Computational Pipeline for the PGV-001 Neoantigen Vaccine Trial - PubMed (original) (raw)

Computational Pipeline for the PGV-001 Neoantigen Vaccine Trial

Alex Rubinsteyn et al. Front Immunol. 2018.

Abstract

This paper describes the sequencing protocol and computational pipeline for the PGV-001 personalized vaccine trial. PGV-001 is a therapeutic peptide vaccine targeting neoantigens identified from patient tumor samples. Peptides are selected by a computational pipeline that identifies mutations from tumor/normal exome sequencing and ranks mutant sequences by a combination of predicted Class I MHC affinity and abundance estimated from tumor RNA. The personalized genomic vaccine (PGV) pipeline is modular and consists of independently usable tools and software libraries. We hope that the functionality of these tools may extend beyond the specifics of the PGV-001 trial and enable other research groups in their own neoantigen investigations.

Keywords: computational pipeline; genomics; immunoinformatics; neoantigens; personalized vaccine.

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Figures

Figure 1

Figure 1

Overview of PGV-001 trial.

Figure 2

Figure 2

Schematic of bioinformatics tools used in PGV-001 pipeline.

Figure 3

Figure 3

Overview of Isovar algorithm for determining mutant protein sequences.

Figure 4

Figure 4

Schematic representation of a somatic mutation co-occurring with a germline mutation.

Figure 5

Figure 5

Screenshot from IGV with tumor DNA on top and tumor RNA on bottom. The two somatic variants from patient data 7 amino acids apart. If these mutations were considered without phasing, we would get two different vaccine peptides, neither of which would match the protein sequence produced by tumor cells.

Figure 6

Figure 6

TotalScore used to rank somatic variants in a way that attempts to balance predict MHC binding and abundance. ExpressionScore uses read count (instead of a normalized measure like FPKM) since these scoring criteria are not meant to be compared between patient samples. BindingScore sums normalized binding affinities of mutant peptides across all patient alleles and lengths between 8 and 11.

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