Immu-38. intratumoral correlation of multiplex immunofluorescence and89zr-crefmirlimab berdoxam immunopet in recurrent gbm patients treated with neoadjuvant anti-pd-1 +/- anti-ctla-4 therapy

Abstract Glioblastoma (GBM) is a highly aggressive brain tumor that responds poorly to checkpoint blockade inhibitors (ICIs), such as anti-PD-1. We previously reported that neoadjuvant anti-PD-1 therapy activated and recruited T cells into recurrent GBM (rGBM) tumors, but also increased immune checkpoint interactions between T cells and myeloid cells. To overcome this resistance mechanism, we are currently conducting a phase 1B clinical trial of neoadjuvant anti-PD-1 (Nivolumab, BMS) +/- anti-CTLA-4 (Ipilimumab, BMS) combination therapy for rGBM patients (NCT04606316). To evaluate the systemic and local tumor microenvironment effects of these checkpoint inhibitors, we used immuno-positron emission tomography (CD8 immunoPET, 89Zr-crefmirlimab berdoxam, ImaginAb) to track CD8+ T cells in five rGBM patients before and after neoadjuvant anti-PD-1 or combination therapy with anti-CTLA-4, and used multiplex immunofluorescence (mIF) to analyze the intratumoral immune profile of patient-matched tumors. We found that CD8 ImmunoPET imaging could detect physiologic tracer uptake in the lymph node basins and tumor bed prior to and following checkpoint blockade, suggesting a systemic immunometabolic response within the tumor after therapy. Correlation with mIF found that combination therapy (n=1) increased the density of conventional type 1 and 2 dendritic cells (cDC1: CD3-CD141+XCR1+ and cDC2: CD3-CD1c+) in the tumors, especially cDC1, compared to anti-PD-1 monotherapy (n=4) or untreated patients (n=3) (the densities of cDC1 and cDC2 cells were 163 cells/mm2 and 13.3 cells/mm2 respectively). Moreover, combination ICI therapy was associated with enhanced infiltration of CD8+ and CD4+ T cells in the tumor (28.7 cells/mm2 and 73.8 cells/mm2, respectively) with a specific increase in CD4+ T cells compared to anti-PD-1 monotherapy. In summary, preliminary results of the correlation of the longitudinal brain immunoPET imaging with the intratumoral mIF analysis in these five rGBM patients suggests distinct effects of monotherapy vs. combination neoadjuvant anti-PD-1 and anti-CTLA-4 therapy on the intratumoral immunometabolic profile of rGBM patients.