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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.
Mol Ther ; 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31624015

RESUMO

Here, we present a potent RNA vaccine approach based on a novel bipartite vector system using trans-amplifying RNA (taRNA). The vector cassette encoding the vaccine antigen originates from an alphaviral self-amplifying RNA (saRNA), from which the replicase was deleted to form a transreplicon. Replicase activity is provided in trans by a second molecule, either by a standard saRNA or an optimized non-replicating mRNA (nrRNA). The latter delivered 10- to 100-fold higher transreplicon expression than the former. Moreover, expression driven by the nrRNA-encoded replicase in the taRNA system was as efficient as in a conventional monopartite saRNA system. We show that the superiority of nrRNA- over saRNA-encoded replicase to drive expression of the transreplicon is most likely attributable to its higher translational efficiency and lack of interference with cellular translation. Testing the novel taRNA system in mice, we observed that doses of influenza hemagglutinin antigen-encoding RNA as low as 50 ng were sufficient to induce neutralizing antibodies and mount a protective immune response against live virus challenge. These findings, together with a favorable safety profile, a simpler production process, and the universal applicability associated with this bipartite vector system, warrant further exploration of taRNA.

3.
Jpn J Clin Oncol ; 49(9): 870-876, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31087075

RESUMO

BACKGROUND: The monoclonal antibody zolbetuximab (formerly IMAB362), which is being developed as a potential treatment for gastric cancer (GC), targets Claudin 18.2 (CLDN18.2), a GC biomarker. This study aimed to determine the prevalence of CLDN18.2 in primary tumors and lymph node (LN) metastases of Japanese patients with GC. METHODS: CLDN18.2 expression was investigated in tissue samples from patients with gastric adenocarcinoma archived at Kurume University Medical Center, Japan, between 2000 and 2012. Expression of CLDN18.2 in tumor samples was evaluated by immunohistochemistry using the same detection antibody (43-14A) and assay used in the FAST clinical trial (NCT01630083), a phase 2 randomized trial that compared the safety and antitumor activity of the zolbetuximab-chemotherapy combination with chemotherapy alone. Samples showing any specific staining with ≥1+ intensity were defined as CLDN18.2-positive. RESULTS: Of 263 samples analyzed (134 primary gastric tumors and corresponding LN metastases; 128 primary tumors only; one LN metastases only), CLDN18.2 was detected in 87% (n = 228/262) of all primary tumors and 80% (n = 108/135) of LN metastases. Moderate-to-strong CLDN18.2 expression (≥2+ membrane staining intensity in ≥40% of tumor cells [FAST eligibility criterion]) was observed in 52% (n = 135/262) of primary tumors and 45% (n = 61/135) of (LN) metastases. CLDN18.2 expression was significantly higher in GCs of the diffuse histological subtype per Lauren classification and in high grade (G3) tumors. CONCLUSIONS: The high prevalence of CLDN18.2 among Japanese patients with GC supports the therapeutic assessment of zolbetuximab in this population.

4.
Annu Rev Med ; 70: 395-407, 2019 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-30691374

RESUMO

T cells are key effectors of anticancer immunity. They are capable of distinguishing tumor cells from normal ones by recognizing major histocompatibility complex-bound cancer-specific peptides. Accumulating evidence suggests that peptides associated with T cell-mediated tumor rejection arise predominantly from somatically mutated proteins and are unique to every patient's tumor. Knowledge of an individual's cancer mutanome (the entirety of cancer mutations) allows harnessing this enormous tumor cell-specific repertoire of highly immunogenic antigens for individualized cancer vaccines. This review outlines the preclinical and clinical state of individualized cancer vaccine development and the challenges ahead.

5.
Mol Ther ; 27(4): 824-836, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30638957

RESUMO

Synthetic mRNA has emerged as a powerful tool for the transfer of genetic information, and it is being explored for a variety of therapeutic applications. Many of these applications require prolonged intracellular persistence of mRNA to improve bioavailability of the encoded protein. mRNA molecules are intrinsically unstable and their intracellular kinetics depend on the UTRs embracing the coding sequence, in particular the 3' UTR elements. We describe here a novel and generally applicable cell-based selection process for the identification of 3' UTRs that augment the expression of proteins encoded by synthetic mRNA. Moreover, we show, for two applications of mRNA therapeutics, namely, (1) the delivery of vaccine antigens in order to mount T cell immune responses and (2) the introduction of reprogramming factors into differentiated cells in order to induce pluripotency, that mRNAs tagged with the 3' UTR elements discovered in this study outperform those with commonly used 3' UTRs. This approach further leverages the utility of mRNA as a gene therapy drug format.

6.
Eur J Cancer ; 100: 17-26, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29936063

RESUMO

INTRODUCTION: IMAB362 (Zolbetuximab) is a chimeric monoclonal antibody that binds to Claudin-18.2, a target antigen specific to cancer cells. In vitro, IMAB362 mediates cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity; thus, IMAB362 may serve as a potent, targeted immunotherapeutic agent. METHODS: This first-in-human phase I study enroled adult patients (N = 15) with advanced gastric or gastro-oesophageal junction cancer into five sequential single dose-escalation cohorts (33, 100, 300, 600, and 1000 mg/m2) following a 3 + 3 design. Safety/tolerability, including determination of maximum tolerated dose and recommended phase II dose, were the primary objectives; secondary objectives included assessment of the IMAB362 pharmacokinetic profile, immunogenicity, and antitumour activity (assessed by Response Evaluation Criteria in Solid Tumors v1.0). RESULTS: IMAB362 was generally well tolerated at all doses, with gastrointestinal toxicities being the most commonly observed treatment-related adverse events. As dose-limiting toxicity was not observed within 4 weeks of treatment, a maximum tolerated dose was not established. The pharmacokinetic profile of IMAB362 appeared to be proportional across the dose range; and mean half-life ranged from 13 to 24 d. While most patients showed progressive disease at weeks 4-5 after a single intravenous IMAB362 infusion, one patient in the 600 mg/m2 dose group achieved and maintained stable disease for approximately 2 months postinfusion. CONCLUSIONS: Findings from this study demonstrate that IMAB362 is generally well tolerated and support further evaluation in patients with gastric/gastro-oesophageal junction cancer. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov, Identifier NCT00909025.

7.
J Nanobiotechnology ; 16(1): 39, 2018 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-29653575

RESUMO

BACKGROUND: Virus-like-particles (VLPs) are attractive nanoparticulate scaffolds for broad applications in material/biological sciences and medicine. Prior their functionalization, specific adaptations have to be carried out. These adjustments frequently lead to disordered particles, but the particle integrity is an essential factor for the VLP suitability. Therefore, major requirements for particle stabilization exist. The objective of this study was to evaluate novel stabilizing elements for functionalized chimeric hepatitis B virus core antigen virus-like particles (HBcAg-VLP), with beneficial characteristics for vaccine development, imaging or delivery. RESULTS: The effects of a carboxy-terminal polyhistidine-peptide and an intradimer disulfide-bridge on the stability of preclinically approved chimeric HBcAg-VLPs were assessed. We purified recombinant chimeric HBcAg-VLPs bearing different modified C-termini and compared their physical and chemical particle stability by quantitative protein-biochemical and biophysical techniques. We observed lower chemical resistance of T = 3- compared to T = 4-VLP (triangulation number) capsids and profound impairment of accessibility of hexahistidine-peptides in assembled VLPs. Histidines attached to the C-terminus were associated with superior mechanical and/or chemical particle stability depending on the number of histidine moieties. A molecular modeling approach based on cryo-electron microscopy and biolayer interferometry revealed the underlying structural mechanism for the strengthening of the integrity of VLPs. Interactions triggering capsid stabilization occur on a highly conserved residue on the basis of HBcAg-monomers as well as on hexahistidine-peptides of adjacent monomers. This new stabilization mechanism appears to mimic an evolutionary conserved stabilization concept for hepadnavirus core proteins. CONCLUSIONS: These findings establish the genetically simply transferable C-terminal polyhistidine-peptide as a general stabilizing element for chimeric HBcAg-VLPs to increase their suitability.


Assuntos
Antígenos do Núcleo do Vírus da Hepatite B/metabolismo , Histidina/metabolismo , Oligopeptídeos/metabolismo , Proteínas Recombinantes/metabolismo , Vírion/metabolismo , Antígenos do Núcleo do Vírus da Hepatite B/isolamento & purificação , Modelos Moleculares , Controle de Qualidade , Proteínas Recombinantes/isolamento & purificação , Estresse Fisiológico , Vírion/ultraestrutura
8.
Science ; 359(6382): 1355-1360, 2018 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-29567706

RESUMO

Cancer is characterized by an accumulation of genetic alterations. Somatic mutations can generate cancer-specific neoepitopes that are recognized by autologous T cells as foreign and constitute ideal cancer vaccine targets. Every tumor has its own unique composition of mutations, with only a small fraction shared between patients. Technological advances in genomics, data science, and cancer immunotherapy now enable the rapid mapping of the mutations within a genome, rational selection of vaccine targets, and on-demand production of a therapy customized to a patient's individual tumor. First-in-human clinical trials of personalized cancer vaccines have shown the feasibility, safety, and immunotherapeutic activity of targeting individual tumor mutation signatures. With vaccination development being promoted by emerging innovations of the digital age, vaccinating a patient with individual tumor mutations may become the first truly personalized treatment for cancer.


Assuntos
Vacinas Anticâncer/genética , Vacinas Anticâncer/uso terapêutico , Imunoterapia/métodos , Neoplasias/genética , Neoplasias/terapia , Medicina de Precisão/métodos , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Humanos , Epitopos Imunodominantes/genética , Epitopos Imunodominantes/imunologia , Mutação
11.
Hum Gene Ther ; 28(12): 1138-1146, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28877647

RESUMO

Among nucleic acid-based delivery platforms, self-amplifying RNA (saRNA) vectors are of increasing interest for applications such as transient expression of recombinant proteins and vaccination. saRNA is safe and, due to its capability to amplify intracellularly, high protein levels can be produced from even minute amounts of transfected templates. However, it is an obstacle to full exploitation of this platform that saRNA induces a strong innate host immune response. In transfected cells, pattern recognition receptors sense double-stranded RNA intermediates and via activation of protein kinase R (PKR) and interferon signaling initiate host defense measures including a translational shutdown. To reduce pattern recognition receptor stimulation and unleash suppressed saRNA translation, this study co-delivered non-replicating mRNA encoding vaccinia virus immune evasion proteins E3, K3, and B18. It was shown that E3 is far superior to K3 or B18 as a highly potent blocker of PKR activation and of interferon (IFN)-ß upregulation. B18, in contrast, is superior in controlling OAS1, a key IFN-inducible gene involved in viral RNA degradation. By combining all three vaccinia proteins, the study achieved significant suppression of PKR and IFN pathway activation in vitro and enhanced expression of saRNA-encoded genes of interest both in vitro and in vivo. This approach promises to overcome key hurdles of saRNA gene delivery. Its application may improve the bioavailability of the encoded protein, and reduce the effective dose and correspondingly the cost of goods of manufacture in the various fields where saRNA utilization is envisioned.


Assuntos
Expressão Gênica , Técnicas de Transferência de Genes , Vetores Genéticos , Evasão da Resposta Imune , RNA , Vírus Vaccinia/genética , Proteínas Virais , Animais , Linhagem Celular , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , RNA/genética , RNA/metabolismo , Proteínas Virais/biossíntese , Proteínas Virais/genética , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismo
12.
Nature ; 547(7662): 222-226, 2017 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-28678784

RESUMO

T cells directed against mutant neo-epitopes drive cancer immunity. However, spontaneous immune recognition of mutations is inefficient. We recently introduced the concept of individualized mutanome vaccines and implemented an RNA-based poly-neo-epitope approach to mobilize immunity against a spectrum of cancer mutations. Here we report the first-in-human application of this concept in melanoma. We set up a process comprising comprehensive identification of individual mutations, computational prediction of neo-epitopes, and design and manufacturing of a vaccine unique for each patient. All patients developed T cell responses against multiple vaccine neo-epitopes at up to high single-digit percentages. Vaccine-induced T cell infiltration and neo-epitope-specific killing of autologous tumour cells were shown in post-vaccination resected metastases from two patients. The cumulative rate of metastatic events was highly significantly reduced after the start of vaccination, resulting in a sustained progression-free survival. Two of the five patients with metastatic disease experienced vaccine-related objective responses. One of these patients had a late relapse owing to outgrowth of ß2-microglobulin-deficient melanoma cells as an acquired resistance mechanism. A third patient developed a complete response to vaccination in combination with PD-1 blockade therapy. Our study demonstrates that individual mutations can be exploited, thereby opening a path to personalized immunotherapy for patients with cancer.


Assuntos
Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Melanoma/imunologia , Melanoma/terapia , Mutação/genética , Medicina de Precisão/métodos , RNA/genética , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/imunologia , Antígenos CD8/imunologia , Vacinas Anticâncer/uso terapêutico , Epitopos/genética , Epitopos/imunologia , Humanos , Imunoterapia/métodos , Melanoma/genética , Metástase Neoplásica , Recidiva Local de Neoplasia/prevenção & controle , Nivolumabe , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T/imunologia , Vacinação , Microglobulina beta-2/deficiência
13.
Nat Med ; 23(7): 815-817, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28604701

RESUMO

The potential of bispecific T cell-engaging antibodies is hindered by manufacturing challenges and short serum half-life. We circumvented these limitations by treating mice with in vitro-transcribed pharmacologically optimized, nucleoside-modified mRNA encoding the antibody. We achieved sustained endogenous synthesis of the antibody, which eliminated advanced tumors as effectively as the corresponding purified bispecific antibody. Because manufacturing of pharmaceutical mRNA is fast, this approach could accelerate the clinical development of novel bispecific antibodies.


Assuntos
Anticorpos Biespecíficos/genética , Citocinas/efeitos dos fármacos , Neoplasias/terapia , RNA Mensageiro/farmacologia , Linfócitos T/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Animais , Anticorpos Biespecíficos/imunologia , Linhagem Celular Tumoral , Citocinas/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Immunoblotting , Imuno-Histoquímica , Técnicas In Vitro , Medições Luminescentes , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Neoplasias/imunologia , Neoplasias/patologia , RNA Mensageiro/genética , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Methods Mol Biol ; 1499: 203-222, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27987152

RESUMO

A variety of different mRNA-based drugs are currently in development. This became possible, since major breakthroughs in RNA research during the last decades allowed impressive improvements of translation, stability and delivery of mRNA. This article focuses on antigen-encoding RNA-based vaccines that are either directed against tumors or pathogens. mRNA-encoded vaccines are developed both for preventive or therapeutic purposes. Most mRNA-based vaccines are directly administered to patients. Alternatively, primary autologous cells from cancer patients are modified ex vivo by the use of mRNA and then are adoptively transferred to patients. In the EU no regulatory guidelines presently exist that specifically address mRNA-based vaccines. The existing regulatory framework, however, clearly defines that mRNA-based vaccines in most cases have to be centrally approved. Interestingly, depending on whether RNA-based vaccines are directed against tumors or infectious disease, they are formally considered gene therapy products or not, respectively. Besides an overview on the current clinical use of mRNA vaccines in various therapeutic areas a detailed discussion of the current regulatory situation is provided and regulatory perspectives are discussed.


Assuntos
Vacinas Anticâncer/imunologia , RNA Mensageiro/imunologia , Animais , Antígenos/imunologia , Europa (Continente) , Terapia Genética/métodos , Humanos , Neoplasias/imunologia , Neoplasias/terapia
15.
Methods Mol Biol ; 1499: 223-236, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27987153

RESUMO

Cancer accumulates 10s to 1000s of genomic mutations of which a fraction is immunogenic and may serve as an Achilles' heel of tumor cells. Mutation-specific T cells can recognize these antigens and destroy malignant cells. Strategies to immunotherapeutically address individual tumor mutations employing peptide or mRNA based vaccines are now actively investigated in mice and humans. An important step of determining the therapeutic potential of a mutanome vaccine is the detection of mutation reactive T-cell responses. In this chapter we provide protocols to identify and subtype mutation specific T cells in mice based on IFN-γ ELISpot and flow cytometry.


Assuntos
Epitopos de Linfócito T/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Linfócitos T/imunologia , Animais , Humanos , Imunoterapia/métodos , Interferon gama/imunologia , Camundongos , Mutação/imunologia
16.
Cancer Immunol Immunother ; 65(9): 1075-83, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27422115

RESUMO

Intradermal administration of antigen-encoding RNA has entered clinical testing for cancer vaccination. However, insight into the underlying mechanism of RNA uptake, translation and antigen presentation is still limited. Utilizing pharmacologically optimized naked RNA, the dose-response kinetics revealed a rise in reporter signal with increasing RNA amounts and a prolonged RNA translation of reporter protein up to 30 days after intradermal injection. Dendritic cells (DCs) in the dermis were shown to engulf RNA, and the signal arising from the reporter RNA was significantly diminished after DC depletion. Macropinocytosis was relevant for intradermal RNA uptake and translation in vitro and in vivo. By combining intradermal RNA vaccination and inhibition of macropinocytosis, we show that effective priming of antigen-specific CD8(+) T-cells also relies on this uptake mechanism. This report demonstrates that direct antigen translation by dermal DCs after intradermal naked RNA vaccination is relevant for efficient priming of antigen-specific T-cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/metabolismo , RNA/farmacocinética , Animais , Células Dendríticas/imunologia , Feminino , Humanos , Injeções Intradérmicas , Camundongos , Camundongos Endogâmicos C57BL , Pinocitose , RNA/administração & dosagem
17.
Nature ; 534(7607): 396-401, 2016 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-27281205

RESUMO

Lymphoid organs, in which antigen presenting cells (APCs) are in close proximity to T cells, are the ideal microenvironment for efficient priming and amplification of T-cell responses. However, the systemic delivery of vaccine antigens into dendritic cells (DCs) is hampered by various technical challenges. Here we show that DCs can be targeted precisely and effectively in vivo using intravenously administered RNA-lipoplexes (RNA-LPX) based on well-known lipid carriers by optimally adjusting net charge, without the need for functionalization of particles with molecular ligands. The LPX protects RNA from extracellular ribonucleases and mediates its efficient uptake and expression of the encoded antigen by DC populations and macrophages in various lymphoid compartments. RNA-LPX triggers interferon-α (IFNα) release by plasmacytoid DCs and macrophages. Consequently, DC maturation in situ and inflammatory immune mechanisms reminiscent of those in the early systemic phase of viral infection are activated. We show that RNA-LPX encoding viral or mutant neo-antigens or endogenous self-antigens induce strong effector and memory T-cell responses, and mediate potent IFNα-dependent rejection of progressive tumours. A phase I dose-escalation trial testing RNA-LPX that encode shared tumour antigens is ongoing. In the first three melanoma patients treated at a low-dose level, IFNα and strong antigen-specific T-cell responses were induced, supporting the identified mode of action and potency. As any polypeptide-based antigen can be encoded as RNA, RNA-LPX represent a universally applicable vaccine class for systemic DC targeting and synchronized induction of both highly potent adaptive as well as type-I-IFN-mediated innate immune mechanisms for cancer immunotherapy.


Assuntos
Antígenos de Neoplasias/imunologia , Antígenos Virais/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Imunoterapia/métodos , Melanoma/imunologia , Melanoma/terapia , RNA/administração & dosagem , Administração Intravenosa , Animais , Apresentação do Antígeno/imunologia , Antígenos de Neoplasias/genética , Antígenos Virais/genética , Autoantígenos/genética , Autoantígenos/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/genética , Ensaios Clínicos Fase I como Assunto , Células Dendríticas/citologia , Modelos Animais de Doenças , Portadores de Fármacos/administração & dosagem , Feminino , Humanos , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Ativação Linfocitária/imunologia , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/administração & dosagem , RNA/genética , Eletricidade Estática , Linfócitos T/citologia , Linfócitos T/imunologia , Receptor 7 Toll-Like/imunologia
18.
Oncoimmunology ; 5(3): e1091555, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27141353

RESUMO

The fetal tight junction molecule claudin 6 (CLDN6) is virtually absent from any normal tissue, whereas it is aberrantly and frequently expressed in various cancers of high medical need. We engineered 6PHU3, a T-cell-engaging bispecific single chain molecule (bi-(scFv)2) with anti-CD3/anti-CLDN6 specificities, and characterized its pharmacodynamic properties. Our data show that upon engagement by 6PHU3, T cells strongly upregulate cytotoxicity and activation markers, proliferate and acquire an effector phenotype. 6PHU3 exerts potent killing of cancer cells in vitro with EC50 values in the pg/mL range. Subcutaneous xenograft tumors in NSG mice engrafted with human PBMCs are eradicated by 6PHU3 treatment and survival of mice is significantly prolonged. Tumors of 6PHU3-treated mice are strongly infiltrated with activated CD4+, CD8+ T cells and TEM type cells but not Tregs and display a general activation of a mostly inflammatory phenotype. These effects are only observed upon bispecific but not monospecific engagement of 6PHU3. Together with the exceptionally cancer cell selective expression of the oncofetal tumor marker CLDN6, this provides a safeguard with regard to toxicity. In summary, our data shows that the concept of T-cell redirection combined with that of highly selective targeting of CLDN6-positive solid tumors is effective. Thus, exploring 6PHU3 for clinical therapy is warranted.

19.
Methods Mol Biol ; 1428: 163-75, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27236799

RESUMO

Intranodal immunization with antigen-encoding naked mRNA has proven to be an efficacious and safe approach to induce antitumor immunity. Thanks to its unique characteristics, mRNA can act not only as a source for antigen but also as an adjuvant for activation of the immune system. The search for additional adjuvants that can be combined with mRNA to further improve the potency of the immunization revealed Fms-like tyrosine kinase 3 (FLT3) ligand as a potent candidate. Systemic administration of the dendritic cell-activating FLT3 ligand prior to or along with mRNA immunization-enhanced priming and expansion of antigen-specific CD8(+) T cells in lymphoid organs, T-cell homing into melanoma tumors, and therapeutic activity of the intranodally administered mRNA. Both compounds demonstrate a successful combination in terms of boosting the immune response. This chapter describes methods for intranodal immunization with naked mRNA by co-administration of FLT3 ligand, which leads to strong synergistic effects.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Células da Medula Óssea/citologia , Proteínas de Membrana/administração & dosagem , RNA Mensageiro/administração & dosagem , Animais , Células da Medula Óssea/imunologia , Células Cultivadas , Células Dendríticas/imunologia , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/imunologia , Vacinação/métodos
20.
Sci Transl Med ; 8(334): 334ps9, 2016 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-27075624

RESUMO

Cancer vaccine development has been vigorously pursued for 40 years. Immunity to tumor antigens can be elicited by most vaccines tested, but their clinical efficacy remains modest. We argue that a concerted international effort is necessary to understand the human antitumor immune response and achieve clinically effective cancer vaccines.


Assuntos
Vacinas Anticâncer/imunologia , Antígenos de Neoplasias/imunologia , Humanos , Memória Imunológica , Linfócitos T/imunologia
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