Window-of-opportunity clinical trial of pembrolizumab in patients with recurrent glioblastoma reveals predominance of immune-suppressive macrophages

Abstract

Background We sought to ascertain the immune effector function of pembrolizumab within the glioblastoma (GBM) microenvironment during the therapeutic window. Methods In an open-label, single-center, single-arm phase II “window-of-opportunity” trial in 15 patients with recurrent (operable) GBM receiving up to 2 pembrolizumab doses before surgery and every 3 weeks afterward until disease progression or unacceptable toxicities occurred, immune responses were evaluated within the tumor. Results No treatment-related deaths occurred. Overall median follow-up time was 50 months. Of 14 patients monitored, 10 had progressive disease, 3 had a partial response, and 1 had stable disease. Median progression-free survival (PFS) was 4.5 months (95% CI: 2.27, 6.83), and the 6-month PFS rate was 40%. Median overall survival (OS) was 20 months, with an estimated 1-year OS rate of 63%. GBM patients’ recurrent tumors contained few T cells that demonstrated a paucity of immune activation markers, but the tumor microenvironment was markedly enriched for CD68+ macrophages. Conclusions Immune analyses indicated that pembrolizumab anti–programmed cell death 1 (PD-1) monotherapy alone can’t induce effector immunologic response in most GBM patients, probably owing to a scarcity of T cells within the tumor microenvironment and a CD68+ macrophage preponderance.

Neutralizing PD-L1 and PD-L2 Enhances the Efficacy of Immune Checkpoint Inhibitors in Ovarian Cancer

“…The recent JAVELIN Ovarian 100 trial, which evaluated a αPD-1 antibody (avelumab) in combination with and/or following platinum-based chemotherapy in 998 previously untreated patients, found a poor overall response. Similar outcomes have been also reported in gastric, and brain malignancies (24,25,34,35). The immunosuppressive TME in these cancer types is particularly challenging to overcome.…”

“…To date, the single agent activities of anti-PD-1 and anti-PD-L1 inhibitors in some cancers have being disappointing (24,26). The recent JAVELIN Ovarian 100 trial, which evaluated a αPD-1 antibody (avelumab) in combination with and/or following platinum-based chemotherapy in 998 previously untreated patients, found a poor overall response.…”

“…To evaluate whether high PD-L2 expression is a potential biomarker for low ICB responding cancer types, we also examined PD-L1 and PD-L2 expression in gastric cancer (n=76), esophageal cancer (n=72) and glioblastoma (n=152) tissue microarrays (TMA). These cancers also reported as having poor clinical respond to ICB inhibitors (24)(25)(26). Similarly, high PD-L2 expression was observed in tumors samples but not normal tissues (Sup.…”

The High Expression of CD276/HAVCR2 and CD163 is an Adverse Immune Subtype of Glioblastoma and is Closely Related to Epithelial-Mesenchymal Transition

“…The most widely studied immune checkpoint in the eld of cancer is PD-L1/PD-1. But study found that the therapeutic effect was not satisfactory and there were differences in therapeutic effect [48]. Current clinical studies of non-small cell lung cancer have assumed that people with PD-L1 high levels of expression bene t more from the use of immune checkpoint inhibitors than patients with low or no PD-L1 expression [49].…”

Challenges to Successful Implementation of the Immune Checkpoint Inhibitors for Treatment of Glioblastoma

“…The study demonstrated that patients treated with Pembrolizumab did not experience improved survival with treatment [75]. In view of the failure of ICIs in the clinic, a Phase II window-of-opportunity trial (NCT02337686) was conducted to assess the immune effector cells upon treatment with an ICI [76]. This study examined the relative numbers of CD3 + lymphocytes and CD68 + monocytes in tumors in order to determine the composition of the immune infiltrate in recurrent GBM tumors after treatment with Pembrolizumab.…”