Abstract 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 was successfully evaluated as monotherapy in a phase 1/2 in stage 3/4 melanoma patients. SCIB1 induced T cell responses in 88% patients, 75% RFS at 39 months cut off (n=16) versus 63% for Pembrolizumab (Keynote 054). The current Phase 2 trial tests the hypothesis that unresectable patients may have an improved response when the vaccine is combined with CPI. SCIB1 induced T cell responses in HLA-A2 patients, iSCIB1+ has a modified Fc and contains 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+ (i. m) in combination with nivolumab and ipilimumab. Clinical response was assessed by RECIST 1. 1. T cell responses to SCIB1 and iSCIB1+ were assessed using a cultured IFNγ ELISpot assay, single cell RNA- and TCR-seq analysis. Results: 41 patients received SCIB1 and had a PFS of 55% and OS of 77% at 26 months. 39 patients received iSCIB1+ and had an improved PFS of 74% at 16 months when compared to SCIB1, possibly due to the modified Fc and additional epitopes. This compares favorably with CPI alone in checkmate 067 which had a median PFS of 11. 5 months and similar patient demographics. Among 200 grade 3 or greater adverse events only 4 (uveitis), were solely related to vaccine and were rapidly resolved upon treatment. Vaccine induced T cell responses peaked at 25 weeks and strongly correlated with PFS and DCR. Patients that generated a strong T cell response to both gp100 and TRP2 peptides post-vaccination exhibited better tumor control, with tumors reducing in size or disappearing (PR/CR, 70%). Seventy percent (23/32) of patients responded to both TRP2 and gp100 making antigen loss less likely. iSCIB1+ specific TCRs cloned from these patients confirmed epitope and HLA restriction and showed strong recognition and killing of melanoma target cells. T cells expressing iSCIB1+ specific TCRs showed a strong cytotoxic and polyfunctional Tpex transcriptional profile. Conclusions: iSCIB1+ in combination with nivolumab and ipilimumab as first line treatment for unresectable melanoma showed improved PFS of 74% at 16 months without an increase in clinically meaningful adverse events. Clinical benefit was correlated with strong iSCIB1+ induced T cell responses. These data support a registrational, randomized, controlled trial of iSCIB1 + with potential to redefine frontline therapy for unresectable advanced melanoma. Citation Format: Joseph Chadwick, Samantha Paston, Kate Young, Heather Shaw, Pippa Corrie, Sarah Danson, Miranda Payne, Poulam Patel, Maria Marples, Ioannis Karydis, Satish Kumar, Clare Barlow, Rebecca Lee, Martin Highley, Kellati Prasad, Georgia Goodhew, Olivia Howard, Joe Thornton, Nermeen Varawalla, Lindy Durrant. SCOPE, A phase 2 clinical trial with off-the-shelf DNA plasmid vaccine in first line advanced melanoma combined with check point blockade, shows good T cell responses which correlate with long progression free survival abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT237.
Chadwick et al. (Fri,) studied this question.