild-type HER2 or HER2 vaccines with more extensive modifications. The elevation of tumor immunity by ph(es)E2TM vaccination would create a favorable tumor microenvironment for neoantigen priming, further enhancing the protective immunity. The fundamental principle of exploiting evolution-selected amino acid substitutions is novel, effective and applicable to vaccine development in general.


Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Imunoterapia/métodos , Neoplasias Mamárias Experimentais/terapia , Receptor ErbB-2/imunologia , Substituição de Aminoácidos/genética , Substituição de Aminoácidos/imunologia , Animais , Antígenos de Neoplasias/genética , Vacinas Anticâncer/genética , Vacinas Anticâncer/uso terapêutico , Linhagem Celular Tumoral/transplante , Células Dendríticas/imunologia , Evolução Molecular , Feminino , Imunogenicidade da Vacina/genética , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Receptor ErbB-2/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Tolerância a Antígenos Próprios/genética , Microambiente Tumoral/imunologia , Vacinas de DNA/genética , Vacinas de DNA/imunologia , Vacinas de DNA/uso terapêutico
15.
Cancer Treat Res ; 178: 189-205, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31209846

RESUMO

Repairing defects in anti-tumor immunity has been a longstanding challenge in cancer therapy, and in recent years, immunotherapy has emerged as a promising approach for treating advanced disease. While the interactions between the immune system and cancer have been studied for more than a century, only in recent years has the field realized the tremendous potential in stimulating the immune system to eradicate cancer. From early investigations by William Coley in using bacteria to treat cancer patients to more recent work in adoptively transferred engineered T cells to identify and kill cancer cells has opened up an entire field dedicated to re-educating the immune system in a cancer patient. A multitude of immunotherapy strategies have been proposed and tested in clinical trials, from recombinant proteins, agonistic antibodies, and checkpoint inhibitors designed to re-invigorate anti-tumor immunity, to vaccine approaches and adoptive T-cell strategies, we are now on the cusp of an exciting revolution that will ultimately become an arsenal of therapies to treat any cancer type, at any stage, with the hope of robust and durable responses in cancer patients. In this chapter, we will examine the various immunotherapy strategies under active clinical investigation, with a particular focus on the latest advances in cellular immunotherapies and the future of precision medicine-enabled immunotherapy.


Assuntos
Vacinas Anticâncer , Imunoterapia , Neoplasias , Medicina de Precisão , Humanos , Neoplasias/imunologia , Neoplasias/terapia , Linfócitos T
16.
Clin Cancer Res ; 25(16): 4871-4873, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31227502

RESUMO

Induction of antitumor responses by vaccines requires strong immunogens. Heterologous viral prime/boost immunization with the BN-CV301 vaccine promotes activation of immune responses that provide a clinical benefit to patients with cancer. This viral platform may be used to harbor different antigens and prime tumor immunity potentially useful for combinatorial strategies.See related article by Gatti-Mays et al., p. 4933.


Assuntos
Vacinas Anticâncer , Vacinas de DNA , Humanos , Vacinação
17.
Vet Clin North Am Small Anim Pract ; 49(5): 903-915, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31153610

RESUMO

Lymphoma is a common disease in companion animals. Although conventional chemotherapy has the potential to induce remission and prolong life, relapse is common, and novel treatments are needed to improve outcome. This review discusses recent modifications/adjustments to conventional standard of care therapy for canine and feline lymphoma, as well as cutting-edge immunotherapy and small-molecule-based approaches that are in varying stages of regulatory approval.


Assuntos
Doenças do Gato/terapia , Doenças do Cão/terapia , Linfoma/veterinária , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Gatos , Cães , Imunoterapia/métodos , Imunoterapia/veterinária , Linfoma/terapia , Recidiva Local de Neoplasia , Prognóstico , Radioterapia/métodos , Radioterapia/veterinária
18.
Vet Clin North Am Small Anim Pract ; 49(5): 881-902, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31186125

RESUMO

The enhanced understanding of immunology experienced over the last 4 decades afforded through the tools of molecular biology has recently translated into cancer immunotherapy becoming one of the most exciting and rapidly expanding fields. Human cancer immunotherapy is now recognized as one of the pillars of treatment alongside surgery, radiation, and chemotherapy. The field of veterinary cancer immunotherapy has also rapidly advanced in the last decade with a handful of commercially available products and a plethora of investigational cancer immunotherapies that will hopefully expand the veterinary oncology treatment toolkit over time.


Assuntos
Doenças do Gato/terapia , Doenças do Cão/terapia , Imunoterapia/veterinária , Neoplasias/veterinária , Animais , Vacinas Anticâncer/uso terapêutico , Gatos , Ensaios Clínicos como Assunto , Cães , Humanos , Imunidade , Imunoterapia/métodos , Melanoma/imunologia , Melanoma/veterinária , Neoplasias/terapia
19.
Nat Commun ; 10(1): 2688, 2019 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-31217437

RESUMO

Neoantigens (nAgs) are promising tumor antigens for cancer vaccination with the potential of inducing robust and selective T cell responses. Genetic vaccines based on Adenoviruses derived from non-human Great Apes (GAd) elicit strong and effective T cell-mediated immunity in humans. Here, we investigate for the first time the potency and efficacy of a novel GAd encoding multiple neoantigens. Prophylactic or early therapeutic vaccination with GAd efficiently control tumor growth in mice. In contrast, combination of the vaccine with checkpoint inhibitors is required to eradicate large tumors. Gene expression profile of tumors in regression shows abundance of activated tumor infiltrating T cells with a more diversified TCR repertoire in animals treated with GAd and anti-PD1 compared to anti-PD1. Data suggest that effectiveness of vaccination in the presence of high tumor burden correlates with the breadth of nAgs-specific T cells and requires concomitant reversal of tumor suppression by checkpoint blockade.


Assuntos
Adenoviridae/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Neoplasias/terapia , Vacinas Virais/uso terapêutico , Adenoviridae/genética , Animais , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/farmacologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral/transplante , Terapia Combinada/métodos , Modelos Animais de Doenças , Feminino , Humanos , Imunoterapia/métodos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/imunologia , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Vacinas Sintéticas/uso terapêutico , Vacinas Virais/genética , Vacinas Virais/imunologia
20.
Chem Commun (Camb) ; 55(54): 7729-7736, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31225574

RESUMO

In the last two decades, the paramount importance of Tumor Associated Carbohydrate Antigens (TACAs) as targets for anticancer vaccine development has been firmly assessed. The Tn antigen is an ideal target for immunotherapy, in that it is masked on normal cells, but exposed on cancer cells. However, it is difficult to elicit an effective and long-lasting response against Tn antigen and other TACAs. Here we report on the Tn antigen analogues developed to boost the latent Tn immune response. Hopefully, the results reported herein will be of help for the rational design of effective TACA-based immunostimulants.


Assuntos
Adjuvantes Imunológicos/química , Antígenos Glicosídicos Associados a Tumores/imunologia , Materiais Biomiméticos/química , Galactosídeos/imunologia , Adjuvantes Imunológicos/síntese química , Animais , Antígenos Glicosídicos Associados a Tumores/química , Materiais Biomiméticos/síntese química , Vacinas Anticâncer/imunologia , Galactosídeos/síntese química , Galactosídeos/química , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/imunologia , Neoplasias/terapia , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Peptídeos Cíclicos/imunologia , Células RAW 264.7
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