SCOPE：一项在一线晚期黑色素瘤中联合检查点阻断的现成DNA质粒疫苗II期临床试验，显示出良好的T细胞应答，且与长期无进展生存相关

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 IFNgamma 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.