Immunotherapy for primary brain tumors: no longer a matter of privilege

Abstract

Immunotherapy for cancer continues to gain both momentum and legitimacy as a rational mode of therapy and a vital treatment component in the emerging era of personalized medicine. Gliomas, and their most malignant form, glioblastoma, remain as a particularly devastating solid tumor for which standard treatment options proffer only modest efficacy and target specificity. Immunotherapy would seem a well-suited choice to address such deficiencies given both the modest inherent immunogenicity of gliomas and the strong desire for treatment specificity within the confines of the toxicity-averse normal brain. This review highlights the caveats and challenges to immunotherapy for primary brain tumors, as well as reviewing modalities that are currently used or are undergoing active investigation. Tumor immunosuppressive countermeasures, peculiarities of central nervous system immune access, and opportunities for rational treatment design are discussed.

Figure 1

Targeting typical GBM antigens. Immunotherapy takes a variety of forms that may ultimately target glioma surface antigens or antigens expressed in the cytoplasm that are processed and presented in the context of MHC class I. In this figure, a sampling of surface (left) and intracellular (right) glioma antigens that have been commonly targeted are represented, along with pertinent immunotherapeutic effectors. Some of the primary modalities targeting surface antigens/receptors are antibodies/ligands (unarmed or armed with toxins (black ring) or radionucleotides (red ring)); BiTEs, which recruit T-cells to the tumor cell surface; and CAR+ T-cells, which provide surface-antigen specificity to otherwise non-reactive T-cells. For intracellular antigens presented in the context of MHC I, T-cells are the primary effectors. These may be adoptively transferred (ALT), or activated by DC, antigenic, HSPPC, or DNA/viral vaccines. Their activity may also be non-specifically perpetuated by immune checkpoint blockade with antibodies to CTLA-4 and PD-1, for instance, which can also inhibit T_reg-mediated T-cell suppression. Recent work to build a vaccine against a mutated IDH-1 has revealed mostly class II epitopes for mutation-spanning peptides, which may provide a target to CD4 T-cells in the context of low levels of glioma class II MHC, or may stimulate a CD4 helper response via APC-mediated class II MHC presentation to CD4 T-cells.

Figure 2

GBM immuno-evasive and –suppressive mechanisms. GBM employs a variety of mechanisms, both cell intrinsic and extrinsic, meant to sidestep or even directly counter host immune responses. GBM is pictured here as red cells amongst orange normal brain (glial cells). Inset on the left represents magnification of tumor, normal glia, and a CD8 T-cell with typical exhausted phenotype. GBM cell-intrinsic mechanisms (visible on inset) include IDO expression (leading to recruitment of tumor-associated T_regs (black dotted arrow)) (88), down regulated MHC and B7 family proteins (89, 90), increased PD-L1 (91), PTEN loss (which can precipitate PD-L1 expression) (92), STAT3 expression/activation (pleotropic immunosuppression) (93), TGF-β and IL-10 production (causing counterproductive TH2 shifts and elaborating T_regs) (94), MICA/B secretion (inhibiting both T- and NK-cell activity) (95, 96), and HLA-E expression (inhibiting NK cells) (97). Cell-extrinsic mechanisms comprise effects on surrounding and systemic immune cells, and include lymhopenia and depressed cellular immunity. Patient T-cells are hampered by anergy (82, 83), IL-2 system dysfunction (84), TH2-biased responsiveness (85), decreased NKG2D expression (86), and inhibition by disproportionate representations of T_regs (81).