Objectives Ovarian carcinosarcoma (OCS) are rare aggressive cancers with poor prognosis and limited effective treatments. The tumour mutation burden in OCS is often low. Therefore, these tumours are immunologically ‘cold’ and relatively irresponsive to single agent immunotherapy. We explored tumour neoantigen discovery in an OCS using various genomic and proteomic platforms for personalised T-cell receptor (TCR) therapy.
Methods Whole genome sequencing (WGS) was performed on SFRC01177 OCS tumour specimen taken at surgery. Fresh tumour specimens obtained at surgery and biopsy at recurrence were engrafted subcutaneously in NOD-scidIL2Rgammanull (NSG) to generate a paired patient derived xenograft (PDX) model. Whole exome sequencing and RNA sequencing (WES/RNAseq) together with nano-ultra-performance liquid chromatography coupled to high-resolution mass spectrometry were performed on the snap frozen tumours from the baseline and recurrent PDX for tumour neoantigen (TNA) discovery.
Results A total of 6,500 mutant TNA were predicted in silico from the baseline WGS data which were narrowed down to 65 and 33 respectively based on the baseline and recurrent PDX tumours WES/RNAseq data. The immunopeptidomic analysis revealed over 100 major histocompatibility complex bound antigens including mutant, spliced and cancer testis antigens. The PDX was re-established in NSG MHCnull mouse model and was shown to retain the platinum refractory in vivo response as well as to tolerate 1 million HLA-matched donor CD8+ T-cell injections.
Conclusions We have discovered multiple tumour specific neoantigens using the comprehensive TNA discovery platforms, which will direct our TCR engineering. In parallel, we have also established an OCS PDX model suitable for cell-based therapy testing.
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