RNA as a tumor vaccine: a review of the literature
TL;DR: The possible utility of RNA‐based vaccines for tumor immunotherapy should be further explored to determine whether such approaches are clinically useful.
Abstract: Many approaches have been attempted to harness the host immune system to act against malignant tumors. These have included animal and clinical trials with agents to non-specifically boost immunity, factors to augment specific immunity, transfer of lymphokine-activated killer cells and transfer of expanded populations of tumor-infiltrating lymphocytes. Therapeutic vaccination strategies have been employed using tumor extracts, purified tumor antigens, recombinant peptide tumor antigens and specific DNA sequences coding for a tumor antigen (genetic vaccination) both through direct administration to the host and by administration of antigen presenting cells exposed to these materials ex vivo. Recently, the use of RNA has been proposed for use in tumor vaccination protocols. The use of RNA has several potential advantages. Since total cellular RNA or mRNA can be utilized, it is not necessary to know the molecular nature of the putative tumor antigen(s). RNA can be effectively amplified; thus, unlike tumor-extract vaccines, only a small amount of tumor is needed to prepare the material for vaccination. Also, unlike DNA-based vaccines, there is little danger of incorporation of RNA sequences into the host genome. The possible utility of RNA-based vaccines for tumor immunotherapy should be further explored to determine whether such approaches are clinically useful.
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TL;DR: Immunization with mRNA‐transfected DCs is a promising strategy to stimulate potent antitumor immunity and could serve as a foundation for developing effective treatments for cancer.
Abstract: Bone marrow-derived dendritic cells (DCs) are the most potent antigen-presenting cells capable of activating naive T cells. Loading DCs ex vivo with tumor antigens can stimulate potent antitumor immunity in tumor-bearing mice. This review describes the use of mRNA-encoded tumor antigens as a form of antigen loaded onto DCs, including our early experience from clinical trials in urological cancers. Transfection of DCs with mRNA is simple and effective. Comparative studies suggest that mRNA transfection is superior to other antigen-loading techniques in generating immunopotent DCs. The ability to amplify RNA from microscopic amounts of tumor tissue extends the use of DC vaccination to virtually every cancer patient. The striking observation from two phase I clinical trials, in patients with prostate cancer immunized with prostate-specific antigen mRNA-transfected DCs and patients with renal cancer immunized with autologous tumor RNA-transfected DCs, was that the majority of patients exhibited a vaccine-induced T-cell response. Suggestive evidence of clinically related responses was seen in both the trials. Immunization with mRNA-transfected DCs is a promising strategy to stimulate potent antitumor immunity and could serve as a foundation for developing effective treatments for cancer.
384 citations
Cites background from "RNA as a tumor vaccine: a review of..."
...Despite the fact that mRNA transfection was successfully used for ectopic gene expression in mammalian cells (4), the initial reports describing the immunostimulatory capacity of mRNA-transfected DCs were met with healthy skepticism, reflecting to some extent a myth that RNA is extremely labile and could not withstand the transfection protocols....
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TL;DR: This review offers a comprehensive overview of current knowledge of the major theoretical as well as practical aspects of mRNA-mediated transfection, showing both its possibilities and its pitfalls and should therefore be useful for a diverse scientific audience.
289 citations
Cites background from "RNA as a tumor vaccine: a review of..."
...Moreover, when considering vaccination against infectious diseases, genetic vaccinations eliminate the risk of mutation and uncontrollable proliferation of inactivated pathogens [109]....
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TL;DR: It is reported here that injection of naked β-globin untranslated region (UTR)-stabilized mRNA coding for β-galactosidase is followed by detectable translation in vivo, and it is shown that such a vaccination strategy primes a T helper 2 type of response which can be enhanced and shifted to a Th1-type immune response by application of recombinant granulocyte/macrophage colony-stimulating factor 1 day after mRNA injection.
Abstract: In the context of developing a safe genetic vaccination strategy we tested and studied globin-stabilized mRNA-based vaccination in mice. This vaccination strategy has the advantages of genetic vaccination (easy production, adaptability to any disease and inexpensive storage when lyophilized), but not the drawbacks of DNA vaccination (long-term uncontrolled expression of a transgene, possibility of integration into the host genome and possible induction of anti-DNA antibodies). We report here that injection of naked β-globin untranslated region (UTR)-stabilized mRNA coding for β-galactosidase is followed by detectable translation in vivo. In addition, we show that such a vaccination strategy primes a T helper 2 (Th2) type of response which can be enhanced and shifted to a Th1-type immune response by application of recombinant granulocyte/macrophage colony-stimulating factor 1 day after mRNA injection. Our data demonstrate that the administration of globin UTR-stabilized mRNA is a versatile vaccination strategy that can be manipulated to fit the requirement of antiviral, antibacterial or antitumor immunity.
208 citations
Patent•
03 Oct 2012
TL;DR: The present disclosure provides modified nucleosides, nucleotides, and nucleic acids, and methods of using them as discussed by the authors, as well as a detailed discussion of their properties.
Abstract: The present disclosure provides modified nucleosides, nucleotides, and nucleic acids, and methods of using them.
194 citations
Patent•
30 Sep 2009
TL;DR: In this paper, an immunostimulatory composition comprising an adjuvant component, comprising or consisting of at least one (m)RNA, complexed with a cationic or polycationic compound, and encoding at least 1 therapeutically active protein, antigen, allergen and/or antibody, is described, which is capable to elicit or enhance an innate and optionally an adaptive immune response in a mammal.
Abstract: The present invention relates to an immunostimulatory composition comprising a) an adjuvant component, comprising or consisting of at least one (m)RNA, complexed with a cationic or polycationic compound, and b) at least one free mRNA, encoding at least one therapeutically active protein, antigen, allergen and/or antibody, wherein the immunostimulatory composition is capable to elicit or enhance an innate and optionally an adaptive immune response in a mammal. The inventive immunostimulatory composition may be a pharmaceutical composition or a vaccine. The invention furthermore relates to a method of preparation of the inventive immunostimulatory composition. The invention also relates to the use of the inventive immunostimulatory composition or its components (for the preparation of a pharmaceutical composition or a vaccine) for the treatment of various diseases. Finally, the invention relates to kits containing the inventive immunostimulatory composition, its components and/or the pharmaceutical composition or vaccine.
191 citations
References
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TL;DR: Dendritic cells are specialized to mediate several physiologic components of immunogenicity such as the acquisition of antigens in tissues, the migration to lymphoid organs, and the identification and activation of antigen-specific T cells.
Abstract: Dendritic cells are a system of antigen presenting cells that function to initiate several immune responses such as the sensitization of MHC-restricted T cells, the rejection of organ transplants, and the formation of T-dependent antibodies. Dendritic cells are found in many nonlymphoid tissues but can migrate via the afferent lymph or the blood stream to the T-dependent areas of lymphoid organs. In skin, the immunostimulatory function of dendritic cells is enhanced by cytokines, especially GM-CSF. After foreign proteins are administered in situ, dendritic cells are a principal reservoir of immunogen. In vitro studies indicate that dendritic cells only process proteins for a short period of time, when the rate of synthesis of MHC products and content of acidic endocytic vesicles are high. Antigen processing is selectively dampened after a day in culture, but the capacity to stimulate responses to surface bound peptides and mitogens remains strong. Dendritic cells are motile, and efficiently cluster and activate T cells that are specific for stimuli on the cell surface. High levels of MHC class-I and -II products and several adhesins, such as ICAM-1 and LFA-3, likely contribute to these functions. Therefore dendritic cells are specialized to mediate several physiologic components of immunogenicity such as the acquisition of antigens in tissues, the migration to lymphoid organs, and the identification and activation of antigen-specific T cells. The function of these presenting cells in immunologic tolerance is just beginning to be studied.
4,872 citations
"RNA as a tumor vaccine: a review of..." refers background in this paper
...Dendritic cells (DCs) are known to have a crucial role in the activation of T- and Bcell immunity (10)....
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TL;DR: RNA and DNA expression vectors containing genes for chloramphenicol acetyltransferase, luciferase, and beta-galactosidase were separately injected into mouse skeletal muscle in vivo and expression was comparable to that obtained from fibroblasts transfected in vitro under optimal conditions.
Abstract: RNA and DNA expression vectors containing genes for chloramphenicol acetyltransferase, luciferase, and beta-galactosidase were separately injected into mouse skeletal muscle in vivo. Protein expression was readily detected in all cases, and no special delivery system was required for these effects. The extent of expression from both the RNA and DNA constructs was comparable to that obtained from fibroblasts transfected in vitro under optimal conditions. In situ cytochemical staining for beta-galactosidase activity was localized to muscle cells following injection of the beta-galactosidase DNA vector. After injection of the DNA luciferase expression vector, luciferase activity was present in the muscle for at least 2 months.
4,022 citations
"RNA as a tumor vaccine: a review of..." refers background in this paper
...The first indication that mRNA could be used without a protective liposome came in 1990 when Wolff and colleagues (42) injected naked mRNA for luciferase, ß-galactosidase and chloramphenicol acetyltransferase directly into muscle and demonstrated gene expression for several days....
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...The translation of exogenous RNA into antigen has been shown in dendritic cells (59) and in myocytes (42, 43)....
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...ELISA testing of antigen production (38), b-gal tissue staining (8), luciferase activity measurement (42) have all shown that injected mRNA for a particular protein results in increased production of that specific protein....
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TL;DR: Vaccination with autologous DCs generated from peripheral blood is a safe and promising approach in the treatment of metastatic melanoma and antigen-specific immunity was induced during DC vaccination.
Abstract: Melanoma is the main cause of death in patients with skin cancer1. Cytotoxic T lymphocytes (CTLs) attack melanoma cells in an HLA-restricted and tumor antigen-specific manner. Several melanoma-associated tumor antigens have been identified2. These antigens are suitable candidates for a vaccination therapy of melanoma. Dendritic cells (DCs) are antigen-presenting cells (APCs) specialized for the induction of a primary T-cell response3. Mouse studies have demonstrated the potent capacity of DCs to induce antitu-mor immunity4–11. In the present clinical pilot study, DCs were generated in the presence of granulocyte/macrophage-colony stimulating factor (GM-CSF) and interleukin 4 (IL-4) and were pulsed with tumor lysate or a cocktail of peptides known to be recognized by CTLs, depending on the patient's HLA haplotype. Keyhole limpet hemocyanin (KLH) was added as a CD4 helper antigen and immunological tracer molecule. Sixteen patients with advanced melanoma were immunized on an outpatient basis. Vaccination was well tolerated. No physical sign of autoimmunity was detected in any of the patients. DC vaccination induced de-layed-type hypersensitivity (DTH) reactivity toward KLH in all patients, as well as a positive DTH reaction to peptide-pulsed DCs in 11 patients. Recruitment of peptide-specific CTLs to the DTH challenge site was also demonstrated. Therefore, antigen-specific immunity was induced during DC vaccination. Objective responses were evident in 5 out of 16 evaluated patients (two complete responses, three partial responses) with regression of metastases in various organs (skin, soft tissue, lung, pancreas) and one additional minor response. These data indicate that vaccination with autologous DCs generated from peripheral blood is a safe and promising approach in the treatment of metastatic melanoma. Further studies are necessary to demonstrate clinical effectiveness and impact on the survival of melanoma patients.
2,993 citations
TL;DR: The results have important implications for the clinical use of genetically modified tumor cells as therapeutic cancer vaccines and the levels of anti-tumor immunity reported previously in cytokine gene transfer studies involving live, transduced cells could be achieved through the use of irradiated cells alone.
Abstract: To compare the ability of different cytokines and other molecules to enhance the immunogenicity of tumor cells, we generated 10 retroviruses encoding potential immunomodulators and studied the vaccination properties of murine tumor cells transduced by the viruses. Using a B16 melanoma model, in which irradiated tumor cells alone do not stimulate significant anti-tumor immunity, we found that irradiated tumor cells expressing murine granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulated potent, long-lasting, and specific anti-tumor immunity, requiring both CD4+ and CD8+ cells. Irradiated cells expressing interleukins 4 and 6 also stimulated detectable, but weaker, activity. In contrast to the B16 system, we found that in a number of other tumor models, the levels of anti-tumor immunity reported previously in cytokine gene transfer studies involving live, transduced cells could be achieved through the use of irradiated cells alone. Nevertheless, manipulation of the vaccine or challenge doses made it possible to demonstrate the activity of murine GM-CSF in those systems as well. Overall, our results have important implications for the clinical use of genetically modified tumor cells as therapeutic cancer vaccines.
2,844 citations
Additional excerpts
...The use of GM-CSF as an adjuvant to peptide and DNA vaccines has been shown to have an enhancing anti-tumor effect in human and mice tumor models (50, 52)....
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TL;DR: It is shown that human dendritic cells, but not macrophages, efficiently present antigen derived from apoptotic cells, stimulating class I-restricted CD8+ CTLs, suggesting a mechanism by which potent APCs acquire antigens from tumours, transplants, infected cells, or even self-tissue, for stimulation or tolerization of C TLs.
Abstract: CD8+ cytotoxic T lymphocytes (CTLs) mediate resistance to infectious agents and tumours. Classically, CTLs recognize antigens that are localized in the cytoplasm of target cells, processed and presented as peptide complexes with class I molecules of the major histocompatibility complex (MHC). However, there is evidence for an exogenous pathway whereby antigens that are not expected to gain access to the cytoplasm are presented on MHC class I molecules. The most dramatic example is the in vivo phenomenon of cross-priming: antigens from donor cells are acquired by bone-marrow-derived host antigen-presenting cells (APCs) and presented on MHC class I molecules. Two unanswered questions concern the identity of this bone-marrow-derived cell and how such antigens are acquired. Here we show that human dendritic cells, but not macrophages, efficiently present antigen derived from apoptotic cells, stimulating class I-restricted CD8+ CTLs. Our findings suggest a mechanism by which potent APCs acquire antigens from tumours, transplants, infected cells, or even self-tissue, for stimulation or tolerization of CTLs.
2,437 citations
"RNA as a tumor vaccine: a review of..." refers background in this paper
...Previous studies have shown that apoptotic cells are more readily taken up by DCs (44)....
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