Mutanome Engineered RNA Immunotherapy: Towards Patient-Centered Tumor Vaccination - PubMed (original) (raw)

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Mutanome Engineered RNA Immunotherapy: Towards Patient-Centered Tumor Vaccination

Mathias Vormehr et al. J Immunol Res. 2015.

Abstract

Advances in nucleic acid sequencing technologies have revolutionized the field of genomics, allowing the efficient targeting of mutated neoantigens for personalized cancer vaccination. Due to their absence during negative selection of T cells and their lack of expression in healthy tissue, tumor mutations are considered as optimal targets for cancer immunotherapy. Preclinical and early clinical data suggest that synthetic mRNA can serve as potent drug format allowing the cost efficient production of highly efficient vaccines in a timely manner. In this review, we describe a process, which integrates next generation sequencing based cancer mutanome mapping, in silico target selection and prioritization approaches, and mRNA vaccine manufacturing and delivery into a process we refer to as MERIT (mutanome engineered RNA immunotherapy).

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Figures

Figure 1

Figure 1

Concept of mutanome engineered RNA immunotherapy (MERIT). Next generation sequencing of nucleic acid from a tumor biopsy and healthy tissue is used to identify expressed, nonsynonymous, somatic mutations. Vaccine targets are selected based on several parameters such as expression, their MHC binding prediction, and restriction as well as a false discovery rate (FDR) [16]. Mutations encoded on pentatope RNAs are produced under GMP conditions and used for therapeutic vaccination.

Figure 2

Figure 2

Structure of the pentatope RNA vaccine. Several modifications in the 5′ cap, 5′ and 3′ untranslated regions (UTR), poly(A) tail, and codon usage increased the translation efficiency and stability of the mRNA [30, 31]. Mutated sequences (Mut1–5) encoding 27 amino acids with the mutation in the center (red letter) are separated by nonimmunogenic 10 mer linkers. The antigen encoding sequences are flanked by a signal peptide and the MHC class I trafficking domain (MITD, transmembrane, and cytoplasmic domain of MHC class I) to ensure optimal antigen presentation [32].

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References

    1. Alexandrov L. B., Nik-Zainal S., Wedge D. C., Aparicio S. A. J. R., Behjati S., Biankin A. V., et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415–421. doi: 10.1038/nature12477. - DOI - PMC - PubMed
    1. Boon T., Kellermann O. Rejection by syngeneic mice of cell variants obtained by mutagenesis of a malignant teratocarcinoma cell line. Proceedings of the National Academy of Sciences of the United States of America. 1977;74(1):272–275. doi: 10.1073/pnas.74.1.272. - DOI - PMC - PubMed
    1. Lurquin C., Van Pel A., Mariamé B., et al. Structure of the gene of tum-transplantation antigen P91A: the mutated exon encodes a peptide recognized with Ld by cytolytic T cells. Cell. 1989;58(2):293–303. doi: 10.1016/0092-8674(89)90844-1. - DOI - PubMed
    1. NHGRI. Human Genome Project Completion: Frequently Asked Questions, 2010, http://www.genome.gov/11006943.
    1. Hayden E. C. Technology: the $1,000 genome. Nature. 2014;507(7492):294–295. doi: 10.1038/507294a. - DOI - PubMed

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