Biomarkers for glioma immunotherapy: the next generation

Abstract

The term “biomarker” historically refers to a single parameter, such as the expression level of a gene or a radiographic pattern, used to indicate a broader biological state. Molecular indicators have been applied to several aspects of cancer therapy: to describe the genotypic and phenotypic state of neoplastic tissue for prognosis, to predict susceptibility to anti-proliferative agents, to validate the presence of specific drug targets, and to evaluate responsiveness to therapy. For glioblastoma (GBM), immunohistochemical and radiographic biomarkers accessible to the clinical lab have informed traditional regimens, but while immunotherapies have emerged as potentially disruptive weapons against this diffusely infiltrating, heterogeneous tumor, biomarkers with strong predictive power have not been fully established. The cancer immunotherapy field, through the recently accelerated expansion of trials, is currently leveraging this wealth of clinical and biological data to define and revise the use of biomarkers for improving prognostic accuracy, personalization of therapy, and evaluation of responses across the wide variety of tumors. Technological advancements in DNA sequencing, cytometry, and microscopy have facilitated the exploration of more integrated, high-dimensional profiling of the disease system—incorporating both immune and tumor parameters—rather than single metrics, as biomarkers for therapeutic sensitivity. Here we discuss the utility of traditional GBM biomarkers in immunotherapy and how the impending transformation of the biomarker paradigm—from single markers to integrated profiles—may offer the key to bringing predictive, personalized immunotherapy to GBM patients.

Diversity and divergence of the glioma-infiltrating T-cell receptor repertoire

“…Whereas the immune response itself provides selective pressure and has been associated with both effective tumor clearance and immunoediting of the cancer cell population (41), the combination of the identities and distribution of tumor-responsive TCRs represent a "footprint" of the conditions they face, such as neoantigenic load and dysfunctional immune signaling. Thus, identifying and tracking such T-cell clones has risen to priority as a potential high-dimensional biomarker for tumor development and personalized predictor of the efficacy of immunotherapeutic interventions in cancer (42,43).…”

An Update on the Role of Immunotherapy and Vaccine Strategies for Primary Brain Tumors

“…In preclinical models, radiation combined with antitumor vaccination showed significant survival benefit compared to each modality alone [96], and in another model, radiation significantly increased survival when combined with PD-1 checkpoint blockade compared to either alone [71]. Radiation leads to immune activation by upregulation of MHC-I molecules on irradiated tumor cells [97], enhancement of antigen presentation through danger signals and TAA release [99] following radiation-induced accelerated protein degradation [98], and increased expression of IFN-beta by tumor cells leading to improved DC maturation and antigen presentation [96]. & Clinical studies combining TMZ with rindopepimut surprisingly show augmentation of immune responses rather than the expected response attenuation in the context of cytotoxin-induced lymphopenia [39,48].…”

“…A more generalizable immune-activation signature, however, could enable consistent monitoring and cross-study evaluations. High-throughput molecular profiling is defining immune signatures for both activation and specificity of the immune response [99]. Multi-parameter flow cytometry assessing the relative abundance of effector T cells, Tregs, NK cells, and monocytes including immunosuppressive monocytes shows association with survival in GBM, non-Hodgkin's lymphoma, and RCC [100] and has been enhanced with the development of time-of-flight mass cytometry (CyTOF), enabling flow cytometry analysis in 25 dimensions [99].…”

“…High-throughput molecular profiling is defining immune signatures for both activation and specificity of the immune response [99]. Multi-parameter flow cytometry assessing the relative abundance of effector T cells, Tregs, NK cells, and monocytes including immunosuppressive monocytes shows association with survival in GBM, non-Hodgkin's lymphoma, and RCC [100] and has been enhanced with the development of time-of-flight mass cytometry (CyTOF), enabling flow cytometry analysis in 25 dimensions [99]. High-throughput RNAseq transcriptome profiling of tumor samples has been optimized for the clinical setting (NanoString, nCounter platform) to quantify cell types by markers, tumor antigens, and 9400 immune genes.…”

CHD1L Regulates Cell Cycle, Apoptosis, and Migration in Glioma

“…WHO classification based on the malignancy of the neoplasms ranges from grade I, corresponding to low-proliferative noninvasive tumors, up to grade IV, assigned to cytologically malignant, highly infiltrative, mitotically active, and necrosis-prone glioblastoma multiforme (GBM, malignant glioma) (Sims et al 2015). Current standard of care includes maximal safe surgical resection, fractionated radiation, and systemic temozolomide chemotherapy (Zhuang et al 2009).…”