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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
3.
Cancer Immunol Res ; 7(1): 2-5, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30602506

RESUMO

On September 30 to October 3, 2018, in New York City, the Fourth International Cancer Immunotherapy Conference (CICON) was hosted jointly by the Cancer Research Institute (CRI), the Association for Cancer Immunotherapy (CIMT), the European Academy of Tumor Immunology, and the American Association for Cancer Research (AACR). For the fourth straight year, more than 1,400 people attended the 4-day event, which covered the latest advances in cancer immunology and immunotherapy. This year's meeting also coincided with the announcement that the 2018 Nobel Prize in Medicine or Physiology would be awarded to one of CICON's attendees, James P. Allison.

4.
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.

5.
Chem Soc Rev ; 2018 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-30465669

RESUMO

Immunotherapy is revolutionizing the treatment of cancer. It can achieve unprecedented responses in advanced-stage patients, including complete cures and long-term survival. However, immunotherapy also has limitations, such as its relatively low response rates and the development of severe side effects. These drawbacks are gradually being overcome by improving our understanding of the immune system, as well as by establishing combination regimens in which immunotherapy is combined with other treatment modalities. In addition to this, in recent years, progress made in chemistry, nanotechnology and materials science has started to impact immuno-oncology, resulting in more effective and less toxic immunotherapy interventions. In this context, multiple different nanomedicine formulations and macroscale materials have been shown to be able to boost anti-cancer immunity and the efficacy of immunomodulatory drugs. We here review nanotechnological and materials chemistry efforts related to endogenous and exogenous vaccination, to the engineering of antigen-presenting cells and T cells, and to the modulation of the tumor microenvironment. We also discuss limitations, current trends and future directions. Together, the insights provided and the evidence obtained indicate that there is a bright future ahead for engineering nanomedicines and macroscale materials for immuno-oncology applications.

6.
Hum Vaccin Immunother ; : 1-10, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30111232

RESUMO

The 16th Annual Meeting of the Association for Cancer Immunotherapy (CIMT), Europe's largest meeting series of its kind, took place in Mainz, Germany from 15-17 May, 2018. Cutting-edge advancements in cancer immunotherapy were discussed among more than 700 scientists under the motto "Pushing Frontiers in Cancer Immunotherapy". This meeting report is a summary of some of the CIMT 2018 highlights.

7.
EJNMMI Res ; 8(1): 80, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30112704

RESUMO

BACKGROUND: [18F]Fluoro-2-deoxy-2-D-glucose positron emission tomography (FDG-PET) is commonly used in the clinic for diagnosis of cancer and for follow-up of therapy outcome. Additional to the well-established value in tumor imaging, it bears potential to depict immune processes in modern immunotherapies. T cells enhance their glucose consumption upon activation and are crucial effectors for the success of such novel therapies. In this study, we analyzed the T cell immunity in spleen after antigen-specific stimulation of T cells via highly innovative RNA-based vaccines using FDG-PET/MRI. For this purpose, we employed systemic administration of RNA-lipoplexes encoding the endogenous antigen of Moloney murine leukemia virus (gp70) which have been previously shown to induce potent innate as well as adaptive immune mechanisms for cancer immunotherapy. Feasibility of clinical imaging of increased splenic FDG uptake was demonstrated in a melanoma patient participating in a clinical phase 1 trial of a tetravalent RNA-lipoplex cancer vaccine. RESULTS: We observed exclusive increase of glucose uptake in spleen compared to other organs thanks to liposome-mediated RNA targeting to this immune-relevant organ. In vivo and ex vivo FDG uptake analysis in the spleen of vaccinated mice correlated well with antigen-specific T cell activation. Moreover, the use of an irrelevant (antigen non-specific) RNA also resulted in enhanced FDG uptake early after vaccination through the activation of several other splenic cell populations. The glucose uptake was also dependent on the dose of RNA administered in line with the activation and frequencies of proliferating antigen-specific T cells as well as the general activation pattern of splenic cell populations. CONCLUSIONS: Our preclinical results show rapid and transient vaccination-induced increase of FDG uptake within the spleen reflecting immune activation preceding T cell proliferation. FDG-PET/CT in patients is also capable to image this immune activation resulting in a new potential application of FDG-PET/CT to image immune processes in new immunological therapies.

8.
Mol Pharm ; 15(9): 3909-3919, 2018 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-30028629

RESUMO

Targeting mRNA to eukaryotic cells is an emerging technology for basic research and provides broad applications in cancer immunotherapy, vaccine development, protein replacement, and in vivo genome editing. Although a plethora of nanoparticles for efficient mRNA delivery exists, in vivo mRNA targeting to specific organs, tissue compartments, and cells remains a major challenge. For this reason, methods for reporting the in vivo targeting specificity of different mRNA nanoparticle formats will be crucial. Here, we describe a straightforward method for monitoring the in vivo targeting efficiency of mRNA-loaded nanoparticles in mice. To achieve accurate mRNA delivery readouts, we loaded lipoplex nanoparticles with Cre-recombinase-encoding mRNA and injected these into commonly used Cre reporter mouse strains. Our results show that this approach provides readouts that accurately report the targeting efficacy of mRNA into organs, tissue structures, and single cells as a function of the used mRNA delivery system. The method described here establishes a versatile basis for determining in vivo mRNA targeting profiles and can be systematically applied for testing and improving mRNA packaging formats.

9.
Oncoimmunology ; 7(4): e1409929, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29632723

RESUMO

The B16F10 murine melanoma cell line displays a low expression of MHC class I molecules favoring immune evasion and metastases in immunocompetent C57 BL/6 wild-type mice. Here, we generated metastases to the liver, an organ that is skewed towards immune tolerance, by intrasplenic injection of B16F10 cells in syngeneic C57 BL/6 compared to allogeneic Balb/c mice. Surprisingly, Balb/c mice, which usually display a pronounced M2 macrophage and Th2 T cell polarization, were ∼3 times more susceptible to metastasis than C57 BL/6 mice, despite a much higher M1 and Th1 T cell immune response. The anti-metastatic advantage of C57 BL/6 mice could be attributed to a more potent NK-cell mediated cytotoxicity against B16F10 cells. Our findings highlight the role of NK cells in innate anti-tumor immunity in the context of the liver - particularly against highly aggressive MHC I-deficient cancer cells. Moreover, the B16F10 model of melanoma liver metastasis is suited for developing novel therapies targeting innate NK cell related immunity in liver metastases and liver cancer.

10.
J Allergy Clin Immunol ; 142(5): 1558-1570, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29382591

RESUMO

BACKGROUND: Nanoparticle (NP)-based vaccines are attractive immunotherapy tools because of their capability to codeliver antigen and adjuvant to antigen-presenting cells. Their cellular distribution and serum protein interaction ("protein corona") after systemic administration and their effect on the functional properties of NPs is poorly understood. OBJECTIVES: We analyzed the relevance of the protein corona on cell type-selective uptake of dextran-coated NPs and determined the outcome of vaccination with NPs that codeliver antigen and adjuvant in disease models of allergy. METHODS: The role of protein corona constituents for cellular binding/uptake of dextran-coated ferrous nanoparticles (DEX-NPs) was analyzed both in vitro and in vivo. DEX-NPs conjugated with the model antigen ovalbumin (OVA) and immunostimulatory CpG-rich oligodeoxynucleotides were administered to monitor the induction of cellular and humoral immune responses. Therapeutic effects of this DEX-NP vaccine in mouse models of OVA-induced anaphylaxis and allergic asthma were assessed. RESULTS: DEX-NPs triggered lectin-induced complement activation, yielding deposition of activated complement factor 3 on the DEX-NP surface. In the spleen DEX-NPs targeted predominantly B cells through complement receptors 1 and 2. The DEX-NP vaccine elicited much stronger OVA-specific IgG2a production than coadministered soluble OVA plus CpG oligodeoxynucleotides. B-cell binding of the DEX-NP vaccine was critical for IgG2a production. Treatment of OVA-sensitized mice with the DEX-NP vaccine prevented induction of anaphylactic shock and allergic asthma accompanied by IgE inhibition. CONCLUSIONS: Opsonization of lectin-coated NPs by activated complement components results in selective B-cell targeting. The intrinsic B-cell targeting property of lectin-coated NPs can be exploited for treatment of allergic immune responses.

11.
Cancer Immunol Res ; 6(1): 10-13, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29298782

RESUMO

On September 6 to 9, 2017, in Mainz, Germany, the Third International Cancer Immunotherapy Conference was hosted jointly by the Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research. For the third straight year, more than 1,400 people attended the four-day event, which covered the latest advances in cancer immunology and immunotherapy. This report provides an overview of the main topics discussed. Cancer Immunol Res; 6(1); 10-13. ©2017 AACR.

12.
Matrix Biol ; 66: 34-49, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29122677

RESUMO

Organ fibrosis is characterized by a chronic wound-healing response, with excess deposition of extracellular matrix components. Here, collagen type I represents the most abundant scar component and a primary target for antifibrotic therapies. Liver fibrosis can progress to cirrhosis and primary liver cancer, which are the major causes of liver related morbidity and mortality. However, a (pro-)collagen type I specific therapy remains difficult and its therapeutic abrogation may incur unwanted side effects. We therefore designed tetracycline-regulated procollagen alpha1(I) short hairpin (sh)RNA expressing mice that permit a highly efficient inducible knockdown of the procollagen alpha1(I) gene in activated (myo-)fibroblasts, to study the effect of induced procollagen type I deficiency. Transgenic mice were generated using recombinase-mediated integration in embryonic stem cells or zinc-finger nuclease-aided genomic targeting combined with miR30-shRNA technology. Liver fibrosis was induced in transgenic mice by carbon tetrachloride, either without or with doxycycline supplementation. Doxycycline treated mice showed an 80-90% suppression of procollagen alpha1(I) transcription and a 40-50% reduction in hepatic collagen accumulation. Procollagen alpha1(I) knockdown also downregulated procollagens type III, IV and VI and other fibrosis related parameters. Moreover, this was associated with an attenuation of chronic inflammation, suggesting that collagen type I serves not only as major scar component, but also as modulator of other collagens and promoter of chronic inflammation.

13.
Nat Commun ; 8(1): 1523, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-29142217

RESUMO

The set of events that convert adherent epithelial cells into migratory cells are collectively known as epithelial-mesenchymal transition (EMT). EMT is involved during development, for example, in triggering neural crest migration, and in pathogenesis such as metastasis. Here we discover FBXO32, an E3 ubiquitin ligase, to be critical for hallmark gene expression and phenotypic changes underlying EMT. Interestingly, FBXO32 directly ubiquitinates CtBP1, which is required for its stability and nuclear retention. This is essential for epigenetic remodeling and transcriptional induction of CtBP1 target genes, which create a suitable microenvironment for EMT progression. FBXO32 is also amplified in metastatic cancers and its depletion in a NSG mouse xenograft model inhibits tumor growth and metastasis. In addition, FBXO32 is essential for neuronal EMT during brain development. Together, these findings establish that FBXO32 acts as an upstream regulator of EMT by governing the gene expression program underlying this process during development and disease.


Assuntos
Oxirredutases do Álcool/genética , Encéfalo/metabolismo , Proteínas de Ligação a DNA/genética , Transição Epitelial-Mesenquimal/genética , Proteínas Musculares/genética , Proteínas Ligases SKP Culina F-Box/genética , Microambiente Tumoral/genética , Oxirredutases do Álcool/metabolismo , Animais , Encéfalo/patologia , Linhagem Celular Tumoral , Células Cultivadas , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Células MCF-7 , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Proteínas Musculares/metabolismo , Metástase Neoplásica , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Interferência de RNA , Proteínas Ligases SKP Culina F-Box/metabolismo , Transplante Heterólogo
14.
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
16.
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
17.
Bioorg Med Chem Lett ; 27(7): 1530-1537, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28254484

RESUMO

We have previously demonstrated the nucleic acid binding capacity of phenanthridine derivatives (PHTs). Because nucleic acids are potent inducers of innate immune response through Toll-like receptors (TLRs), and because PTHs bear a structural resemblance to commonly used synthetic ligands for TLR7/8, we hypothesized that PHTs could modulate/activate immune response. We found that compound M199 induces secretion of IL-6, IL-8 and TNFα in human PBMCs and inhibits TLR3/9 activation in different cellular systems (PBMCs, HEK293 and THP-1 cell lines).


Assuntos
Fatores Imunológicos/farmacologia , Fenantridinas/farmacologia , Receptor 3 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismo , Ureia/análogos & derivados , Ureia/farmacologia , Linhagem Celular , Regulação para Baixo , Humanos , Substâncias Intercalantes/farmacologia , Interferon-alfa/genética , Interferon-alfa/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Oligodesoxirribonucleotídeos/farmacologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
18.
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
19.
Curr Issues Mol Biol ; 22: 113-128, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27801664

RESUMO

mRNA vaccines are finally ready to assume their rightful place at the forefront of nucleic acid- based vaccines. Major achievements within the last two decades have turned this highly versatile molecule into a safe and very attractive pharmaceutical platform that combines many positive attributes able to address a broad range of diseases, including cancer. The simplicity of mRNA vaccines greatly reduces complications generally associated with the production of biological vaccines. Intrinsic costimulatory and inflammatory triggers in addition to the provision of the antigenic information makes mRNA an all- in-one molecule that does not need additional adjuvants and that does not pose the risk of genomic integration. Clinical studies in various cancer types are moving forward and promising results with favorable clinical outcome are awaited. This review will recapitulate conceptual, mechanistic and immune-related features of this highly versatile molecule, elucidate how these features have been addressed in the past, and how comprehensive understanding can foster further optimization for broad application possibilities in cancer treatment.


Assuntos
Vacinas Anticâncer/imunologia , Neoplasias/terapia , RNA Mensageiro/genética , Vacinas Anticâncer/genética , Humanos , Imunoterapia Ativa/normas , Imunoterapia Ativa/tendências , RNA Mensageiro/imunologia
20.
J Control Release ; 248: 10-23, 2017 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-27940184

RESUMO

Cationic nanohydrogel particles have become an attractive tool for systemic siRNA delivery, but improvement of their in vivo tolerance is desirable, especially to prevent potential long term side effects by tissue and cellular accumulation. Here, we designed novel ketal cross-linked cationic nanohydrogel particles that were assessed for reduced tissue accumulation and robust siRNA delivery in vitro and in vivo. An oligo-amine cross-linker equipped with a ketal moiety in its core was synthesized and applied to nanohydrogel cross-linking of self-assembled reactive ester block copolymers in DMSO. The resulting acid-sensitive cationic nanoparticles spontaneously disassembled over time in acidic milieu, as investigated by dynamic light scattering. Fluorescent correlation spectroscopy showed effective complexation with siRNA as well as its release upon particle degradation at endosomal pH. These properties resulted in an enhanced in vitro gene knockdown for the acid-degradable cationic nanoparticles compared to their non-degradable spermine analogues. In a murine liver fibrosis model enhanced carrier and payload accumulation in the fibrotic tissue facilitated sequence-specific gene knockdown and prevented fibrosis progression. Long-term monitoring of the carrier in the body showed an enhanced clearance for the acid-degradable carrier, even after multiple dosing. Therefore, these acid-degradable cationic nanohydrogel particles can be considered as promising siRNA carriers for in vivo purposes towards therapeutic applications.


Assuntos
Hidrogéis/química , Interferência de RNA , RNA Interferente Pequeno/administração & dosagem , Células 3T3 , Animais , Cátions/química , Feminino , Fibrose , Técnicas de Silenciamento de Genes , Fígado/patologia , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Polímeros/química , Células RAW 264.7 , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacocinética
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