Immunotherapy of Malignant Tumors in the Brain: How Different from Other Sites?

Abstract

Immunotherapy is now advancing at remarkable pace for tumors located in various tissues, including the brain. Strategies launched decades ago, such as tumor antigen-specific therapeutic vaccines and adoptive transfer of tumor-infiltrating lymphocytes are being complemented by molecular engineering approaches allowing the development of tumor-specific TCR transgenic and chimeric antigen receptor T cells. In addition, the spectacular results obtained in the last years with immune checkpoint inhibitors are transfiguring immunotherapy, these agents being used both as single molecules, but also in combination with other immunotherapeutic modalities. Implementation of these various strategies is ongoing for more and more malignancies, including tumors located in the brain, raising the question of the immunological particularities of this site. This may necessitate cautious selection of tumor antigens, minimizing the immunosuppressive environment and promoting efficient T cell trafficking to the tumor. Once these aspects are taken into account, we might efficiently design immunotherapy for patients suffering from tumors located in the brain, with beneficial clinical outcome.

Responsiveness to anti-PD-1 and anti-CTLA-4 immune checkpoint blockade in SB28 and GL261 mouse glioma models

“…1,2 In other cancers immunotherapy is already revolutionizing therapeutic options, which has encouraged testing similar approaches in GBM. [3][4][5][6] Nevertheless, the absence of any clinical breakthrough to date indicates that better understanding of the particularities of human GBM in response to immunotherapy is needed. Unfortunately, to achieve this, human GBM cells cannot be used for most preclinical mechanistic studies of immunotherapy because of the obligation to use a fully immunocompetent animal model.…”

Cellular and molecular characterization of IDH1‐mutated diffuse low grade gliomas reveals tumor heterogeneity and absence of EGFR/PDGFRα activation

“…Recent therapeutic developments aim at targeting the mutated IDH1 enzyme with promising inhibitors (Rohle et al, 2013). In addition, several immunotherapy approaches such as vaccine therapies against the mutated form of IDH1 enzyme are being evaluated in early-phase trials (Dutoit, Migliorini, Dietrich, & Walker, 2016;Schumacher et al, 2014).…”

Immunotherapy in Glioblastoma: Current Shortcomings and Future Perspectives

“…Different studies have predicted the presence of only a handful of low expressed glioma neoantigens derived from mutated genes [44][45][46][47]. While other, non-mutated targets (e.g., Cancer Germline Antigens (CGAs)) are frequently expressed in glioblastoma, expression levels are low or, at best, highly variable [44,48]. Besides gene expression, tumor antigens need to pass through the antigen processing and presenting machinery (APM) to enable recognition by T cells.…”