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Background SCIB1 and iSCIB1+, are novel DNA cancer vaccines incorporating CD8 and CD4 epitopes from TRP-2/gp100 into an antibody framework to allow direct and Fc targeting of activated dendritic cells. iSCIB1+ has additional epitopes applicable to more HLA haplotypes, A2, A3, A31, Bw4, B35 & B44 that represent 80% of the population ( figure 1).Methods This phase 2 open label single arm parallel multi-cohort clinical program evaluates the immune response, safety and efficacy of SCIB1/iSCIB1+ in 140 advanced first line melanoma patients at 16 clinical sites in the United Kingdom.Cohort 1 has 43 patients all with HLA A2 receiving ipilimumab and nivolumab with 10 doses of intra-muscular SCIB1 over 24-months. Cohort 3 evaluates iSCIB1+ in 50 patients, 39 with the matched HLA haplotypes. Ongoing Cohort 4 has 31 patients with intra-dermal accelerated dosing. Cohort 2 has 10 HLA A2 patients who received SCIB 1 with pembrolizumab and was stopped due to slow enrolment.Results ELISpot assays demonstrated that 19/31 (61.2%) patients made a T-cell response to iSCIB1+ which increased to 79% (15/19) amongst clinical responders. All six iSCIB1+ epitopes generated T cell responses. SCIB1 reactive T cells expressed IFNg, GZMB and PRF1.The ORR (Objective Response Rate) and DCR (Disease Control Rate) determined by RECIST 1.1 scans were:Cohort 1: 63.4% (26/41) and 83% (34/41), respectively with a Progression Free Survival (PFS) of 55.6% at 23 months, following exclusion of two non-protocol patients, with acral melanoma and active brain metastases.Cohort 3: 64.5% (20/31) and 80.6% (25/31), respectively with a PFS of 77.8% at 11 months. 1 patient with active brain metastases excluded. 7 yet to reach their first 13 week imaging timepoint (figure 2).Cohort 3 with non-matched HLA haplotypes: 27.3% (3/11) and 54.5% (6/11), respectively with a PFS of 45.5% at 12 months. Statistically significant difference in ORR (p value < 0.043) when compared to HLA matched patients.Cohort 2: 70% (7/10) for both outcomes with a PFS of 80% at 6 months.Vaccines were well tolerated with no increase in clinically meaningful adverse events. Of the 163 treatment emergent adverse events of Grades 3 or more, 30 were related to the vaccine whilst 113 to checkpoint inhibitors.Conclusions Following on from this compelling interim readout we progress to registrational trials evaluating iSCIB1+ in stage III and IV melanoma in the advanced and neoadjuvant settings.Trial Registration Registry Name - Clinicaltrials.gov Registration Number: NCT04079166Ethics Approval This phase 2 study was conducted in keeping with ICH GCP guidelines with all participants giving their informed consent before taking part. The protocol, patient information sheet and informed consent form were reviewed and approved by the institutional ethics committees of each of the recruiting clinical trial sites located in the United Kingdom as listed below, prior to site initiation and patient enrolment: (1)Mount Vernon Cancer Centre, Northwood (2)University College London Hospital (3)Nottingham Hospitals University Trust (4)Churchill Hospital, Oxford University Hospitals (5) Velindre University NHS Trust, Cardiff (6) Sheffield Teaching Hospital NHS Trust, (7) University Hospitals NHS Trust, Plymouth (8)Somerset NHS Foundation Trust, Taunton (9) Royal Preston Hospital (10) Southampton General Hospital (11) St James’s University Hospital, Leeds (12) The Royal Marsden Hospital, Surrey (13) The Royal Marsden Hospital, London (14) Addenbrooke’s Hospital, Cambridge, (15) Royal Free Hospitals, London (16) Guys Hospital London.Abstract 1325 Figure 1Vaccine design with T cell response to all six epitopes. SCIB1 & iSCIB1+ encoding two clusters of CD8 epitopes, TRP-2 and gp100, with ELISpot T cell responses to all epitopes in HLA matched patientsAbstract 1325 Figure 2RECIST 1.1 best overall response and progression free survival. Waterfall plot and progression free survival curves for HLA matched patients in Cohorts 1 & 3 showing an ORR of 46/72 (63.8%)