T lymphocyte-targeted immune checkpoint modulation in glioma

Abstract

Immunomodulatory therapies targeting inhibitory checkpoint molecules have revolutionized the treatment of solid tumor malignancies. Concerns about whether systemic administration of an immune checkpoint inhibitor could impact primary brain tumors were answered with the observation of definitive responses in pediatric patients harboring hypermutated gliomas. Although initial clinical results in patients with glioblastoma (GBM) were disappointing, recently published results have demonstrated a potential survival benefit in patients with recurrent GBM treated with neoadjuvant programmed cell death protein 1 blockade. While these findings necessitate verification in subsequent studies, they support the possibility of achieving clinical meaningful immune responses in malignant primary brain tumors including GBM, a disease in dire need of additional therapeutic options. There are several challenges involved in treating glioma with immune checkpoint modulators including the immunosuppressive nature of GBM itself with high inhibitory checkpoint expression, the immunoselective blood brain barrier impairing the ability for peripheral lymphocytes to traffic to the tumor microenvironment and the high prevalence of corticosteroid use which suppress lymphocyte activation. However, by simultaneously targeting multiple costimulatory and inhibitory pathways, it may be possible to achieve an effective antitumoral immune response. To this end, there are now several novel agents targeting more recently uncovered “second generation” checkpoint molecules. Given the multiplicity of drugs being considered for combination regimens, an increased understanding of the mechanisms of action and resistance combined with more robust preclinical and early clinical testing will be needed to be able to adequately test these agents. This review summarizes our current understanding of T lymphocyte-modulating checkpoint molecules as it pertains to glioma with the hope for a renewed focus on the most promising therapeutic strategies.

Molecular and Clinical Characterization of a Novel Prognostic and Immunologic Biomarker FAM111A in Diffuse Lower-Grade Glioma

“…Immunomodulatory therapies targeting immune checkpoint molecules have revolutionized the treatment of solid tumor malignancies (40,41). Due to the significance of ICB therapy, we evaluated the correlations between FAM111A and inhibitory checkpoint molecules.…”

WITHDRAWN: Anti-Oncogenic Activities Exhibited By Secretomes Of Mesenchymal Stem Cells Are Mediated By Modulation Of KITLG and DKK1 Genes In Glioma Stem Cells.

“…There are several challenges involved in treating glioma, including the immunosuppressive nature of GBM itself with high inhibitory checkpoint expression, the immunoselection blood brain barrier impairing the ability for peripheral lymphocytes to tra c to the tumor microenvironment and the high prevalence of corticosteroid use which suppress lymphocyte activation. However, by simultaneously targeting multiple costimulatory and inhibitory pathways, it may be possible to achieve an effective antitumoral immune response (117). This is where a combination of manipulated MSCs-secreted factors has the most signi cant potential.…”

Correlation Between APOBEC3B Expression and Clinical Characterization in Lower-Grade Gliomas

“…CD276 has become a novel Cart-T target for GBM ( 36 ) while inhibition of PD-1/PD-L1 pathway can be a latent treatment strategy for glioma ( 37 ). Other promising immune checkpoint molecules like 4-1BB, GITR, and TIGIT are further being considered to enter early phase clinical trials ( 38 ). Immune checkpoints also take part in immunosuppression: upregulating PD-L1 can bind receptors on immune cells and suppress lymphocyte activation ( 39 , 40 ).…”