OS1.6 Peripheral blood immune profiles at first recurrence of IDH wild type glioblastoma after standard chemoradiotherapy predict overall survival: secondary analyses of the phase II DIRECTOR trial

Abstract

Abstract BACKGROUND Isocitrate dehydrogenase (IDH) wildtype glioblastoma is associated with distinctive peripheral blood immune cell profiles that evolve under first line chemoirradiation with temozolomide. Whether peripheral blood immune cell profiles at recurrence are associated with survival of IDH wildtype glioblastoma has not been studied in detail. PATIENTS AND METHODS Peripheral blood mononuclear cells (PBMC) of 21 healthy donors and of 52 clinically well-annotated patients with IDH wildtype glioblastoma were analyzed by 11-color flow cytometry at 1st recurrence after standard chemoirradiation with temozolomide and at 2nd recurrence after dose-intensified temozolomide re-challenge. Patients were treated within the randomized phase II trial DIRECTOR, which explored the efficacy of dose-intensified temozolomide at first recurrence of glioblastoma. Patients were classified based on unsupervised analyses of PBMC profiles at 1stand 2ndrecurrence. Associations with survival were explored in multivariate Cox models controlling for established prognostic and predictive factors. RESULTS At 1strecurrence, two patient clusters were identified which differed in CD4+ T-cell fractions, but not with respect to CD8+ T-cells, CD4+;CD25+;FoxP3+ regulatory T-cells, B-cells or monocytes. The composition of CD4+, CD8+ or regulatory T-cell fractions was similar in both clusters. All control samples clustered with the CD4high cluster. Patients in both clusters did not differ by established prognostic factors, including age, O6-methylguanine-DNA-methyl-transferase (MGMT) gene promoter methylation, tumor volume, Karfnosky performance score or steroid use. Progression-free survival was similar (CD4high vsCD4low 2.1 vs 2.4 months, p=0.19), whereas post-recurrence overall survival was longer among the CD4highcluster (12.7 vs 8.7 months, p= 0.004). At 2nd recurrence, monocyte fractions increased, whereas memory CD4+ T-cell fractions decreased. Unsupervised segregation of patients by CD4+ subpopulations yielded two clusters characterized by the abundance of memory T-cell fractions and higher memory CD4+ fractions were associated with longer overall survival at 2nd recurrence (p=0.004). The reported prognostic associations were retained in multivariate Cox models controlling for established prognostic factors. CONCLUSION We conclude that temozolomide-associated memory CD4+ T-cell depletion may have deteriorating effects on the survival of glioblastoma patients.