266P Disruption of nonsense-mediated mRNA decay enhances anti-tumour immunity

Background: SCIB1 and iSCIB1+ are off the shelf DNA vaccines incorporating CD8 and CD4 epitopes from TRP2/gp100 into an antibody framework to allow Fc targeting of activated dendritic cells.SCIB1 and iSCIB1+ potentially have a synergistic effect on advanced unresectable melanoma when combined with checkpoint inhibitors (CPI).SCIB1 induced T cell responses in HLA-A2 patients; iSCIB1+ has additional epitopes covering more HLA haplotypes, HLA-A2, A3, A31, Bw4, B35 and B44 representing 80% of the population. Methods:In a phase 2 trial patients with advanced unresectable melanoma were treated with SCIB1 or iSCIB1+ in combination with CPI.Objective response rate (ORR) determined by RECIST 1.1 was assessed along with the immunogenicity of SCIB1 and iSCIB1+ using a cultured IFN ELISpot assay, single cell RNA-and TCR-seq analysis.Results: ELISpot assays showed 24/33 (73%) patients treated with iSCIB1+ had a T cell response to iSCIB1+ peptides.Patients who generated a strong T-cell response post-vaccination exhibited better tumour control, with tumours either reducing in size or disappearing (PR/CR, 15/19 (79%)) or no further increase in size (Stable Disease, 5/7 (71%).All SCIB1/ iSCIB1+ peptides generated potent CD8 T cell responses.Reactive CD8 T cells expressed cytotoxic markers and markers of memory T cells.CD8 epitopes nested in longer peptides have been identified and a range of isolated TCRs have been characterised from HLA-A2 and non-HLA-A2 patients.Clinical responses were analysed by comparing participants with "permissive" alleles: those predicted to present immunotherapeutic peptides with those carrying "nonpermissive" alleles.Patients with permissive alleles demonstrated a higher mean ORR rate of 70% (range 64-75%), compared to 45% (range 33-50) in the nonpermissive group which is consistent with the ORR reported for CPIs.Conclusions: These data support that SCIB1 and iSCIB1+ induces potent T cell responses, resulting in positive clinical responses in 80% of the patient population.Significant T cell responses were induced to peptides included in iSCIB1+.