Immunotherapy in Glioblastoma: Current Shortcomings and Future Perspectives

Abstract

Glioblastomas are aggressive, fast-growing primary brain tumors. After standard-of-care treatment with radiation in combination with temozolomide, the overall prognosis of newly diagnosed patients remains poor, with a 2-year survival rate of less than 20%. The remarkable survival benefit gained with immunotherapy in several extracranial tumor types spurred a variety of experimental intervention studies in glioblastoma patients. These ranged from immune checkpoint inhibition to vaccinations and adoptive T cell therapies. Unfortunately, almost all clinical outcomes were universally disappointing. In this perspective, we provide an overview of immune interventions performed to date in glioblastoma patients and re-evaluate their performance. We argue that shortcomings of current immune therapies in glioblastoma are related to three major determinants of resistance, namely: low immunogenicity; immune privilege of the central nervous system; and immunosuppressive micro-environment. In this perspective, we propose strategies that are guided by exact shortcomings to sensitize glioblastoma prior to treatment with therapies that enhance numbers and/or activation state of CD8 T cells.

Keywords: adoptive T cell therapy; antigens; checkpoint inhibitors; clinical studies; glioblastoma; immune privilege; tumor micro-environment; vaccines.

Figure 1

Exemplary immune-suppressive mechanisms in glioblastoma, and therapeutic interventions to sensitize glioblastoma for T cell treatments. (A) Tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) release immunosuppressive mediators in the glioblastoma microenvironment, such as TGF-β and IL-10 (the latter not depicted). Local production of indoleamine 2,3- dioxygenase (IDO) or tryptophan-2,3-dioxygenase (TDO) by glioblastoma cells depletes tryptophan from the tumor micro-environment, having an adverse effect on the function of CD8 T cells. Also, the immune checkpoint, PD-L1, expressed on glioblastoma cells can engage with PD-1+ T cells to suppress their effector function. (B) Monoclonal antibodies directed against glucocorticoid-induced TNFR related protein (GITR) and IL-2 receptor α (IL-2Rα) may specifically deplete intratumoral Tregs. Immunosuppressive effects exerted by TGF-β can be abolished by small molecule inhibitors, such as galunisertib. IDO and TDO inhibitors (the latter not depicted) may restore tryptophan levels in the micro-environment, causing re-activation of CD8 T cells. TAM-induced immunosuppression may be counteracted using inhibitors against colony-stimulation factor 1 (CSF1) or its receptor. Oncolytic virotherapy and radiotherapy may cause increased release of antigens, which in turn may result in enhanced numbers and activation of intratumoral CD8 T cells. When (one or several of) these interventions are combined with vaccines, immune checkpoint inhibitors (ICIs) or adoptive transfer of effector lymphocytes, this may significantly improve the recruitment and/or activation state of glioblastoma-specific CD8 T cells and lead to restoration of the efficacy of these T cell treatments in glioblastoma.