mRNA vaccine CV9103 and CV9104 for the treatment of prostate cancer

Rausch, Steffen; Schwentner, Christian; Stenzl, Arnulf; Bedke, Jens

doi:10.4161/hv.29553

Cited by 89 publications

(66 citation statements)

References 47 publications

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“…[166][167][168] Antigen expression strongly depends on the ratio between protamine and mRNA. 169 This vaccine platform has raised favorable immune activations against cancer and infectious diseases in both pre-clinical animal models and in patients. [169][170][171] Lipids and Polymers.…”

Section: Non-amplifying Mrna Vaccinesmentioning

confidence: 99%

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Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery

et al. 2019

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mRNA has broad potential as a therapeutic. Current clinical efforts are focused on vaccination, protein replacement therapies, and treatment of genetic diseases. The clinical translation of mRNA therapeutics has been made possible through advances in the design of mRNA manufacturing and intracellular delivery methods. However, broad application of mRNA is still limited by the need for improved delivery systems. In this review, we discuss the challenges for clinical translation of mRNA-based therapeutics, with an emphasis on recent advances in biomaterials and delivery strategies, and we present an overview of the applications of mRNA-based delivery for protein therapy, gene editing, and vaccination. mRNA holds the potential to revolutionize vaccination, protein replacement therapies, and the treatment of genetic diseases. Since the first pre-clinical studies in the 1990s, 1 significant progress in the clinical translation of mRNA therapeutics has been made through advances in the design of mRNA manufacturing and intracellular delivery methods. 2 The translatability and stability of mRNA as well as its immunostimulatory activity are the key factors to be optimized for specific therapeutic application. 3 Increased translation and stability can be affected by many regions of the RNA. mRNA 5 0 and 3 0 UTRs are responsible for recruiting RNA-binding proteins and microRNAs, and they can profoundly affect translational activity. 2,4 The modification of rare codons in protein-coding sequences with synonymous frequently occurring codons, so-called codon optimization, can result in order-of-magnitude changes in expression levels. 5,6 Modification of the 5 0 mRNA cap can also enhance mRNA translation by inhibiting RNA decapping and improving resistance to enzymatic degradation. 7 Chemical modification of RNA bases can be used to modify mRNA immunostimulatory activity. 8,9 The importance of immunostimulation can depend on the application, 10 and, in some cases, it may actually improve performance, as in the case of vaccines. 11Finally, methods and vehicles for intracellular delivery remain the major barrier to the broad application of mRNA therapeutics. 12 With some exceptions, the intracellular delivery of mRNA is generally more challenging than that of small oligonucleotides, and it requires encapsulation into a delivery nanoparticle, in part due to the significantly larger size of mRNA molecules (300-5,000 kDa, 1-15 kb) as compared to other types of RNAs (small interfering RNAs [siRNAs], 14 kDa; antisense oligonucleotides [ASOs], 4-10 kDa). 10,13 In this review, we discuss the challenges for clinical translation of mRNAbased therapeutics, with an emphasis on recent advances in biomaterials and delivery strategies, and we present an overview of the applications of mRNA-based delivery for protein therapy, gene editing, and vaccination. Materials for mRNA Delivery Structural Aspects of Material DesignAmong the many barriers to function, mRNA must cross the cell membrane in order to reach the cytoplasm (Figure 1). The cell me...

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Section: Non-amplifying Mrna Vaccinesmentioning

confidence: 99%

“…169 This vaccine platform has raised favorable immune activations against cancer and infectious diseases in both pre-clinical animal models and in patients. [169][170][171] Lipids and Polymers. Both cationic lipids and polymers have been investigated as vehicles for mRNA vaccines in the past decades.…”

Section: Non-amplifying Mrna Vaccinesmentioning

confidence: 99%

Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery

et al. 2019

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“…It has been found to be highly immunogenic in patients with prostate and renal cancer in a phase I/II trial [142]; the phase II trial NCT02293707 is evaluating the immunological effects of GX301 in mCRPC patients who have achieved response or disease stability after first-line docetaxel-based chemotherapy. CV9103 and CV9104 are RNA vaccines encoding for PSA, prostate stem cell antigen, PSMA, and six transmembrane prostate epithelial antigens [143]. CV9103 was shown to be safe and well tolerated in a phase I/IIa study enrolling mCRPC patients [144]; 79% of 33 patients developed antigen-specific T cells and more than two-thirds of them developed immune responses to multiple antigens.…”

Section: Vaccinesmentioning

confidence: 99%

Immunotherapy for genitourinary cancer

et al. 2016

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In the last few years, cancer immunotherapy has changed the natural history and treatment strategies of a number of solid tumors, including melanoma and lung cancer. The anti-PD-1 nivolumab showed a survival benefit compared with everolimus in the second-line treatment of renal cell carcinoma, resulting in a radical shift in perspective in the treatment of this neoplasia and suggesting a new scenario beyond tyrosine kinase inhibitors. Checkpoint inhibitors might also improve the treatment of urothelial cancer, considering the promising results achieved so far and the relatively low efficacy of currently available treatments. Sipuleucel-T was the first approved immunotherapy for prostate cancer, showing a clear benefit in overall survival, and paved the way for the clinical testing of other novel cancer vaccines. This review provides a comprehensive overview of the current knowledge and new perspectives of immunotherapy in the treatment of urogenital malignancies.

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“…So far, the results have shown that mRNA‐based vaccines induce humoral and cellular immune responses and result in an increased survival rate. To date, there are two interesting clinical trials in progress, one for castration‐resistant prostate cancer and another for nonsmall cell lung cancer . Both studies showed that the application of RNActive® vaccines (from the company CureVac) to humans was safe .…”

Section: Applications Of Ivt Mrnamentioning

confidence: 99%

Concise Review: Application of In Vitro Transcribed Messenger RNA for Cellular Engineering and Reprogramming: Progress and Challenges

Steinle¹,

Behring²,

Schlensak³

et al. 2016

Stem Cells

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Several diseases are caused by missing or defective synthesis of proteins due to genetic or acquired disorders. In recent years, in vitro transcribed (IVT) messenger RNA (mRNA)-based therapy for de novo protein expression in cells has increased in importance. Thereby, desired proteins can be produced in cells by exogenous delivery of IVT mRNA, which does not integrate into the host genome and results in transient production of target proteins. Due to the lack of genomic integration, the risk of mutation and tumor development is minimized. Different approaches using IVT mRNA have been applied to alter the expression profiles of cells by the production of proteins. IVT mRNAs encoding transcription factors have led to the highly efficient induction of pluripotency in somatic cells and generated induced pluripotent stem cells that are free of viral vector components. Furthermore, specific IVT mRNA cocktails containing more than one specific IVT mRNA can be used to directly induce the differentiation into a desired cell type. In theory, every desired mRNA can be produced in vitro and used to enable extrinsic biosynthesis of target proteins in each cell type. Cells can be engineered by IVT mRNA to express antigens on dendritic cells for vaccination and tumor treatment, surface receptors on stem cells for increased homing to distinct areas, and to produce industrial grade human growth factors. In this review, we focus on the progress and challenges in mRNA-based cell engineering approaches. STEM CELLS 2017;35:68-79 SIGNIFICANCE STATEMENTThe use of synthetic messenger RNA (mRNA) to produce desired proteins in cells and thereby reprogramming and transdifferentiation of cells is a very promising technology to enable the application of these engineered cells in clinic. Synthetic mRNA does not integrate into the genome and it is not necessary to enter the nucleus. The protein is directly produced in the cytosol. In this review, we summarize the progress of the synthetic mRNA-based cell engineering strategies and highlight the challenges, which have to be overcome to improve the application.

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mRNA vaccine CV9103 and CV9104 for the treatment of prostate cancer

Cited by 89 publications

References 47 publications

Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery

Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery

Immunotherapy for genitourinary cancer

Concise Review: Application of In Vitro Transcribed Messenger RNA for Cellular Engineering and Reprogramming: Progress and Challenges

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