mrna vaccine for cancer immunotherapy

LM is currently a full time employee of Gilead and this article is not related to the underlying work at Gilead and it is with the approval of Gilead. The dual effect of Type I IFNs on CD8+ T cell immunity have been extensively reviewed elsewhere [21]. Zhang R, Tang L, Tian Y, Ji X, Hu Q, Zhou B, et al. have used design of experiment (DOE) to investigate the impact of ionizable lipid ratios, the type of helper lipids on the mRNA delivery efficiency [97]. As mentioned in section 2, phage polymerase in IVT can yield multiple contaminants, including short RNAs generated from abortive initiation event and dsRNA produced by self-complementary 3 extension [46]. 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)) and cholesterol are incorporated to improve lipid bilayer stability, aid membrane fusion and endosomal escape. Moderna says personalized mRNA cancer vaccine is effective for advanced melanoma The company said that in a phase 2 clinical trial, the vaccine, when combined with immunotherapy drug. In one clinical study, a DC-based mRNA vaccination composed of a mixture of TAAs were administrated together with DCs electroporated with mRNA encoding CD70, CD40 ligand (CD40L), and constitutively active TLR4 (TriMix). During vaccination, naked or vehicle loaded mRNA vaccines efficiently express tumor antigens in antigen-presenting cells (APCs), facilitate APC activation and innate/adaptive immune stimulation. Emerging Immunotherapies against Novel Molecular Targets in Breast Cancer. Moreover, bio-reducible poly (CBA-co-4-amino-1-butanol) (pABOL), developed by Blakeny et al., were used to deliver haemagglutinin-(HA-) encoding SAM in mice [69]. 2020:18. New findings may explain why mRNA vaccines provide limited protection A SARS-CoV-2 mRNA vaccine - preliminary report. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Son S, Nam J, Zenkov I, Ochyl LJ, Xu Y, Scheetz L, et al. Udhayakumar VK, De Beuckelaer A, McCaffrey J, McCrudden CM, Kirschman JL, Vanover D, et al. All authors read and approved the final manuscript. UTRs can impact mRNA degradation rate and translation efficiency through interacting with RNA binding proteins. The previous phase I study showed a median overall survival of 35months and progression-free survival of 31months [143]. Moreover, the sequence can be optimized to have the same ratio of every codons found naturally in highly expressed proteins in the targeted cells or to use the best pairs of codons that are commonly seen in these highly expressed proteins. Rittig SM, Haentschel M, Weimer KJ, Heine A, Muller MR, Brugger W, et al. Multifunctional CD8+ T-cell responses were detected either elicited by TriMixDC-MEL IPI or on subsequent pembrolizumab treatment, may provide a benchmark for the level of immune stimulation needed to achieve a durable clinical remission. A similar LPR platform is currently being evaluated in phase I clinical trial carrying mRNA encoding neoantigens to treat metastatic melanoma by Stemirna Therapeutics. In vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight. Cationic cell-penetrating peptides (CPPs) can complex with RNA. injection of mRNA to induce optimal immunogenicity [54]. Design, assembly, production, and transfection of synthetic modified mRNA. One well-known example of mRNA vaccine platform falls into this category is Lipo-MERIT [141]. In recent decades, we have witnessed the development of different kinds of mRNAs by sequence optimization to overcome the disadvantage of excessive mRNA immunogenicity, instability and inefficiency. The mRNA CNE vaccine was well tolerated and immunogenic in a variety of models. Therapeutic cancer vaccines: past, present, and future. Immunostimulants are commonly cytokines or chemokines that induce APC maturation and activation, activate T-cell mediated immunity and adjust the dysfunctional immune tumor microenvironment (Table (Table1).1). mRNA transfection by a Xentry-protamine cell-penetrating peptide is enhanced by TLR antagonist E6446. Incorporating a personalized mRNA vaccine, designed to match an individual's tumor genetics, into standard immunotherapy substantially boosts survival rates and reduces the recurrence of high-risk skin cancers in patients who have had these malignancies removed. Med Sci Monit. mRNA vaccines have been applied to treat aggressive, less accessible and metastatic solid tumors, including non-small cell lung cancers (NSCLC), colorectal carcinoma (CRC), melanoma, etc. Degradable lipid nanoparticles with predictable in vivo siRNA delivery activity. Finn JD, Smith AR, Patel MC, Shaw L, Youniss MR, van Heteren J, et al. Bethesda, MD 20894, Web Policies For early proof of concept studies, mRNA vaccine has also been tested in treating glioblastoma. Structural changes in the headgroup-linker region also affect the ionization behavior of the headgroup and the orientation of the alkyl chains [78]. . Ultimately, binding of dsRNA with MDA-5 and TLR-3 can activate Type I IFN, eliciting several other genes that inhibit the translation of mRNA [20]. The role of immune subtyping in glioma mRNA vaccine development Kariko et al. One product is mRNA-2416, using mRNA encoding OX40L, either dosed alone or in combination with i.v. Even if the antigen is immunogenic, a suppressive microenvironment could prevent effective T cells infiltration and cause T cell exhaustion. The combination therapy resulted in an encouraging rate of tumor responses in patients with stage III or IV melanoma [58]. Zeng C, Zhang C, Walker PG, Dong Y. Formulation and delivery technologies for mRNA vaccines. The other product is mRNA-2752, which is composed of OX40L/IL-23/IL-36 mRNAs for treatment of lymphoma ({"type":"clinical-trial","attrs":{"text":"NCT03739931","term_id":"NCT03739931"}}NCT03739931). Cancer vaccines are an attractive alternative immunotherapeutic option with both prophylactic and therapeutic potentials. Careers, Unable to load your collection due to an error. Visualizing lipid-formulated siRNA release from endosomes and target gene knockdown. Biodegradable lipids enabling rapidly eliminated lipid nanoparticles for systemic delivery of RNAi therapeutics. or intranodally as anti-cancer vaccine or ex vivo loaded into DCs for cancer vaccinations. The most widely used in vitro post-translational capping enzymatic method is the Vaccinia capping system, which is based on the Vaccinia virus Capping Enzyme (VCE) [27]. Van Nuffel AM, Wilgenhof S, Thielemans K, Bonehill A. Overcoming HLA restriction in clinical trials: immune monitoring of mRNA-loaded DC therapy. Lastly, as a therapeutic vaccine for treating a chronic disease like cancer, multiple/repeatable dosing with higher dosage than prophylactic vaccines is required, raising the safety criteria for both mRNAs and the carriers. Emerging . delivery of siRNAs and mRNAs are between 6.26.5 as screened and confirmed by Jayaraman and Sabnis et al. J Immunother Cancer. Beissert T, Perkovic M, Vogel A, Erbar S, Walzer KC, Hempel T, et al. Miao et al. It uses the same mRNA technology as most Covid vaccines and operates on the same principle . A trans-amplifying RNA vaccine strategy for induction of potent protective immunity. Cancer Immunology Research. In addition, the lipid excipients used to deliver mRNA should be metabolizable and cleared rapidly, thus decreasing the potential systemic toxicity elicited from the vehicles and to allow for repeatable dosing. Therefore, a natural Cap-1 structure is preferred. Although SAMs are an appealing alternative to mRNA-based vaccine due to their inherent self-amplifying property, clinical investigation for cancer applications is only limited to early evaluation of VRPs. Recent study by Lima and coworkers found that shorter poly(A) sequence could promote this closed-loop structure for efficient translation [41]. Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors. Randomized, double-blind, phase 1 trial of an alphavirus replicon vaccine for cytomegalovirus in CMV seronegative adult volunteers. Tumor antigens are highly variable across different individuals, and some are less immunogenic and can invade the recognition by the host immune system. Jayaraman M, Ansell SM, Mui BL, Tam YK, Chen JX, Du XY, et al. Exogeneous IVT mRNA is intrinsically immunostimulatory, as it is recognized by a variety of cell surface, endosome and cytosolic PRRs [11]. These studies revealed several immune subtypes of glioma, each one linked to unique prognoses and genetic/immune-modulatory changes . Received 2021 Jan 7; Accepted 2021 Feb 16. These PRRs can sense different RNAs, including dsRNA and single stranded RNA (ssRNA), blocking mRNA translation as reviewed elsewhere [17]. For example, the optimal length of poly(A) in human monocyte-derived DCs are 120150 nucleotides, in human primary T cells are 300 nucleotides [17]. These immunostimulants are not considered as cancer vaccines, but are usually co-administered with cancer vaccines or other immunotherapeutic agents (e.g. A neutral lipid envelope-type nanoparticle composed of a pH-activated and vitamin E-scaffold lipid-like material as a platform for a gene carrier targeting renal cell carcinoma. Geall AJ, Verma A, Otten GR, Shaw CA, Hekele A, Banerjee K, et al. administration was similar to a viral vector. The ratio of cationic lipid and DOPE can be tuned to selectively target splenic APCs for mRNA vaccine delivery [18]. Individualised mRNA vaccine shows promise in pancreatic cancer patients DOTAP containing liposomes were also used as a shell for encapsulating mRNA in core-shell structures. In addition, DOTAP containing cationic CNE, which is derived from the Novartiss first FDA approval CNE MF-59 have been used for mRNA delivery. Twelve out of thirteen patients treated by monotherapy were reported to be disease-free [148]. to deliver mRNA into DC through micropinocytosis. Recent promising preclinical and clinical results that epitomize the advancement in mRNA and nanoformulation-based delivery technologies have highlighted the tremendous potential of mRNA in cancer immunotherapy. Once, twice, three times a finding: reproducibility of dendritic cell vaccine trials targeting Cytomegalovirus in Glioblastoma. and transmitted securely. Kariko K, Muramatsu H, Ludwig J, Weissman D. Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, protein-encoding mRNA. The vaccination was very well tolerated. The highest liver distribution was observed when 0.75% of C18-PEG1000 were incorporated into C12200 LNP formulations [98]. Guo C, Manjili MH, Subjeck JR, Sarkar D, Fisher PB, Wang XY. These SLPs were shown to induce both CD4+ T cells and CD8+ T cells response. In one clinical study ({"type":"clinical-trial","attrs":{"text":"NCT02410733","term_id":"NCT02410733"}}NCT02410733), the mRNA vaccine (BNT111) encoding four TAAs (NY-ESO-1, MAGE-A3, tyrosinase, and TPTE) was evaluated in patients bearing advanced melanoma. 2023 Jun 13;22(1):94. doi: 10.1186/s12943-023-01797-9. In addition to chemical modifications of the ionizable lipids, formulation of LNPs were also optimized to potentiate antigen expression and adaptive immune response. To further improve the potency of mRNA anticancer vaccines, multiple clinical trials are ongoing to evaluate the combination of mRNA vaccines with either cytokine therapies or checkpoint inhibitor therapies. With the recent U.S. Food and Drug Administration (FDA) approvals of LNP-loaded mRNA vaccines for the prevention of COVID-19 and the promising therapeutic outcomes of mRNA cancer vaccines achieved in several clinical trials against multiple aggressive solid tumors, we envision the rapid advancing of mRNA vaccines for cancer immunotherapy in the near future. injection [69]. IVT has been commonly used for synthesizing both non-replicating mRNA (modified and unmodified) and SAMs. In some cases, CD4+ T cell-mediated immune response is partially involved and required, whereas CD8+ cytotoxic T cells play crucial roles in the clearance of malignant cells with somatic mutations. Neoantigens are derived from random somatic mutations in tumor cells and not present in normal cells. This additional antigen boost causes . LH is a consultant for PDS Biotechnology, Samyang Biopharmaceuticals, and Stemirna Therapeutics. injection. Vaccinia capping system provides a near 100% capping efficiency with proper orientation, but efficient expression and purification for VCE are required for large scale capped RNA production [29]. Systemic inflammation may be a major concern for mRNA vaccines due to its intrinsic immunostimulant-like function to activate the TLR7/8 pathway and to induce the type I IFN responses. With the recent U.S. FDAs approval of two mRNA-based vaccines from Pfizer-BioNTech and Moderna for emergency use in COVID-19 prevention, the mRNA vaccine field will encompass a dramatic rise in the market value and will attract widespread interest in both cancer and infectious disease applications [14, 15]. Gilleron J, Querbes W, Zeigerer A, Borodovsky A, Marsico G, Schubert U, et al. Furthermore, D-amino acid-based truncated protamine was fused with a short CPP called Xentry. Cancer immunotherapies aim to activate the host anti-tumor immunity, modify the suppressive tumor microenvironment and ultimately result in tumor reduction and increased overall patients survival rate. Up to now, over twenty mRNA-based immunotherapies have entered clinical trials with some promising outcomes in solid tumor treatments. CNN An experimental personalized mRNA vaccine in combination with the immunotherapy Keytruda reduced the risk of recurrence or death from melanoma in patients who had already had surgery,. Brito LA, Kommareddy S, Maione D, Uematsu Y, Giovani C, Berlanda Scorza F, et al. The rationale behind mRNA as an appealing cancer vaccination platform is to deliver the transcript of interest(s), encoding one or more TAAs or TSAs, into the host cell (typically APCs) cytoplasm, to be expressed into the targeted antigen(s). Clinical applications of SAM (delivered by VRPs and LNPs) in the prevention of infectious disease are promising, which have been extensively reviewed elsewhere by Bloom et al. On the other side, mRNA is non-infectious and non-integrating, and therefore its quite tolerable and has posed no genetic risks. [100, 102]. One hypothesis for the instability nature of LNPs is that the ionizable lipids are neutral and oil-like at storage pH (usually neutral), and thus they may not tend to stay at the interface at ambient temperature. In principle, the cone shape ionizable lipid, which contains lipid tails with larger cross-sectional areas than the lipid headgroups, could pair with the anionic endosomal membranes (i.e. Front Immunol. Ionizable lipids play crucial roles in fulfilling all these purposes. PDF mRNA vaccine for cancer immunotherapy - BioMed Central Moreover, the dsRNA activates RNase L upon binding to OAS [19], causing degradation of the exogenous RNAs. Feb 17, 2021. The challenges of developing cancer vaccines versus infectious disease vaccines lie in: firstly, most infectious disease vaccines are prophylactic, whereas cancer vaccines are therapeutic. Next, mutations with the highest immunogenicity are screened, analyzed, and identified using major histocompatibility complex (MHC) class I epitope prediction algorithms. Decoding mRNA translatability and stability from the 5 UTR. Intracellular trafficking of LNP loaded siRNA/mRNA have been visualized using electron microscope (EM) [100], high-dynamic range live-cell imaging confocal [102], single-molecule fluorescence in situ hybridization (FISH) [92], etc.. By directly detecting colloidal-gold particles conjugated to siRNAs using EM, Gilleron and coworkers demonstrated that only 12% of siRNA delivered by DLin-MC3-DMA LNPs could escape from the endosomes into cytosols. to deliver the long SAM, from which they have shown that 64-fold less dose of SAM achieved the equivalent immunity to the non-replicating mRNA [68]. Despite the encouraging initial results, the wide application of i.n. Self-amplifying mRNA vaccines. The mannose modified LNPs were shown to impove the uptake of the particles in DCs through mannose receptor CD206. Nonviral delivery of self-amplifying RNA vaccines.
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