IMMU-28. HIGH-DIMENSIONAL SINGLE CELL CHARACTERIZATION OF THE SYSTEMIC INFLUENCE OF NEOADJUVANT PD-1 BLOCKADE IN PATIENTS WITH RECURRENT GLIOBLASTOMA

PD-1 blockade has demonstrated efficacy in numerous cancer types; however, responses vary widely. Consequently, numerous studies have sought to identify reliable biomarkers that predict response to PD-1 inhibition. Documented responses to PD-1 blockade in GBM are limited to patients with hypermutated phenotypes, which are rare in this disease. We opened a multi-institutional pilot study of pembrolizumab in patients with recurrent, surgically resectable GBM, randomizing patients 1:1 to receive neoadjuvant plus adjuvant pembrolizumab or adjuvant-only therapy. We hypothesized that neoadjuvant PD-1 blockade would lead to statistically significant differences in peripheral immune cell populations, using time-of-flight mass cytometry (CyTOF) to achieve our aims. Patients who received neoadjuvant pembrolizumab demonstrated decreases in a CD33+CD11b+CD11c+CD14+CD16+ intermediate monocyte population between baseline and after surgery (adjusted P value = 0.027), whereas no changes were seen in the adjuvant-only group. When evaluating the median expression of markers of antigen experience and activation on various cell populations, we noted increases in CD127 and CTLA4 (P = 0.016 and 0.006, respectively) as well as decreases in PD-1 and CD25 (P = 0.016 and 0.027, respectively) expression on CD4+ T-cells in the neoadjuvant group before and after the first dose of pembrolizumab, but not the adjuvant-only cohort. On CD8+ T-cells, there was a significant decrease in PD-1 expression in the neoadjuvant group only (P = 0.004). Furthermore, in penalized regression survival analyses, a CD4+ T-cell population has emerged as a potential predictor of clinical response. Leveraging time-of-flight mass cytometry, we have demonstrated that neoadjuvant PD-1 blockade elicits distinct changes in myeloid and lymphoid cell populations in patients with recurrent, surgically resectable glioblastoma. We hypothesize that this is reflective of tumor-specific T-cell activation in the presence of tumor antigens; these T-cells are subsequently expanded and activated in a tumor- and interferon-γ-driven process following surgical resection.