BIOM-83. INTEGRATED MONITORING OF RNA-SEQUENCING AND COMPLETE BLOOD COUNT PREDICTS IMMUNE RESPONSE AND OUTCOME IN A CLINICAL TRIAL OF DUAL NEOADJUVANT IMMUNE CHECKPOINT BLOCKADE IN GLIOBLASTOMA

Abstract BACKGROUND While immune checkpoint blockade (ICB) has revolutionized cancer therapy, its effectiveness in glioblastoma remains limited. Our phase I trial (NCT04606316) enrolled relapsed, IDH wildtype glioblastoma patients undergoing surgical resection. Participants received either dual ICB (ipilimumab + nivolumab, n=25), single-agent PD-1 blockade (nivolumab, n=25), or a placebo (n=10) before surgery. Post-surgery, Arms 1 and 3 continued dual ICB, while Arm 2 remained on nivolumab until progression or toxicity. Dual ICB showed improved survival over single-agent nivolumab, but variability within the cohort highlights the need to develop a rapid blood-based biomarker that can better monitor immune responses and identify patients most likely to benefit from ICB. METHODS We conducted bulk RNA sequencing (RNAseq) on peripheral blood mononuclear cells (PBMCs) from 58 trial participants across two neoadjuvant and two adjuvant time points. Concurrently, we analyzed complete blood count (CBC) with differential values from the same patients at identical time points. We integrated RNAseq and CBC data to characterize systemic immune responses across different ICB regimens. RESULTS Dual ICB significantly induced white blood cell count in CBC and interferon gene signatures in PBMCs, confirming a systemic pharmacodynamic effect. Multivariate analysis highlighted a strong interferon gene signature at the pre-surgery (post-neoadjuvant) time point that correlated with improved survival. However, concomitant myeloid CBC (monocytes/neutrophils) elevation and related gene signatures following dual ICB treatment were negatively associated with survival at post-adjuvant timepoints, suggesting that chronic systemic inflammation may impair anti-tumor immune responses. CONCLUSION Integrated analysis of RNAseq and CBC suggests that dual ICB induces an immediate, productive immune response, but chronic, myeloid-driven inflammation may hinder durable therapeutic efficacy. CBC profiling offers a rapid biomarker for monitoring systemic immune responses to ICB. Implementation of these biomarkers could predict patients most likely to benefit from ICB and inform strategies to counteract chronic inflammation that may attenuate treatment effectiveness.