IMMU-34. SYSTEMIC IMMUNE SUPPRESSION IN GLIOBLASTOMA IS TARGETED BY CONCURRENT VEGF AND PD-1 INHIBITION IN A DOSE-DEPENDENT MANNER: TRANSCRIPTOMIC FINDINGS THROUGH CITE-SEQ FROM A RANDOMIZED CONTROLLED TRIAL

Anti-PD1 blockade has had poor efficacy in recurrent glioblastoma (rGBM) across three RCTs. VEGF, a proangiogenic factor that is upregulated in rGBM, contributes to tumor-associated immunosuppression and is widely targeted through bevacizumab. Preclinical data indicate a potential dose-dependent effect of anti-VEGF therapy on immunomodulation. Hence, a combination of anti-PD-1 and anti-VEGF agents is a promising approach for rGBM, for which an RCT was conducted. This work sought to utilize a multimodal approach capturing single-cell gene and protein expression by ‘cellular indexing of transcriptomes and epitopes by sequencing’ (CITE-Seq) to interrogate the systemic immunological changes in response to concurrent VEG and PD-1 inhibition.

Patients with rGBM were administered nivolumab (240mg IV q2weeks) plus either standard-dose bevacizumab (10mg/kg) or low-dose bevacizumab (3mg/kg) IV q2weeks, with 1:1 randomization. Stratification factors were age, performance status, extent of resection, and MGMT methylation status. Primary endpoint was overall survival (OS) at 12 months. CITE-Seq was performed on 16 patients across trial arms, both pre- and on-therapy, yielding total 32 immunological profiles. For control, CITE-seq was done on three patients receiving anti-VEGF therapy alone.

90 patients were enrolled with median age of 60.6 years and 45 patients per arm. Both arms had similar OS at 12 months (P=0.14). Significantly higher OS was found in posthoc analysis for patients aged ≥60 years with standard dose. Distinct immune cell populations were identified, and differential changes in myeloid-derived suppressor cells (MDSCs) found across trial arms on-therapy. Network medicine approach identified VEGF as target to reduce MDSCs, with VEGF primarily expressed by responders’ MDSCs. Differential gene expression analysis identified increased pro-inflammatory signatures in standard-dose arm.

Standard dose bevacizumab was associated with increased inflammatory response and reduction of immunosuppressive MDSC. These mechanistic insights potentially explain survival benefit seen with concurrent VEGF and PD-1 inhibition in elderly rGBM patients.