An RNA toolbox for cancer immunotherapy

Abstract

Cancer immunotherapy has revolutionized oncology practice. However, current protein and cell therapy tools used in cancer immunotherapy are far from perfect, and there is room for improvement regarding their efficacy and safety. RNA-based structures have diverse functions, ranging from gene expression and gene regulation to pro-inflammatory effects and the ability to specifically bind different molecules. These functions make them versatile tools that may advance cancer vaccines and immunomodulation, surpassing existing approaches. These technologies should not be considered as competitors of current immunotherapies but as partners in synergistic combinations and as a clear opportunity to reach more efficient and personalized results. RNA and RNA derivatives can be exploited therapeutically as a platform to encode protein sequences, provide innate pro-inflammatory signals to the immune system (such as those denoting viral infection), control the expression of other RNAs (including key immunosuppressive factors) post-transcriptionally and conform structural scaffoldings binding proteins that control immune cells by modifying their function. Nascent RNA immunotherapeutics include RNA vaccines encoding cancer neoantigens, mRNAs encoding immunomodulatory factors, viral RNA analogues, interference RNAs and protein-binding RNA aptamers. These approaches are already in early clinical development with promising safety and efficacy results.

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Figure 1: Schematic representation of the different RNA subtypes and their functions.
Figure 2: RNA recognition by the innate immune system.
Figure 3: Personalized mRNA-based antitumour vaccines.
Figure 4: Immunomodulatory RNA aptamers.

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Acknowledgements

This work was supported by Worldwide Cancer Research grants 15–1146 and 15–1208, the Asociación Española Contra el Cáncer (AECC) Foundation under grant GCB15152947MELE, Red Temática de Investigación Cooperativa en Cáncer under grants RD12/0036/0040 and RD12/0036/0062, Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional (FEDER) under grants PI14/01686, PI13/00207, PI16/00668 and PI17/00372, the H2020 PROCROP project under grant 635122, the Melanoma Research Alliance under grant 509510 and the Fundación Ramón Areces under grant CIVP18A3916. F.P. is supported by Ramón y Cajal (10699). P.B. is supported by a Miguel Servet II (CPII15/00004) contract from the Instituto de Salud Carlos III.

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Contributions

I.M., F.P., P.B. and I.E. researched data for the article and I.M., F.P. and P.B wrote the article. All of the authors provided substantial contribution to the discussion of the content and reviewed and edited the article before submission.

Corresponding author

Correspondence to Ignacio Melero.

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Competing interests

I.M. declares financial and non-financial competing interests. I.M. reports receiving commercial research funding (grants) from Bristol-Myers Squibb (BMS) and Roche and serves as a consultant and/or advisory board member for Alligator, AstraZeneca, Bioncotech, BMS, F-STAR, Genmab, Incyte, Merck Serono, Molecular Partners, Roche–Genentech and Tusk. E.G. is founder of Sebastian Biopharma that licensed IP from the University of Miami to develop methods of inducing neoantigens. U.S. is CEO and co-founder of BioNTech, a company that develops mRNA therapeutics.

PowerPoint slides

Glossary

RNA moieties

Defined structures in RNA that determine its binding and functional activity.

Promoter

A specific DNA sequence upstream of the gene that is recognized by the RNA polymerase complex to initiate the transcription process.

Polyadenylation

Incorporation of a tail of multiple adenosine monophosphates at the 3′ end of the nascent mRNA, thereby conferring stability.

Splicing

A process in eukaryotes by which the nascent transcribed mRNA is edited by removing part of the RNA (introns) and keeping the protein-encoding sequence (exons).

Alternative splicing

A variation in the splicing process to include or exclude different exons such that a single gene can encode for multiple translated proteins.

Ribonucleoproteins

Conjugates of RNA and protein that usually have enzymatic or scaffold functions.

Lariat RNAs

Circular introns released during the splicing process in the nucleus.

Codon rewiring

Changes in codon reassignment during the translation process.

Kozak sequence

A conserved sequence within the mRNA (ACCAUGG) that leads the ribosome to initiate the translation of the encoded protein.

Nonsense-mediated mRNA decay

(NMD). An RNA surveillance mechanism that identifies and eliminates mRNA with premature stop codons.

Toll-like receptor

(TLR). A type of pattern recognition receptor named because of homology to the fruitfly protein Toll. Such structures on the cell surface or in endosomes detect moieties that denote the presence of danger signals.

RNA helicases

A group of enzymes that rearrange RNA folding structures usually by unwinding the double-stranded RNA helix.

Type I interferon

A group of interferon proteins including interferon-β (IFNβ) and the different subtypes of IFNα, which are cytokines with antiviral, antitumour and multiple immunomodulatory activities.

Dendritic cells

(DCs). Professional antigen-presenting cells of leukocyte lineage. Several subsets are specialized at inducing and sustaining different types of immune response.

Immune-desert tumours

Tumours with lack of infiltration of immune cells due to defects in the priming phase of the antitumour immune response or problems in leukocyte trafficking.

T cell receptor

(TCR). A transmembrane protein expressed on T lymphocytes that recognizes peptides presented in the context of major histocompatibility complex (MHC) class I and MHC class II proteins. TCR-encoding genes are clonally rearranged, constituting an antigen recognition repertoire.

C12-200 lipidoid

An epoxide-derived, oligoamine-containing, lipid-like compound used to deliver small interfering RNA to the liver.

DNA cassettes

DNA fragments that contain a gene and the regulatory elements required for the gene expression in the transfected cell.

Partial tolerance

A status of unresponsiveness to a given specific antigen as a result of previous exposure to such antigen. Degrees of tolerance to a given antigen are possible, and tolerance relies on the dysfunction or elimination of specific T cells.

Protamine

An arginine-rich nucleoprotein that condensates DNA through electrostatic interactions.

Immune checkpoint

A co-inhibitory molecule that reduces the proliferation, differentiation and effector functions of lymphocytes.

Antisense antidotes

Molecules that absorb nucleic acid aptamer, disrupting its structure and therefore its function. This is achieved by complementary antisense sequence205 or positively charged polymers206.

Gene-editing nucleases

Engineered nucleases that modify the genome by targeting specific genomic sequences.

Nucleofection

Transfection of RNA or DNA to the nucleus and cytosol by an electroporation-based approach using a Nucleofector device.

Infusion reactions

Signs or symptoms that occur during the infusion of a therapeutic agent or on the first day of administration. Clinical manifestations vary in severity and can include many different symptoms involving different body systems

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Pastor, F., Berraondo, P., Etxeberria, I. et al. An RNA toolbox for cancer immunotherapy. Nat Rev Drug Discov 17, 751–767 (2018). https://doi.org/10.1038/nrd.2018.132

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