Three decades of messenger RNA vaccine development

In the paper

“In a phase I/IIa trial of a RNactive ® -based vaccine for non-small cell lung carcinoma (NSCLC), common diagnostic indicators for autoimmunity were found to be elevated up to 20% of the patients after a RNactive ® schedule of five intradermal injections (dose of 400-1600 µg) [187].”

What the sources say

• Not checked yetcites [187] source

In the paper

“Another study testing the safety and immunogenicity of the RNactive ® platform as prophylactic vaccine against rabies, elicited a moderate case of Bell's palsy one week after a second i.m. administration of the highest dose of 640 µg (1/37 patients).”

What the sources say

• Not checked yetcites [188]

In the paper

“They demonstrated that mRNA packaged within a liposomal nanoparticle could successfully transfect mRNA into a variety of eukaryotic cells [1].”

What the sources say

• Not checked yetcites [1]

In the paper

“These preliminary data provided the first evidence that in vitro transcribed (IVT) mRNA could deliver the genetic information to produce proteins within living tissue.”

In the paper

“As pioneers, Martinon et al. showed that liposomes containing mRNA encoding the influenza virus nucleoprotein elicited virus-specific cytotoxic T lymphocytes (CTLs) [3].”

What the sources say

• Not checked yetcites [3] source

In the paper

“Conry et al. demonstrated the activation of humoral immune responses, as they confirmed that a prophylactic vaccine consisting of mRNA encoding a carcinoembryonic antigen resulted in the induction of anti-tumoral antibody responses [4].”

What the sources say

• Not checked yetcites [4]

In the paper

“A few months later, Wolff et al. reported on their experiments where 'naked', unprotected mRNA was directly administrated in the muscle of mice.”

What the sources say

• Not checked yetcites [2]

In the paper

“In small and large animal models, mRNA vaccines were able to elicit immunity against emerging infections such as zika, ebola and HIV [19][20][21][22][23].”

What the sources say

• Not checked yetcites [19][20][21][22][23]

In the paper

“By comparison with protein-based vaccines, it was recently found that the extended antigen availability that can be obtained via mRNA had a profound effect on the magnitude and the affinity maturation of antibody responses, resulting in a more durable protection [11][12][13].”

What the sources say

• Not checked yetcites [11][12][13]

In the paper

“Interestingly, they found that the strongly reduced immune-modulatory capacity of endogenous mRNA could be attributed to the presence of modified nucleotides in the mRNA construct, such as methylated nucleosides or pseudouridine.”

In the paper

“Alternatively, tandem constructs can be engineered which connect multiple antigenic epitopes within a single mRNA strand.”

In the paper

“For instance, the replacement of uridine with pseudouridine in IVT mRNA was found to reduce the activity of 2'-5'-oligoadenylate synthetase, which regulates the mRNA cleavage by RNase L.”

In the paper

“In a therapeutic setting, Kormann et al., demonstrated that nucleoside-modified mRNA encoding erythropoietin (Epo), in which 25% thio-uridine and 25% 5-methylcytidine was incorporated, resulted in five times higher Epo levels compared to untreated mice, two weeks after i.m. administration.”

What the sources say

• Not checked yetcites [44] source

In the paper

“With respect to vaccination purposes, one should consider that the modifications that favour the mRNA's translation capacity involve a partial or complete reduction of the interaction between mRNA molecules and one or multiple virusspecific PRRs [66].”

What the sources say

• Not checked yetcites [66]

In the paper

“Furthermore, mRNA has the advantage of offering a high degree of versatility in the type and number of antigenic determinants it encodes.”

In the paper

“In this context, prophylactic mRNA vaccines were already considered safe and effective in phase I clinical trials for infectious diseases, such as influenza and rabies [16][17][18].”

What the sources say

• Not checked yetcites [16][17][18]

In the paper

“In the early 2000s, mRNA delivery was shown to trigger an antiviral activation state in DCs, which involves the recognition of single-stranded RNA through TLR7 and TLR8 located in the endosomes [30,31].”

What the sources say

• Not checked yetcites [30]
• Not checked yetcites [31]

In the paper

“Using this strategy, the company BioNTech AG has developed personalized mRNAbased cancer vaccines by identifying individual and immunogenic tumor mutations and producing on-demand mRNA vaccines encoding these neo-epitopes [14].”

What the sources say

• Not checked yetcites [14]

In the paper

“In addition, modified nucleosides allowed the design of mRNA vaccines with strongly enhanced stability and translation capacity, as they could avoid the direct antiviral pathways that are induced by type IFNs and are programmed to degrade and inhibit invading mRNA [41][42][43][44][45].”

What the sources say

• Not checked yetcites [41][42][43][44][45]

In the paper

“Already in 1995, Johanning et al. found that the i.m. injection of self-amplifying mRNA derived from the Sindbis virus, resulted in a ten-fold increase in protein expression levels, which could be maintained much longer (from 2 days up to 10 days) compared to nonamplifying mRNA [51].”

What the sources say

• Not checked yetcites [51]

In the paper

“Together with an mRNA sequence against the CMV glycoprotein gB, this multiple-antigenic mRNA vaccine induced potent and durable neutralizing antibody titers in immunized mice and non-human primates [24].”

What the sources say

• Not checked yetcites [24] source

In the paper

“In similarity to viral infections, (IVT) mRNA allows the transient expression and accumulation of the selected antigens in the cytoplasm, which can then efficiently be processed into peptides and loaded in the MHC class I pathway”

In the paper

“In addition to these TLRs, dsRNA was shown to activate the cytosolic RNA sensors retinoic acid inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) [32][33][34].”

What the sources say

• Not checked yetcites [32][33][34]

In the paper

“In 2007, Probst et al. proved that somatic cells of the dermis, such as muscle cells, fibroblasts or keratinocytes, are capable of taking up β-galactosidase-coding mRNA in a saturable and iondependent manner [76].”

What the sources say

• Not checked yetcites [76]

In the paper

“This glaring discrepancy between the in vitro and in vivo delivery of mRNA was further demonstrated by Bhosle et al., who observed that completely different cellular uptake pathways were involved in vitro and in vivo, and this for both naked mRNA as well as a lipid-based nanoparticle (LNP) containing mRNA [90].”

What the sources say

• Not checked yetcites [90]

In the paper

“This key challenge of finding an optimal balance between the translation capacity and adjuvanticity of mRNA vaccines, in order to obtain adequate, but safe immunogenicity, will be discussed later on in this review (see section 4).”

In the paper

“Independent of the administration route, several evolutionary barriers are designed to prevent any intrusion of foreign nucleic acids and thus limit the delivery of exogenous mRNA [74].”

What the sources say

• Not checked yetcites [74] source

In the paper

“Alternatively, Van Lint et al. showed increased T cell stimulatory effects by the administration of a mixture of four naked mRNAs encoding an antigen and three additional immunomodulatory molecules; CD40 ligand, constitutive active TLR 4 and CD70, patented as the TriMix mRNA technology by the 'Vrije Universiteit Brussel' (VUB), and licensed to eTheRNA immunotherapies [88].”

What the sources say

• Not checked yetcites [88]

In the paper

“This was underscored by Kreiter and colleagues, who reported that the potency of an unmodified, naked mRNA vaccine to induce T cell immunity could be drastically increased by injecting it i.n.compared to injections in the skin [81].”

What the sources say

• Not checked yetcites [81]

In the paper

“More details on mRNA uptake were uncovered by Lorenz et al., who used a fibroblast cell line to demonstrate that mRNA molecules are initially recognized by scavenger receptors prior to their internalization by caveolae and lipid raft-dependent uptake mechanisms [77].”

What the sources say

• Not checked yetcites [77]

In the paper

“First of all, it was found that APCs could not be directly transfected with self-amplifying mRNA, which is significantly longer in length (10kb versus 2-3 kb for nonamplifying mRNA).”

In the paper

“As such, this might come at the cost of the adjuvant effect of the mRNA vaccine.”

In the paper

“In general, the alternative of in vivo approaches that directly target mRNA to APCs, holds a number of key benefits to ex vivo generated DC vaccines.”

In the paper

“The co-delivery of immune adjuvants, such as polyinosinic:polycytidylic acid (Poly(I:C)) and lipopolysaccharide (LPS), was found to rapidly mature the APCs, which abrogated the cellular uptake of mRNA molecules [82].”

What the sources say

• Not checked yetcites [82]

In the paper

“Moreover, anti-viral host defence mechanisms are induced by the mRNA immune recognition increasing enzymatic activities that destroy mRNA and inhibit its further cellular translation (see section 2.2) [45].”

What the sources say

• Not checked yetcites [45] source

In the paper

“Nevertheless, this inability to directly transfect APCs, did not abrogate the priming of CTLs following the i.m. delivery of a self-amplifying mRNA vaccine [85].”

What the sources say

• Not checked yetcites [85]

In the paper

“Moreover, crucial immune events, such as the release of inflammatory cytokines and chemokines, that peak within a couple of hours after transfection, can be lost in time and place when preparing ex vivo DC vaccines [72,73].”

What the sources say

• Not checked yetcites [72]
• Not checked yetcites [73]

In the paper

“After all, both outcomes are oppositely regulated by type I IFN-induced genes.”

In the paper

“One of the key barriers that affects the overall transfection efficiency, is endosomal degradation of the engulfed mRNA LNPs.”

In the paper

“They demonstrated that within the LNs, naked mRNA was predominantly taken up by resident DCs (and macrophages) via macropinocytosis [82].”

What the sources say

• Not checked yetcites [82]

In the paper

“This implies that even when intact mRNA is taken up by APCs, almost all mRNA molecules will eventually be entrapped and degraded in the endo-lysosomal compartment.”

In the paper

“Although it is clear that the choice and optimisation of a nanoparticle is essential to achieve successful mRNA transfection, it is important to realize that many studies suggest that the transfection experiments in cultured cells may not reliably predict the in vivo behaviour of mRNA formulations.”

In the paper

“In preclinical testing, the incorporation of DOPE was linked to an increased serum-induced disintegration of cationic (DNA) LNPs and thus poor in vivo transfection efficiency [110].”

What the sources say

• Not checked yetcites [110]

In the paper

“For instance, the transporter Niemann-Pick Type C-1, located on late endolysomes, was found to be responsible for the exocytosis of a large fraction of internalized (si)RNA LNPs, hence strongly reducing the cytosolic delivery [121].”

What the sources say

• Not checked yetcites [121] source

In the paper

“In addition, they could detect mature, mRNA-transfected APCs in the draining LNs.”

What the sources say

• Not checked yetcites [127] source

In the paper

“As such, (mRNA) nanovaccines have been targeted towards the C-type lectins DEC-205, CLEC9A and mannose receptor, which are also involved in pathways that favour the uptake, endocytic protection and crosspresentation of dead cell antigens [124][125][126].”

What the sources say

• Not checked yetcites [124][125][126]

In the paper

“For both administration routes, they could show a rapid recruitment of neutrophils, monocytes and different DC subsets to the injection site (skin or muscle).”

What the sources say

• Not checked yetcites [127] source

In the paper

“Although the theory of membrane fusion has been around for more than a decade, the mechanism of LNPs to promote the cytosolic delivery of mRNA cannot be reduced to merely this single aspect [120].”

What the sources say

• Not checked yetcites [120]

In the paper

“More recent studies describe that the endocytic trafficking of mRNA LNPs is a dynamic process, which involves recycling pathways and signalling pathways that affect the cytosolic entry and translation of mRNA.”

In the paper

“The skin represents a very convenient route, which can result in an immune response by two separate mechanisms: either mRNA LNPs locally transfect and activate APCs which consequently migrate to the lymphatics, or the mRNA LNPs are passively drained via the lymphatic system, thus delivering the mRNA payload directly in close proximity to LNresident APCs and T cells.”

In the paper

“By contrast, the recruitment of the mechanistic target of rapamycin complex 1 to the lysosomal membrane was key to trigger the translation of delivered mRNA [122].”

What the sources say

• Not checked yetcites [122] source

In the paper

“This core was surrounded by a lipid monolayer containing mainly the DSPC and DMPE-PEG2000 content, as well as a fraction of D-Lin-MC3-DMA and cholesterol [113].”

What the sources say

• Not checked yetcites [113] source

In the paper

“By targeting mRNA LNPs to selective surface receptors expressed by DCs, the particles may be routed into intracellular trafficking pathways that are less degradative for the mRNA cargo [123].”

What the sources say

• Not checked yetcites [123]

In the paper

“Next, during the dialysis step these particles undergo fusion as the pH is neutralized, which generates the final LNP system.”

What the sources say

• Not checked yetcites [111] source
• Not checked yetcites [112] source

In the paper

“These microfluidic devices producing LNPs in a wellcontrolled and high-throughput manner have certainly advanced the clinical translation of novel LNPs for gene delivery.”

In the paper

“However, the latter may hold true only in in vitro conditions.”

In the paper

“The skin represents a very convenient route, which can result in an immune response by two separate mechanisms: either mRNA LNPs locally transfect and activate APCs which consequently migrate to the lymphatics, or the mRNA LNPs are passively drained via the lymphatic system, thus delivering the mRNA payload directly in close proximity to LNresident APCs and T cells.”

In the paper

“Furthermore, they demonstrated that the PEG-lipid content dictates the eventual LNP size by exerting repulsive forces at the particle surface that limits further fusion.”

What the sources say

• Not checked yetcites [111] source
• Not checked yetcites [112] source

In the paper

“By contrast, mRNA LNPs with an enriched DSPC content at the surface (approaching an almost pure monolayer of DSPC) exhibited a weak transfection capacity.”

What the sources say

• Not checked yetcites [113] source

In the paper

“Another key parameter that will determine the efficacy and safety of mRNA LNPs is the choice of administration route (see Figure 5).”

In the paper

“Interestingly, by adjusting the molar ratios of the different lipids, the authors could produce mRNA LNPs with varying surface characteristics.”

What the sources say

• Not checked yetcites [113] source

In the paper

“By contrast, the unsaturated phospholipid DOPE facilitates the formation of a non-lamellar lipid phase (i.e.inverted hexagonal phase), which was found to contribute to the endosomal escape [109].”

What the sources say

• Not checked yetcites [109]

In the paper

“They found that LNP compositions that favour a partial segregation of D-Lin-MC3-DMA lipids from the internal core to the outer surface, correlated with an increased transfection efficiency.”

What the sources say

• Not checked yetcites [113] source

In the paper

“By contrast, the unsaturated phospholipid DOPE facilitates the formation of a non-lamellar lipid phase (i.e.inverted hexagonal phase), which was found to contribute to the endosomal escape [109].”

What the sources say

• Not checked yetcites [109]

In the paper

“In general, i.v.injected nanoparticles are known to react with opsonic blood proteins, such as complement fragments, immunoglobulins, and fibronectin, which facilitates uptake by phagocytic cells, hence nanoparticle clearance [146,147].”

What the sources say

• Not checked yetcites [146]
• Not checked yetcites [147]

In the paper

“As example, Akinc et al. found that the selective adsorption of apolipoprotein E onto an ionizable (neutral) LNP was responsible for the specific and potent delivery of (si)RNA to hepatocytes through receptor mediated endocytosis [156].”

What the sources say

• Not checked yetcites [156] source

In the paper

“PEGylation accelerates the drainage of (lipid) nanoparticles into the lymphatic system, while targeting ligands such as mannose and antibodies against selective DC receptors can increase the entrapment of liposomes inside draining LNs [131][132][133].”

What the sources say

• Not checked yetcites [131][132][133]

In the paper

“Importantly, the amount and identity of the individual proteins present in this biomolecular corona will depend on both the (”

What the sources say

• Not checked yetcites [138]

In the paper

“Based on prior reports, particle size is a critical factor to obtain efficient lymphatic transport of nanoparticles.”

What the sources say

• Not checked yetcites [128][129][130]

In the paper

“To give an example of an optimized mRNA LNP for lymphatic transport, Wang et al. generated a nanoparticle system consisting of a pre-condensed core of mRNA and calcium phosphate, stabilized by DOPA and coated by a lipid shell of DOTAP and DSPE-PEG [135].”

What the sources say

• Not checked yetcites [135] source

In the paper

“In addition, studies suggested that PEGylation is required to prevent a complete immobilization of the particles in the extracellular matrix (ECM) of the skin, explained by the fact that ECM components, such as glycosaminoglycans can inhibit both the distribution and cellular uptake of non-PEGylated LNPs at the injection site [134].”

What the sources say

• Not checked yetcites [134]

In the paper

“It is beyond any doubt that particle features such as size, surface charge, and structural conformation might drastically change once the mRNA LNPs enter the bloodstream.”

In the paper

“Indeed, the interaction of (mRNA) nanoparticles with biological fluids, gives rise to the adsorption of endogenous proteins and other biomolecules to the particular surface, resulting in the formation of a biomolecular or protein corona [138].”

What the sources say

• Not checked yetcites [138]

In the paper

“Schöttler et al. demonstrated that PEGylated nanoparticles evade the macrophage system, not only by lowering the deposition of complement fragments and immunoglobulins on the nanoparticle surface, but rather by a selective higher presence of clusterin that functions as a strong dysopsonin [143].”

What the sources say

• Not checked yetcites [143]

In the paper

“In addition, studies suggested that PEGylation is required to prevent a complete immobilization of the particles in the extracellular matrix (ECM) of the skin, explained by the fact that ECM components, such as glycosaminoglycans can inhibit both the distribution and cellular uptake of non-PEGylated LNPs at the injection site [134].”

What the sources say

• Not checked yetcites [134]

In the paper

“PEGylation accelerates the drainage of (lipid) nanoparticles into the lymphatic system, while targeting ligands such as mannose and antibodies against selective DC receptors can increase the entrapment of liposomes inside draining LNs [131][132][133].”

What the sources say

• Not checked yetcites [131][132][133]

In the paper

“The creation of a biomolecular corona causes the exposure of self-epitopes, to which naturally occurring antibodies can bind.”

In the paper

“For one, cholesterol is typically used to increase the rigidity of LNPs (i.e.reducing the permeability of the lipid membrane), and therefore contributes to improved LNP stability and integrity in the presence of serum [110,142].”

What the sources say

• Not checked yetcites [110]
• Not checked yetcites [142]

In the paper

“This can lead to severe autoimmune consequences, such as systemic lupus erythematosus and diabetes.”

In the paper

“Of note, the Dan Peer lab recently proposed a modular targeting platform for the selective delivery of (si)RNA LNPs to diverse leukocytes in vivo.Here, the conjugation of targeting antibodies was based on the incorporation of a lipoprotein inside the LNP system that non-covalently binds to the Fc domain of a selected targeting antibody [161,162].”

What the sources say

• Not checked yetcites [161]
• Not checked yetcites [162]

In the paper

“However, it should be noted that the incorporation of a targeting ligand adds an extra layer of complexity to the LNP system, involving additional synthetic steps, costs and regulatory hurdles [163].”

What the sources say

• Not checked yetcites [163]

In the paper

“Where type I IFN is highly valuable to trigger an effective T cell response, other papers showed that an early type I IFN response inhibits the expression of antigen-encoding mRNA, which was rather detrimental for the mRNA vaccine's outcome [165][166][167].”

What the sources say

• Not checked yetcites [165][166][167]

In the paper

“Additionally, the robust and sustained antigen expression of nucleoside-modified mRNA was associated with more optimal antibody responses compared to unmodified mRNA [12,13].”

What the sources say

• Not checked yetcites [12] source
• Not checked yetcites [13] source

In the paper

“By contrast, in case of a different timeframe, where the interaction between APCs and T cells is delayed or even absent, type I IFNs have completely opposite effects: rather than stimulating T cells, they activate an antiproliferative and pro-apoptotic programme [168].”

What the sources say

• Not checked yetcites [168]

In the paper

“Importantly, type I IFNs directly act as a signal 3 cytokine for T cell activation, promoting the clonal expansion, survival and effector differentiation of both CTLs and T helper cells [168,172,176].”

What the sources say

• Not checked yetcites [168]
• Not checked yetcites [172]
• Not checked yetcites [176]

In the paper

“In general, acute type I IFN responses mediate pleotropic and pro-inflammatory effects in both innate and adaptive immune cells [36,[168][169][170][171].”

What the sources say

• Not checked yetcites [36]

In the paper

“This finding of specifically targeting anionic mRNA LNPs to the spleen could be confirmed in a patient participating in a phase I trial for melanoma [159].”

What the sources say

• Not checked yetcites [159]

In the paper

“De Beuckelaer and colleagues demonstrated that the efficacy to evoke (CTL) antitumor immune responses in a B16 melanoma model of s.c. or i.d.administered DOTAP-DOPE mRNA LNPs, was strongly increased after type I IFN blockade [165].”

What the sources say

• Not checked yetcites [165] source

In the paper

“In comparison, cationic mRNA LNPs composed of a cationic lipid and cholesterol, or DOPE were found to primarily target the lungs, where they transfect tissueresident DCs, macrophages and endothelial cells [142,157,158].”

What the sources say

• Not checked yetcites [142]
• Not checked yetcites [157] source
• Not checked yetcites [158]

In the paper

“To give a few other examples, Parhiz et al. demonstrated that ionizable mRNA LNPs conjugated with antibodies against the vascular cell adhesion molecule, PECAM-1, promoted the mRNA transfection of endothelial cells in the lungs after systemic delivery [160].”

What the sources say

• Not checked yetcites [160]

In the paper

“Also, antitumor responses in a lung metastasis model were significantly impaired when tumor-bearing mice were immunized i.v. with mRNA LNPs while receiving i.p. injections with anti-IFNAR1 antibodies [92].”

What the sources say

• Not checked yetcites [92] source

In the paper

“demonstrated that the systemic type I IFN response evoked by mRNA LNPs was crucial to activate APCs and effector cells.”

What the sources say

• Not checked yetcites [92] source

In the paper

“Moreover, the targeting ability of such functionalized nanoparticles can be overruled by the deposition of endogenous proteins and the passive transport and clearance of nanoparticles [164].”

What the sources say

• Not checked yetcites [164]

In the paper

“The involvement of type I IFNs in the regulation of immune tolerance, which can promote the development of autoreactive B cells and T cells, poses an even greater threat [183][184][185].”

What the sources say

• Not checked yetcites [183][184][185]

In the paper

“Indeed, accumulating pre-clinical evidence shows that T cell responses and antitumor effects evoked by mRNA cancer therapeutics can strongly be strengthened by combining them with checkpoint inhibitors, such as anti-PD-1(L)-, and also anti-CTLA-4 antibodies [135,196,214,218,219].”

What the sources say

• Not checked yetcites [135] source
• Not checked yetcites [196]
• Not checked yetcites [214]
• Not checked yetcites [218]
• Not checked yetcites [219] source

In the paper

“To give an outstanding example, the Santangelo lab combined the delivery of fluorescentlylabelled mRNA with proximity-based assays [195].”

What the sources say

• Not checked yetcites [195]

In the paper

“Alterations in these mRNA vaccine parameters are therefore expected to impact on the role of type I IFN signalling on the mRNA vaccine's outcome, thus deciding if it is good, bad, or ugly.”

In the paper

“Excitingly, new imaging tools have been implemented in the evaluation of novel mRNA delivery systems, which allows visualization of mRNA pharmacology at the single cell and tissue level.”

What the sources say

• Not checked yetcites [90,158,[192][193][194][195]

In the paper

“For mRNA therapeutics in oncology or for cancer vaccines in general, it might not be enough to activate effector immune responses against cancer.”

In the paper

“Furthermore, Van Hoecke et al. showed that established tumors could be turned into an in situ vaccine, mediated by electroporating tumors with mRNA that codes for the mixed lineage kinase domain-like (MLKL) protein [204].”

What the sources say

• Not checked yetcites [204]

In the paper

“As such, they were able to simultaneously detect cell-specific uptake, translation and in situ activation of the TLR7, RIG-I, MDA5 pathways upon the delivery of naked-or LNP formulated mRNA in the muscle of mice [194].”

What the sources say

• Not checked yetcites [194]

In the paper

“Several studies demonstrated that mRNA cancer vaccines upregulated the expression of the checkpoint molecules programmed death 1 (PD-1) on effector T cells, and its ligand (PD-L1) on tumor cells and APCs [196,214].”

What the sources say

• Not checked yetcites [196]
• Not checked yetcites [214]

In the paper

“Stadler et al. designed mRNA constructs that encode bispecific antibodies directed against the T cell receptor associated molecule CD3 and tumor antigens, referred to as RiboMABs [197].”

What the sources say

• Not checked yetcites [197] source

In the paper

“Nevertheless, it can be expected that an mRNA vaccine that achieves high and sustained antigen availability, will benefit the magnitude and duration of both T cell and B cell responses [11,[189][190][191].”

What the sources say

• Not checked yetcites [11] source

In the paper

“In line with this, Moderna Therapeutics recently published on an anti-cancer immunotherapy, using direct intratumoral-and LNP-mediated delivery of a mixture of mRNA encoding IL-23, IL-36γ, and OX40(L) ligand [203].”

What the sources say

• Not checked yetcites [203] source

In the paper

“A first alternative to the de novo priming of adaptive immune cells, is to explore passive immunization approaches by using mRNA that directly encodes different antibody formats, including monoclonal antibodies, antibody fragments or bi-specific antibodies [197][198][199][200].”

What the sources say

• Not checked yetcites [197][198][199][200]

In the paper

“In monotherapy, checkpoint inhibitors have resulted in impressive effects and durable responses in patients with highly refractory and late-stage cancers, such as metastatic melanoma and non-small cell lung cancer (NSCLC) [216].”

What the sources say

• Not checked yetcites [216] source

In the paper

“Upon the activation of T cells, the expression of checkpoint molecules forms a strong negative feedback loop to maintain T cell responses within a desired physiologic range.”

In the paper

“However, only a subset of the patients benefits from these checkpoint therapies.”

In the paper

“A second hard-to-find balance is the one between the mRNA-encoded antigen expression and adequate immunostimulation.”

In the paper

“A number of reports have revealed that the capacity of mRNA LNPs to evoke CTL responses strongly depended on the production of type I IFNs.”

In the paper

“More specifically, although the mRNA-induced type I IFN response might add to the immunogenicity of the mRNA vaccine, it also interferes with the mRNA-encoded antigen expression and possibly even lead to deleterious immune effects.”

In the paper

“More specifically, although the mRNA-induced type I IFN response might add to the immunogenicity of the mRNA vaccine, it also interferes with the mRNA-encoded antigen expression and possibly even lead to deleterious immune effects.”