Modulations in the Peripheral Immune System of Glioblastoma Patient Is Connected to Therapy and Tumor Progression-A Case Report from the IMMO-GLIO-01 Trial

Abstract

Immune responses are important for efficient tumor elimination, also in immune privileged organs such as the brain. Fostering antitumor immunity has therefore become an important challenge in cancer therapy. This cannot only be achieved by immunotherapies as already standard treatments such as radiotherapy and chemotherapy modify the immune system. Consequently, the understanding of how the tumor, the tumor microenvironment, and immune system are modulated by cancer therapy is required for prognosis, prediction, and therapy adaption. The prospective, explorative, and observational IMMO-GLIO-01 trial was initiated to examine the detailed immune status and its modulation of about 50 patients suffering from primary glioblastoma multiforme (GBM) or anaplastic astrocytoma during standard therapy. Prior to the study, a flow cytometry-based assay was established allowing the analysis of 34 immune cell subsets and their activation state. Here, we present the case of the first and longest accompanied patient, a 53-year-old woman suffering from GBM in the front left lobe. In context of tumor progression and therapy, we describe the modulation of the peripheral immune status over 17 months. Distinct immune modulations that were connected to therapy response or tumor progression were identified. Inter alia, a shift of CD4:CD8 ratio was observed that correlated with tumor progression. Twice we observed a unique composition of peripheral immune cells that correlated with tumor progression. Thus, following up these immune modulations in a closely-meshed manner is of high prognostic and predictive relevance for supporting personalized therapy and increasing therapy success. Clinical Trial registration: ClinicalTrials.gov, identifier NCT02022384 (registered retrospectively on 13th of December, 2013).

Keywords: glioblastoma multiforme; immune status; immunophenotyping; liquid biopsy; personalized medicine; radiochemotherapy.

Figures

Figure 1

Individual therapy schedule and clinical response of the reported patient with glioblastoma. The time line depicts treatment (left side) and clinical response (right side) including pathological abnormalities and tumor progression. All numbers stated are in weeks with zero simultaneously being the starting point of radiochemotherapy and the evaluation of the immune status (indicated by red blood drops). The colors represent treatments or therapy outcomes according to the color code presented in the top right corner. This color code was also used for data presentation in Figure 3. The magnetic resonance imaging scans directly refer to the according image in Figures 2C–G.

Figure 2

Tumor progression identified by consecutive magnetic resonance imaging (MRI) scans reveals transient therapy success and two relapses. MRI scans showing T1- (upper panel) and T2-weighted images (lower panel) of a glioblastoma multiforme in the right temporal lobe, from primary diagnosis through the different stages of tumor progression. After primary diagnosis (A) and subsequent complete resection (B), standard concomitant radiochemotherapy (RCT) followed by adjuvant chemotherapy with Temodal (TMZ) according to Stupp et al. was performed. The first follow-up MRI (3 months after RCT) showed no signs of tumor recurrence (C). Two months later, an MRI was performed due to TMZ cytotoxicity. There were hints of tumor relapse (D), which was histologically confirmed after the lesion had been completely removed by surgery. Yet only 2 (E) and 3 months (F) after this second resection, tumor progression was first suspected and then confirmed. Thus, a conversion of therapy was decided, the therapy of choice being secondary radiotherapy combined with Avastin. This led to tumor regression as observed during the 3-month follow-up during aftercare with Avastin and irinotecan (G).

Figure 3

Multimodal therapy of glioblastoma has high impact on immune cells of the peripheral blood. The graphs of (A) and (C–F) display the absolute cell counts of immune cells or immune cell subsets in the peripheral blood, and in (B), the ratio from CD4+ helper T cells to CD8+ cytotoxic T cells is displayed. All immune cells were determined by a multicolor flow cytometry-based assay and directly detected in whole blood samples. The blood was always drawn prior to administering the drug or radiotherapy on the respective day. The color code represents the last applied therapy or pathological finding (red) and was applied according to Figure 1. The green background marks normal values and the red one deviation from it.