Abstract 486P
Background
Tumor neoantigens are essential in modern cancer immunotherapies. The most frequently studied neoantigens are derived from single-nucleotide variants (SNVs) and insertions or deletions (Indels). However, tumors with high SNV or Indel mutation burdens are relatively uncommon. To expand the application of neoantigen-based immunotherapies to more patients, it is necessary to broaden the repertoire of tumor neoantigens. Gene fusions are also excellent sources of tumor neoantigens, as they can create new open reading frames and are implicated in the development of approximately 16% of all cancers.
Methods
In this study, we characterized gene fusion profiles identified from RNA-seq data using a combination of three pipelines in tumor tissues from 100 patients with colorectal and lung cancer. To demonstrate the efficacy of gene fusion-derived neoantigens (GFNs), we conducted ELISpot assays using long synthesis peptides (sLP) on peripheral blood mononuclear cells (PBMCs) from seven patients and employed 10X single-cell sequencing to identify T cell receptor (TCR)-specific neoantigens.
Results
Our results demonstrate that GFNs are highly immunogenic, with their epitopes binding strongly to MHC class I molecules compared to SNV and Indel neoantigens. They represent a significant class of tumor neoantigens, as 4 out of 7 patients exhibited at least one positive GFN, and the proportion of positive neoantigens reached up to 33.3% in a patient. Furthermore, we found evidence of memory T cells specific to the ARHGEF1-GTPBP3 neoantigen in the peripheral blood of one patient. We discovered highly activated TCR clones specifically targeting fusion neoantigens versus SNV neoantigens in a patient, a novel finding previously unreported.
Conclusions
This work establishes GFNs as promising targets for personalized cancer immunotherapy. Our study emphasizes the critical need to analyze the entire alternative genetic cancer genome, addressing gaps in the current neoantigen repertoire, and offering a valuable resource for advancing cancer vaccine development.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Medical Genetics Institute, Ho Chi Minh City, Vietnam.
Funding
Nexcalibur Therapeutics, NGS lab, Biopolis, Singapore.
Disclosure
All authors have declared no conflicts of interest.