IMMU-23. NEOADJUVANT ANTI-PD-1 AND ANTI-CTLA-4 COMBINATION THERAPY INDUCED INTRATUMORAL IMMUNOLOGIC ALTERATIONS IN RECURRENT GBM PATIENTS

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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 local tumor microenvironment effects of these checkpoint inhibitors, we used multiplex immunofluorescence (mIF), bulk RNA sequencing, and T cell receptor sequencing to analyze the intratumoral immune profile of tumors. Using mIF, we are able to determine the density of key immune cell phenotypes within the section of tumor sample as well as the proximity between phenotypes to better understand their interactions. Patients who received the combination therapy (n=15) trended to have a higher median density of cytotoxic T cells (CD45+CD8+; median density of 27.13 cells/mm2 for combination therapy and 13.78 cells/mm2 for anti-PD-1), helper T cells (CD45+CD4+; median density of 33.73 cells/mm2 for combination therapy and 9.82 cells/mm2 for anti-PD-1), monocytes (CD14+), and HLA-DR+ macrophages (CD45+CD14+HLA-DR+) while patients treated with anti-PD-1 alone (n=16) trended to have densities similar to placebo treated patients (n=6). Patients treated with combination therapy are also trending to have a higher density of macrophages in close proximity (≤20μm) to T cells, particularly HLA-DR+ macrophages, suggesting a higher frequency of interactions within their tumor microenvironments. This data set is currently incomplete, but the final data set will be completed by the meeting. Nonetheless, these preliminary results, as well as the bulk RNA sequencing and T cell receptor sequencing, suggest distinct immunologic effects of monotherapy vs. combination neoadjuvant anti-PD-1 and anti-CTLA-4 therapy in the tumor microenvironment of rGBM patients.