Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma

Abstract

Glioblastoma is the most common primary malignant brain tumor in adults and associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical PD-1 blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell and interferon-γ-related gene expression, but downregulation of cell cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 (PD-L1) in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells, and a decreasing monocytic population was observed more frequently in the neoadjuvant group than patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances the local and systemic anti-tumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.

Clinical chimeric antigen receptor‐T cell therapy: a new and promising treatment modality for glioblastoma

“…18 In other trial arms exploring combinations of nivolumab with ipilimumab, the response rate was a disappointing 7%. [20][21][22] Although acute ICI sensitivity of tumors with a high mutation burden, because of mismatch repair deficiency has been described, 23,24 recent data suggest that only 3.5% of primary or recurrent glioblastoma patients had a high somatic tumor mutation burden and so may benefit from ICI therapy. [20][21][22] Although acute ICI sensitivity of tumors with a high mutation burden, because of mismatch repair deficiency has been described, 23,24 recent data suggest that only 3.5% of primary or recurrent glioblastoma patients had a high somatic tumor mutation burden and so may benefit from ICI therapy.…”

“…19 In three recently reported studies of neoadjuvant anti-PD1 therapy in recurrent glioblastoma patients, although clinical responses were lacking, evidence on surgical resection specimens of persistent T-cell inflammation and pro-inflammatory cytokine profiles tended to favor an improved prognosis and may suggest a rationale for ICI use in conjunction with CAR-T cell therapy. [20][21][22] Although acute ICI sensitivity of tumors with a high mutation burden, because of mismatch repair deficiency has been described, 23,24 recent data suggest that only 3.5% of primary or recurrent glioblastoma patients had a high somatic tumor mutation burden and so may benefit from ICI therapy. 2 Notwithstanding promising case reports, [25][26][27][28] formal testing of the sensitivity of this group of patients to ICI therapy is awaited.…”

CAR T cells for brain tumors: Lessons learned and road ahead

“…Several preclinical studies have shown benefit in blocking PD‐1 or CTLA‐4 in murine glioma models. Importantly, two recent clinical reports have shown benefit for neoadjuvant anti‐PD‐1 immunotherapy in promoting survival and modifying the TME in glioma patients. These promising reports suggest that blocking PD‐1 changes the TME and could synergize with CAR T therapy in improving the survival of glioma patients.…”

“…Several preclinical studies have shown benefit in blocking PD- 1 181 or CTLA-4 182 in murine glioma models. Importantly, two recent clinical reports have shown benefit for neoadjuvant anti-PD-1 immunotherapy in promoting survival 20 and (IL13Rα2-CAR T + Nivolumab). Although, the clinical impact of CAR-T cells combined with checkpoint inhibitors in GBM is still unknown, results from these trials will provide important information regarding safety, feasibility, and potential anti-tumor activity.…”

“…Most brain tumors, however, including GBM and pediatric brain tumors, have low TMB and have been less responsive to ICIs . Encouragingly, neoadjuvant ICI prior to surgical resection has been shown to mediate a survival benefit in recurrent GBM, possibly by augmenting endogenous T cell responses . These studies are important as they establish that brain tumors are not impervious to immunological recognition and attack, and point to immunotherapy making inroads in brain tumor treatment.…”