77. Mining COSMIC for frameshift neoantigens as ‘off-the-shelf’ therapeutic cancer vaccine candidates

Aly Abdelkareem

My Hoang

My Hoang is a PhD candidate in the Computational and Systems Biology program at Washington University in St. Louis. She graduated from Earlham College in 2020 with a B.A. in Biochemistry. My is interested in using various bioinformatic analyses to study etiology of cancer, response to cancer treatment, and development of cancer vaccine. Her current research topics include utilization of whole genome sequencing to study mechanism of chemotherapy resistance in small cell lung cancer (SCLC), development of cancer vaccine in dog and human, and public dataset mining in search for shared frameshift variants as target for off-the-shelf cancer vaccine.


My Hoang, Bryan Fisk,Jon A. Weidanz, Georgios Alexandrakis, Obi L. Griffith, Malachi Griffith

Washington University in St. Louis, St. Louis, MO, United States

Introduction: A frameshift mutation is an insertion or deletion which shifts the reading frame and consequently creates novel peptide sequences, usually resulting in premature termination but occasionally extension at the C-terminus. Since multiple frameshift mutations can give rise to the same alternate amino acid sequences, frameshift neoantigens are more commonly shared between different patients compared to many individual missense neoantigens. Frameshift peptides are also highly distinct from self, and hence more likely to induce robust immune responses. These characteristics make frameshift neoantigens attractive candidates for ‘off-the-shelf’ cancer vaccines and targets for other immunotherapies. Here, we mine COSMIC (Catalogue of Somatic Mutations in Cancer) and other public databases to identify frameshift neoantigens suitable for ‘off-the-shelf’ therapeutics.

Methods & Results: Frameshift variants from COSMIC were analyzed with pVACseq to predict derived neoantigens and binding affinity against a list of 70+ common HLAs. Neoantigens were then filtered with consideration of antigen processing, agretopicity and binding affinity (IC50 < 500nM). Peptide candidates were further prioritized based on expression data from the DepMap Cancer Cell Line Encyclopedia (CCLE). Information on presence of the peptide candidates in CCLE and the Cancer Cell Line Project (CLP) was also incorporated to facilitate in vitro exploration. Using this workflow, we identified a list of high-quality frameshift peptide candidates in GATA3, TP53, and RUNX1 for breast cancer.

Significance: This study will add to existing literature a database of clinically actionable variants and shared epitopes, and advance understanding of characteristics underpinning immunogenic frameshifts.