gms | German Medical Science

Objective: Glioblastoma (GBM) has a devastating prognosis and recent advances in the treatment of variety of cancer entities e.g. through checkpoint inhibition could so far not be translated into improved outcome in GBM. Characterizing rare cases of peripheral metastasis, which formed as a result of immune evasion might enable understanding the mechanisms of immune escape. Here we describe the first reported case of a detailed genetic and immunological characterization of peripheral bone metastasis of a GBM, which could be controlled intracranially using anti-PD1 checkpoint inhibition

Methods: We performed whole genome sequencing (WGS) of the primary- and recurrent tumor, as well as the bone metastasis. Genomic data was analyzed for copy number variations (CNV) and mutational profiles were compared to known genomic alteration in the TCGA. In addition, immune monitoring with flow cytometric phenotyping and next-generation sequencing of the T-cell repertoire was used.

Results: We report about a 70-year old patient who was primarily diagnosed with IDHwt GBM. After primary resection and adjuvant radio-chemotherapy, his recurrent tumor was again resected, followed by intensified temozolomide. After progressive growth was detected, chemotherapy was replaced by anti-PD1 antibody treatment, which led to a complete intracranial remission. Two months later, still with intracranially remission, he was re-admitted with back pain. MR-imaging revealed multiple osseous lesions. Biopsy confirmed the peripheral GBM metastases. Immunophenotyping reflected the effective activation of the peripheral T-cell response, with, however, upregulation of regulatory T-cells during disease progression. WGS sequencing demonstrated a distinct molecular profile of the GBM metastasis, with amplification in chromosome 3 and 9, as well as genomic loss on chromosome 4, 10 and 11. Mutational analysis revealed new mutations in "immunologically vulnerable" regions, potentially affecting immune recognition and escape.

Conclusion: This case represents a unique opportunity to analyze potential mechanisms of GBM-mediated immune escape during immune activation with anti-PD1 checkpoint therapy. It highlights the fact, that although an effective, disinhibited immune response can control the cranial GBM disease, tumor clones have the ability to evade the tumor-specific T-cell response and disseminate to distant organs.