Pelareorep联合atezolizumab和化疗在晚期胰腺癌中显示免疫转化活性:GOBLET试验队列1的生物标志物结果

Introduction: Pancreatic cancer features a profoundly immunosuppressive microenvironment and no approved immunotherapy to date. Pelareorep (REOLYSIN®) is a wildtype oncolytic reovirus that preferentially replicates in RAS upregulated tumor cells. In cohort 1 of the phase 1/2 GOBLET trial, patients with advanced pancreatic cancer were enrolled to receive first line (1L) pelareorep combined with atezolizumab and gemcitabine/nab-paclitaxel yielding a previously reported confirmed objective response rate (ORR) of 54% (7/13) and disease control rate (DCR) of 85% (11/13). Methods: In an exploratory biomarker analysis, routine serum markers (CA19-9, CEA, CRP) and 172 circulating proteins quantified via proximity extension assay (PEA; Olink®) were integrated with selected T cell receptor (TCR) sequencing and clinical outcomes. Linear mixed effects models and semi supervised clustering were applied to identify protein patterns reflecting immune and inflammatory activity. Results: Early on-treatment effects included increased abundance of adaptive immune (e.g. IFN-gamma, CXCL11, TNF) or cytotoxicity associated proteins (e.g. GZMB/H/A) and reduced tumor/stroma-associated proteins (MUC-16, MMP12). A 14-protein signature linked to oncolytic activity (IFN gamma signaling, CD8+ and NK cytotoxic functions) stratified patients at week 4 into “hot” versus “cold” immune phenotypes relative to baseline. Despite small numbers, the ‘hot' phenotype was associated with significantly longer median progression free survival (n=6; mPFS; 7.5 mo, 95% CI: 7.1-14.3) compared with “cold” (n=6; mPFS 5.6 mo, 95% CI: 1.7-6.0; log rank p<0.005). Conclusion: Pelareorep combined with atezolizumab and gemcitabine/nab-paclitaxel demonstrated promising activity in 1L pancreatic cancer. A hot/cold immune signature detectable after 4 weeks may serve as an early stratification biomarker, supporting identification of patients likely to achieve durable benefit