Immunotherapy of Primary Brain Tumors: Facts and Hopes

Abstract

The field of cancer immunotherapy has made exciting progress for some cancer types in recent years. However, recent failures of late-phase clinical trials evaluating checkpoint blockade in patients with glioblastoma (GBM) represent continued challenges for brain cancer immunotherapy. This is likely due to multiple factors including but not limited to marked genetic and antigenic heterogeneity, relatively low mutational loads, and paucity of GBM-infiltrating T cells. We review recent and ongoing studies targeting the checkpoint molecules as monotherapy or in combination with other modalities, and discuss the mechanisms underlying the unresponsiveness of GBM to single-modality immunotherapy approaches. We also discuss other novel immunotherapy approaches that may promote T-cell responses and overcome the "cold tumor" status of GBM, including oncolytic viruses and adoptive T-cell therapy. .

Convection-enhanced delivery of temozolomide and whole cell tumor immunizations in GL261 and KR158 experimental mouse gliomas

“…Current therapeutic regimens are insufficient to treat GBM and median survival is less than two years [1]. GBM displays an intrinsic resistance to therapy and is considered a "cold tumor" due to, among other factors, a highly immunosuppressive tumor milieu, defects in tumor antigen presentation, and features of the physical microenvironment such as necrosis and hypoxia [2,3]. These obstacles underscore the need to develop novel treatments, based on combined treatment strategies.…”

“…Within the GBM tumor microenvironment, tumor cells down-regulate costimulatory molecules and secrete a repertoire of cytokines to avoid immune surveillance, shifting myeloid cells into myeloid-derived suppressor cells (MDSC) and suppressive tumor-associated macrophages (TAM) [4]. Therefore, intratumoral immunosuppression is a decisive factor responsible for the overall poor outcome in patients with GBM [3] and it also could impact the potential antitumor effect generated by immunotherapy [5,6].…”

Reduced Neoantigen Expression Revealed by Longitudinal Multiomics as a Possible Immune Evasion Mechanism in Glioma

“…In gliomas, however, thus far there has been very limited success of immune-based therapies, not only ICI, but also vaccination and adoptive chimeric antigen receptor T-cell (CAR-T) treatment (18,19). This may be at least partly due to the relatively low number of neoantigens on gliomas that can be targeted by the immune system, together with several immune resistance mechanisms that have been documented for this cancer type (20,21). It remains unclear whether the small number of neoantigens that may be present are in fact recognized and edited by the immune system during glioma progression.…”

A tumor‐targeting nanomedicine carrying the p53 gene crosses the blood–brain barrier and enhances anti‐PD‐1 immunotherapy in mouse models of glioblastoma

“…Intrinsic unresponsiveness and acquired drug resistance coupled with restricted accessibility of brain tumors to drugs tied to the impermeability of the blood–brain barrier (BBB) may all contribute to the treatment failure. In addition, glioblastoma has developed an array of strategies to evade/suppress the antitumor immune responses, which also likely contribute to the failure . Therefore, novel therapeutic approaches are greatly needed to improve the outcomes currently seen with conventional therapies.…”

“…In addition, glioblastoma has developed an array of strategies to evade/suppress the antitumor immune responses, which also likely contribute to the failure. 3 Therefore, novel therapeutic approaches are greatly needed to improve the outcomes currently seen with conventional therapies.…”