High tumor mutational burden and T-cell activation are associated with long-term response to anti-PD1 therapy in Lynch syndrome recurrent glioblastoma patient

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2021-03, Vol.70 (3), p.831-842
• Main Authors: Anghileri, Elena, Di Ianni, Natalia, Paterra, Rosina, Langella, Tiziana, Zhao, Junfei, Eoli, Marica, Patanè, Monica, Pollo, Bianca, Cuccarini, Valeria, Iavarone, Antonio, Rabadan, Raul, Finocchiaro, Gaetano, Pellegatta, Serena
• Format: Article
• Language: English
• Subjects: Adult; Biomarkers, Tumor; Biopsy; Brain cancer; Cancer Research; CD163 antigen; CD3 antigen; CD4 antigen; CD8 antigen; Cell activation; Cell density; Colorectal cancer; Colorectal Neoplasms, Hereditary Nonpolyposis - diagnosis; Colorectal Neoplasms, Hereditary Nonpolyposis - drug therapy; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics; Combined Modality Therapy; Exome Sequencing; Female; Flow cytometry; Genetic disorders; Glioblastoma; Glioblastoma - diagnostic imaging; Glioblastoma - pathology; Glioblastoma - therapy; Humans; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunohistochemistry; Immunology; Immunotherapy; Infiltration; Lymphocytes; Lymphocytes T; Magnetic Resonance Imaging; Medicine; Medicine & Public Health; Memory cells; Metastases; Molecular Targeted Therapy; Monoclonal antibodies; MSH2 protein; Mutation; Neoplasm Recurrence, Local; Neuroimaging; Oncology; Original; Original Article; Patients; PD-1 protein; Phenotypes; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Radiation therapy; Retreatment; Surgery; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Targeted cancer therapy; Temozolomide; Treatment Outcome
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-020-02769-4

Background Glioblastomas (GBMs) in patients harboring somatic or germinal mutations of mismatch-repair (MMR) genes exhibit a hypermutable phenotype. Here, we describe a GBM patient with increased tumor mutational burden and germline MMR mutations, treated using anti-PD1 therapy. Methods A woman with newly diagnosed GBM (nGBM) was treated by surgery, radiotherapy, and temozolomide. The tumor recurred after 13 months leading to a second surgery and treatment with nivolumab. Whole-exome sequencing was performed on the nGBM, recurrent GBM (rGBM), and blood. Immune infiltration was investigated by immunohistochemistry and the immune response in the blood during treatment was analyzed by flow cytometry. Results High density of infiltrating CD163 + cells was found in both GBM specimens. Large numbers of CD3 + and CD8 + T cells were homogeneously distributed in the nGBM. The infiltration of CD4 + T cells and a different CD8 + T cell density were observed in the rGBM. Both GBM shared 12,431 somatic mutations, with 113 substitutions specific to the nGBM and 1,683 specific to the rGBM. Germline variants included pathogenic mutation in the MSH2 (R359S) gene, suggesting the diagnosis of Lynch syndrome. Systemic immunophenotyping revealed the generation of CD8 + T memory cells and persistent activation of CD4 + T cells. The patient is still receiving nivolumab 68 months after the second surgery. Conclusions Our observations indicate that the hypermutator phenotype associated with germinal mutations of MMR genes and abundant T-cell infiltration contributes to a durable clinical benefit sustained by a persistent and robust immune response during anti-PD1 therapy.