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Review
. 2021 Apr 15;20(1):69.
doi: 10.1186/s12943-021-01348-0.

mRNA therapeutics in cancer immunotherapy

Jan D Beck #  1 , Daniel Reidenbach #  2 , Nadja Salomon #  2 , Ugur Sahin  1 , Özlem Türeci  1 , Mathias Vormehr #  1 , Lena M Kranz #  3
Affiliations
Review

mRNA therapeutics in cancer immunotherapy

Jan D Beck et al. Mol Cancer. .

Abstract

Synthetic mRNA provides a template for the synthesis of any given protein, protein fragment or peptide and lends itself to a broad range of pharmaceutical applications, including different modalities of cancer immunotherapy. With the ease of rapid, large scale Good Manufacturing Practice-grade mRNA production, mRNA is ideally poised not only for off-the shelf cancer vaccines but also for personalized neoantigen vaccination. The ability to stimulate pattern recognition receptors and thus an anti-viral type of innate immune response equips mRNA-based vaccines with inherent adjuvanticity. Nucleoside modification and elimination of double-stranded RNA can reduce the immunomodulatory activity of mRNA and increase and prolong protein production. In combination with nanoparticle-based formulations that increase transfection efficiency and facilitate lymphatic system targeting, nucleoside-modified mRNA enables efficient delivery of cytokines, costimulatory receptors, or therapeutic antibodies. Steady but transient production of the encoded bioactive molecule from the mRNA template can improve the pharmacokinetic, pharmacodynamic and safety properties as compared to the respective recombinant proteins. This may be harnessed for applications that benefit from a higher level of expression control, such as chimeric antigen receptor (CAR)-modified adoptive T-cell therapies. This review highlights the advancements in the field of mRNA-based cancer therapeutics, providing insights into key preclinical developments and the evolving clinical landscape.

Keywords: Antibodies; CARs; Cancer immunotherapy; Cancer vaccines; Immunomodulatory proteins; Immunoreceptors; Messenger RNA.

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Conflict of interest statement

NS, US, ÖT, MV and LMK are authors of studies mentioned in this review. JDB, MV and LMK are employees and US and ÖT are cofounders and management board members of BioNTech SE (Mainz, Germany). JDB, US, ÖT, MV and LMK hold securities from BioNTech SE. All other authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Delivery and structural elements of mRNA therapeutics. Structure of a lipid-based mRNA nanoparticle (left) and synthetic mRNA (right), comprising a 5′ cap, 5′ and 3′ UTRs, a start codon initiating the open reading frame (AUG), and a poly(A) tail. Listed are different mRNA delivery methods, as well as tunable structural elements influencing mRNA translation, stability and potential of innate immune activation. UTR: untranslated region; ds: double-stranded
Fig. 2
Fig. 2
mRNA therapeutics in cancer immunotherapy. mRNA is used for anti-cancer vaccination, where it delivers cancer antigens to APCs for the presentation on MHC class I and II (top left) and stimulates innate immune activation by binding to PRRs expressed by APCs (top right), introduces antigen receptors such as CARs and TCRs into lymphocytes (bottom right), and allows the expression of immunomodulatory proteins including TLRs, chemokine receptors, co-stimulatory ligands, cytokines, chemokines and different mAb formats in various cell subsets (bottom left). APC: antigen-presenting cell; CAR: chimeric antigen receptor; mAb: monoclonal antibody; MDA5: melanoma differentiation-associated protein 5; pMHC: peptide-major histocompatibility complex; NKG2D: natural killer group 2D; PRR: pattern recognition receptors; RIG-I: retinoic acid-inducible gene 1; TCR: T-cell receptor; TLR: Toll-like receptor
See this image and copyright information in PMC

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