Immunotherapeutic early-phase clinical trials and malignant gliomas : A single-center experience and comprehensive immunophenotyping of circulating leukocytes

Background. Immunotherapeutic early-phase clinical trials (ieCTs) increasingly adopt large expansion cohorts ex- ploring novel agents across different tumor types. High-grade glioma (HGG) patients are usually excluded from these trials. Methods. Data of patients with recurrent HGGs treated within multicohort ieCTs between February 2014 and August 2019 (experimental group, EG) at our Phase I Unit were retrospectively reviewed and compared to a matched con- trol group (CG) of patients treated with standard therapies. We retrospectively evaluated clinical, laboratory, and molecular parameters through univariate and multivariate analysis. A prospective characterization of circulating leukocyte subpopulations was performed in the latest twenty patients enrolled in the EG, with a statistical signifi- cance cutoff of P < .1. Results. Thirty HGG patients were treated into six ieCTs. Fifteen patients received monotherapies (anti-PD-1, anti-CSF-1R, anti-TGFβ, anti-cereblon), fifteen patients combination regimens (anti-PD-L1 + anti-CD38, anti-PD-1 + anti-CSF-1R). In the EG, median progression-free survival and overall survival (OS) from treat- ment initiation were 1.8 and 8.6 months; twelve patients survived more than 12 months, and two of them more than 6 years. Univariate analysis identified O6-methylguanine DNA methyltransferase (MGMT) pro- moter methylation and total protein value at six weeks as significantly correlated with a better outcome. Decreased circulating neutrophils and increased conventional dendritic cells levels lead to significantly better OS. Conclusions. A subgroup of EG patients achieved remarkably durable disease control. MGMT promoter methyla- tion identifies patients who benefit more from immunotherapy. Monitoring dynamic changes of innate immune cell populations may help to predict clinical outcomes.