Intradermal Vaccinations With RNA Coding for TAA Generate CD8+ and CD4+ Immune Responses and Induce Clinical Benefit in Vaccinated Patients

Rittig, Susanne M; Haentschel, Maik; Weimer, Katrin J; Heine, Annkristin; Müller, Martin; Brugger, Wolfram; Horger, Marius; Maksimovic, Olga; Stenzl, Arnulf; Hoerr, Ingmar; Rammensee, Hans‐Georg; Holderried, Tobias A. W.; Kanz, Lothar; Pascolo, Steve; Brossart, Peter

doi:10.1038/mt.2010.289

Cited by 193 publications

(125 citation statements)

References 37 publications

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“…Successful applications of RNA nanoparticle-based vaccines that are independent of ex vivo transfection of antigenpresenting cells are limited in animal models (reviewed in 32,93), and few such approaches have made it to clinical trials. Although correlates of immune protection in humans have been reported, clinical efficacy has been disappointing (94)(95)(96)(97). Replicons based on RNA viruses of the alphavirus family, such as SFV, VEEV, and Sindbis virus (SIN), have served as vaccine vectors, usually delivered as replication-deficient pseudoviral particles generated through complementation of structural genes in cell culture (98).…”

Section: Discussionmentioning

confidence: 99%

Dendrimer-RNA nanoparticles generate protective immunity against lethal Ebola, H1N1 influenza, and Toxoplasma gondii challenges with a single dose

Chahal

Khan

Cooper

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

343

260

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Vaccines have had broad medical impact, but existing vaccine technologies and production methods are limited in their ability to respond rapidly to evolving and emerging pathogens, or sudden outbreaks. Here, we develop a rapid-response, fully synthetic, single-dose, adjuvant-free dendrimer nanoparticle vaccine platform wherein antigens are encoded by encapsulated mRNA replicons. To our knowledge, this system is the first capable of generating protective immunity against a broad spectrum of lethal pathogen challenges, including H1N1 influenza, Toxoplasma gondii, and Ebola virus. The vaccine can be formed with multiple antigen-expressing replicons, and is capable of eliciting both CD8+ T-cell and antibody responses. The ability to generate viable, contaminant-free vaccines within days, to single or multiple antigens, may have broad utility for a range of diseases.

show abstract

Section: Discussionmentioning

confidence: 99%

Dendrimer-RNA nanoparticles generate protective immunity against lethal Ebola, H1N1 influenza, and Toxoplasma gondii challenges with a single dose

Chahal

Khan

Cooper

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

343

260

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“…In carcinomas that express MUC1, the tumor-associated glycoforms of MUC1 have been shown to be immune targets in vivo (27). In patients with cancer, CD8 þ T cells directed against MUC1 peptide epitopes were detected before and after vaccination (28)(29)(30), and the IgG auto-antibodies against specific tumor-associated glycoforms were found in patients with cancer with early-stage disease (5,31). Early work showed that MUC1 following internalization is blocked in the endolysosomal compartment of dendritic cells (9), suggesting that only a tolerizing CD4 þ T-cell response could be generated against this glycoantigen.…”

Section: Discussionmentioning

confidence: 99%

Microvesicle Cargo of Tumor-Associated MUC1 to Dendritic Cells Allows Cross-presentation and Specific Carbohydrate Processing

Rughetti

Rahimi

Belleudi

et al. 2014

Cancer Immunology Research

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Tumor-associated glycoproteins are a group of antigens with high immunogenic interest: The glycoforms generated by the aberrant glycosylation are tumor-specific and the novel glycoepitopes exposed can be targets of tumor-specific immune responses. The MUC1 antigen is one of the most relevant tumor-associated glycoproteins. In cancer, MUC1 loses polarity and becomes overexpressed and hypoglycosylated. Changes in glycan moieties contribute to MUC1 immunogenicity and can modify the interactions of tumor cells with antigen-presenting cells such as dendritic cells that would affect the overall antitumor immune response. Here, we show that the form of the MUC1 antigen, i.e., soluble or as microvesicle cargo, influences MUC1 processing in dendritic cells. In fact, MUC1 carried by microvesicles translocates from the endolysosomal/HLA-II to the HLA-I compartment and is presented by dendritic cells to MUC1-specific CD8 þ T cells stimulating IFN-g responses, whereas the soluble MUC1 is retained in the endolysosomal/HLA-II compartment independently by the glycan moieties and by the modality of internalization (receptor-mediated or non-receptor mediated). MUC1 translocation to the HLA-I compartment is accompanied by deglycosylation that generates novel MUC1 glycoepitopes. Microvesicle-mediated transfer of tumor-associated glycoproteins to dendritic cells may be a relevant biologic mechanism in vivo contributing to define the type of immunogenicity elicited. Furthermore, these results have important implications for the design of glycoprotein-based immunogens for cancer immunotherapy.

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“…Nonetheless, there have been encouraging preliminary results of recent and ongoing clinical trials using mRNA, underscoring the rapidly emerging importance of mRNA therapeutics in the treatment or prevention of a range of diseases. To date, naked, chemically modified, or protamine-complexed mRNA have shown promise in phase I/II cancer trials (24)(25)(26). Recently, preclinical development of materials specific for mRNA delivery has resulted in cationic polymers such as polymethacrylates (27)(28)(29), poly(aspartamides) (30,31), and polypeptides (32), as well as multicomponent cationic lipid or lipid-like formulations (21,(33)(34)(35)(36).…”

mentioning

confidence: 99%

Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals

McKinlay

Vargas

Blake

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

229

271

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Functional delivery of mRNA to tissues in the body is key to implementing fundamentally new and potentially transformative strategies for vaccination, protein replacement therapy, and genome editing, collectively affecting approaches for the prevention, detection, and treatment of disease. Broadly applicable tools for the efficient delivery of mRNA into cultured cells would advance many areas of research, and effective and safe in vivo mRNA delivery could fundamentally transform clinical practice. Here we report the stepeconomical synthesis and evaluation of a tunable and effective class of synthetic biodegradable materials: charge-altering releasable transporters (CARTs) for mRNA delivery into cells. CARTs are structurally unique and operate through an unprecedented mechanism, serving initially as oligo(α-amino ester) cations that complex, protect, and deliver mRNA and then change physical properties through a degradative, charge-neutralizing intramolecular rearrangement, leading to intracellular release of functional mRNA and highly efficient protein translation. With demonstrated utility in both cultured cells and animals, this mRNA delivery technology should be broadly applicable to numerous research and therapeutic applications.

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Intradermal Vaccinations With RNA Coding for TAA Generate CD8+ and CD4+ Immune Responses and Induce Clinical Benefit in Vaccinated Patients

Cited by 193 publications

References 37 publications

Dendrimer-RNA nanoparticles generate protective immunity against lethal Ebola, H1N1 influenza, and Toxoplasma gondii challenges with a single dose

Dendrimer-RNA nanoparticles generate protective immunity against lethal Ebola, H1N1 influenza, and Toxoplasma gondii challenges with a single dose

Microvesicle Cargo of Tumor-Associated MUC1 to Dendritic Cells Allows Cross-presentation and Specific Carbohydrate Processing

Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals

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