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ICI as High-Grade Gliomas Treatment: History
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Subjects: Oncology
Contributor: Pasquale Persico

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults. Despite significant efforts, no therapies have demonstrated valuable survival benefit beyond the current standard of care. Immune checkpoint inhibitors (ICI) have revolutionized the treatment landscape and improved patient survival in many advanced malignancies. Unfortunately, these clinical successes have not been replicated in the neuro-oncology field so far. This review summarizes the status of ICI investigation in high-grade gliomas, critically presenting the available data from preclinical models and clinical trials. Moreover, we explore new approaches to increase ICI efficacy, with a particular focus on combinatorial strategies, and the potential biomarkers to identify patients most likely to benefit from immune checkpoint blockade.

  • checkpoint inhibitors
  • immunotherapy
  • brain cancer
  • glioma
  • glioblastoma
  • PD-1
  • PD-L1

1. Introduction

Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults, with <10% of newly diagnosed patients alive at five years, despite an aggressive multimodality treatment approach, based on maximal safe surgical resection, followed by radiotherapy (RT) and temozolomide (TMZ) [1]. Previous investigations of different strategies, such as intensification of chemotherapy (CT) [2], targeting dysregulated cell-signaling pathways [3], and antiangiogenic therapy [4][5], failed to improve survival in randomized clinical trials and the standard of care (SOC) remained unchanged over the last decade. No truly effective therapy exists at recurrence, and therefore, innovative therapeutic approaches are urgently needed [6]. In the last years, immunotherapy, with its own concept of boosting tumor-specific adaptive immunity instead of directly targeting cancer cells, has recently emerged as a cornerstone of modern oncology [7].

High-grade gliomas (HGG) tumor microenvironment (TME) is unique in its cellular composition and accessibility to immune cells, being insulated by the blood-brain-barrier (BBB). Tumor-associated macrophages (TAM) are highly prevalent in GBM, constituting up to 30% of TME, and tend to be pro-tumorigenic. Moreover, TAMs produce low pro-inflammatory cytokine levels, poorly express costimulatory molecules involved in T-cells activation and have a pleiotropic capability to suppress cluster differentiation 8 (CD8)+ T cell activity in GBM. Dendritic cells (DC) are professional antigen-presenting cells (APC) with a crucial role in initiating and shaping immune responses. Recent transcriptomic analyses of human GBM samples confirmed DCs’ presence, but their role in glioma is still a matter of debate. Neutrophils are the most prevalent immune population, comprising up to 70% of total leukocytes in the body. In glioma, they support progression, invasiveness, and angiogenesis through the secretion of elastase and metalloproteases. Neutrophils-to-lymphocytes ratio (NLR) in blood correlates with glioma grade and is highest in GBM. Moreover, an elevated NLR is associated with poor clinical outcomes in GBM patients [8][9].

HGG TME is characterized by low numbers of CD8+ cytotoxic infiltrating T cells (TIL). Conversely, CD4+ regulatory T cells (Tregs) levels are increased in GBM. Tregs exert an immune-suppressive role as they secrete transforming growth factor beta and interleukin 10 (IL-10), limiting IL-2 and interferon (IFN) production and suppressing T cells’ survival and activity. GBM actively recruits Tregs producing soluble factors, such as C-C motif chemokine ligand 2. Moreover, TAMs expressing T-cell immunoglobulin and mucin domain-containing molecule-4 and DCs producing indoleamine 2,3 dioxygenase (IDO) also play a direct role in Tregs induction. Lastly, natural killer (NK) cells are innate lymphoid cells representing about 10% of all circulating lymphocytes. In GBM, they represent a minor component of TME and are reduced in glioma patients’ bloodstream as compared to healthy controls [8][10].

In physiological conditions, a series of stimulatory and inhibitory pathways called “immune checkpoints” regulate and optimize immune responses’ strength and magnitude, limiting potential harmful effects on normal tissues [11]. Aberrant immune checkpoint signaling is one of the fundamental mechanisms used by tumor cells to dampen the immune response and avoid detection and killing. The upregulation of the programmed cell death 1(PD-1)/programmed death-ligand 1 (PD-L1) axis is one of the key contributors to immunosuppression in glioma TME. PD-1/PD-L1 signaling impairs T-cell activation, cytotoxicity, and proliferation and enhances Tregs survival. Moreover, glioma cells upregulate PD-L1 in myeloid cells and Tregs. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is expressed by naïve T cells and negatively interacts with APCs reducing early stages of T-cell expansion. CTLA-4 is also constitutively expressed on Tregs, being a key contributor to their immunosuppressive functions. Moreover, the upregulation of alternative immune checkpoints, as T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) and lymphocyte-activation gene 3 (LAG-3), is a hallmark of GBM, leading to a severe exhausted T-cell phenotype [10][12]. Immunomodulating monoclonal antibodies (mAb) targeting these immune checkpoints can reverse T-cell dysfunctionality, enhancing immune control, and restoring antitumor activity [11].

Immune checkpoint inhibitors (ICI) have revolutionized the treatment paradigm of several historically resistant cancers, achieving regulatory approvals for several different malignancies and indications [13][14]. Since the Food and Drug Administration (FDA) approval of ipilimumab (anti-CTLA-4 mAb) in 2011, PD-1 inhibitors nivolumab, pembrolizumab, cemiplimab, and PD-L1 inhibitors atezolizumab, avelumab, and durvalumab have entered clinical use. These remarkable successes have raised great expectations in whether these agents could be such effective also in the context of neuro-oncology, and an intensive clinical investigation has been undertaken. Unfortunately, to date, these efforts have been entirely unsuccessful.

 

2. Biomarkers

Unlike other immune-responsive cancers (e.g., melanoma, lung cancer), malignant gliomas are characterized by poor T-cells infiltration, a low tumor mutational burden (TMB), and a strongly immunosuppressive TME, representing the paradigm of what we call a “cold tumor” [15]. As observed in other immune refractory cancers, clinical investigations demonstrated that only a small fraction of GBM patients achieve durable benefit by immune checkpoint modulation. Waiting for effective combinatorial strategies that will hopefully widen the range of responders, there is an urgent need for biomarkers to guide clinicians in patient selection.

Several factors, such as high PD-L1 expression, microsatellite instability (MSI), deficient DNA mismatch repair (MMRd), and a high TMB, among others, have been identified as predictors of responsiveness to checkpoint blockade in different solid malignancies [16]. It is currently unclear whether these biomarkers could also have a predictive significance in the glioma field.

PD-L1 expression widely varies across the different studies in malignant gliomas specimens, ranging from 7.8% to 88%, due to differences in antibodies used for PD-L1 detection, staining pattern (membranous or fibrillary), and cut-off values for PD-L1 expression [17][18]. Notably, among a series of 43 grade II/III and grade IV gliomas, IDH-wild-type gliomas appeared as more immune-activated tumors due to a higher rate of TILs infiltration and PD-L1 expression in comparison to IDH-mutated gliomas (p < 0.001) [19]. A recent metanalysis of nine studies, including 806 GBM patients, indicated that PD-L1 expression in tumor tissues was significantly related to a poor clinical outcome (HR = 1.63, 95% CI: 1.19–2.24, p = 0.003) [20]. Beyond the negative prognostic value, neither PD-1 nor PD-L1 expression has been definitively shown to be predictive of response to immunotherapies in gliomas.

In the sole prospective phase III trial published so far, the Checkmate 143 trial, PD-L1 tumor expression was determined retrospectively by a central laboratory on archival tumor tissue from first surgery or recurrence, with PD-L1 positivity defined as membranous staining in ≥1% of tumor cells. Only 26% of tumor specimens in the nivolumab group were PD-L1 positive, and no predictive value was found at a prespecified subgroup analysis [21].

Besides its well-recognized predictive role in GBM patients undergoing standard chemoradiation with TMZ, MGMT promoter methylation is emerging as a factor potentially associated with improved outcomes in patients receiving different immunotherapeutic strategies. Again in the Checkmate 143 trial, MGMT methylated patients with no baseline corticosteroid use had a trend toward improved OS with nivolumab (17.0 months) vs. bevacizumab (10.1 months) [21]. Moreover, preliminary data from a phase 3 randomized, double-blinded, placebo-controlled clinical trial of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) for newly diagnosed GBM showed that the median OS was 34.7 months (95% CI 27.0–40.7) and 19.8 months (95% CI 17.9–21.7), in patients with methylated and unmethylated MGMT, respectively [22]. A possible explanation for these findings is that MGMT methylated tumors exhibit four more times the number of somatic mutations than MGMT-unmethylated GBM, making these tumors more immunogenic and more susceptible to the action of different immunotherapeutic approaches [23].

In a retrospective series of 66 adult patients with recurrent GBM treated with PD-1 inhibitors (pembrolizumab or nivolumab), including 17 long-term responders, genomic and transcriptomic analysis revealed a significant enrichment of phosphatase and tensin homolog (PTEN) mutations associated with immunosuppressive expression signatures in non-responders (p < 0.05), and enrichment of mitogen-activated protein kinase (MAPK) pathway alterations (protein tyrosine phosphatase non-receptor type 11, BRAF) in responders (p < 0.05). In the same study, correlation analysis showed that PTEN mutations are significantly associated with higher levels of macrophages, microglia, and neutrophils in the TME (p < 0.05). Of interest, in post-treatment PTEN wild-type samples, the density of CD3+ T cells significantly increased compared with pre-treatment samples (p = 0.0095), while PTEN-mutated samples did not show this pattern [24].

Improved response to checkpoint blockade is associated with a higher TMB across multiple cancer types. This association in HGGs remains uncertain. Fewer than 2% of newly diagnosed GBM and up to 20–30% of recurrent GBM after TMZ exposure exhibit a hypermutated genotype often associated with MMRd. Moreover, lower-grade gliomas treated with TMZ can also recur as hypermutated HGG [25][26]. Previous clinical reports demonstrated the potential activity of ICIs in this setting. Bouffet et al. showed remarkable and durable tumor regressions in two pediatric siblings with recurrent multifocal germline biallelic MMRd GBM treated with nivolumab [27]. In another case, an adult GBM patient diagnosed with a hypermutated genotype in the setting of a polymerase epsilon gene (POLE) germline alteration had a sustained response to pembrolizumab therapy after an intracranial and spinal progression [28]. Touat et al. performed a comprehensive molecular analysis in 10,294 gliomas from clinical sequencing panels datasets and a retrospective review of 11 MMRd glioma patients treated with PD-1 blockade. In this study, MMRd gliomas were predominantly associated with TMZ exposure, lacked significant T-cell infiltrates, were not associated with MSI, and were characterized by extensive intratumoral heterogeneity, poor survival, and a low response-rate to immunotherapy [29].

Recently, in two cohorts stratified by TMB, recurrent GBM patients with ≤ median TMB had more prolonged survival after anti-PD-1/PD-L1 blockade than those with > median TMB [30]. Transcriptomic analyses also showed enriched inflammatory gene signatures in recurrent GBM tumors with a low TMB [30]. Survival differences were maintained after excluding IDH-mutated, MGMT methylated, and hypermutated patients and were not related to steroid dosage [30]. Notably, these associations were not showed in primary GBM patients [30]. Accordingly, in a recent observational study, 13 patients (eight GBM, four anaplastic astrocytomas, one anaplastic oligodendroglioma) with partial or complete loss of mismatch repair proteins had no apparent clinical benefit from pembrolizumab treatment (median PFS 2.2 months, median OS 5.6 months, no partial or complete response) [31]. Likewise, in the phase II study KEYNOTE-158 evaluating pembrolizumab activity in several different non-colorectal cancers harboring MMRd or MSI, only brain tumor patients (n = 13) showed no radiological response with a median PFS and OS of 1.1 and 5.6 months, respectively [32].

This entry is adapted from the peer-reviewed paper 10.3390/jcm10071367

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