Glioma Stem Cells as Immunotherapeutic Targets: Advancements and Challenges

Abstract

Glioblastoma is the most common and lethal primary brain malignancy. Despite major investments in research into glioblastoma biology and drug development, treatment remains limited and survival has not substantially improved beyond 1-2 years. Cancer stem cells (CSC) or glioma stem cells (GSC) refer to a population of tumor originating cells capable of self-renewal and differentiation. While controversial and challenging to study, evidence suggests that GCSs may result in glioblastoma tumor recurrence and resistance to treatment. Multiple treatment strategies have been suggested at targeting GCSs, including immunotherapy, posttranscriptional regulation, modulation of the tumor microenvironment, and epigenetic modulation. In this review, we discuss recent advances in glioblastoma treatment specifically focused on targeting of GCSs as well as their potential integration into current clinical pathways and trials.

Keywords: brain tumors; cancer stem cell; cancer vaccination; glioblastoma; glioblastoma stem cells; immunotherapy; radioresistance; tumor recurrence.

Figure 1

Characterization of glioma stem cells Various required functional characteristics of cancer stem cells (CSCs) and glioma stem cells (GCSs) are shown including self-renewal, proliferation, and initiation. Common characteristics include low frequency within a tumor, stem cell marker expression, and potential for differentiation. Reprinted with permission from Lathia et al. (3).

Figure 2

Methods of targeting glioma stem cells. Methods of targeting glioma stem cells (GSCs) can be divided into treatments targeting epigenetic regulation, metabolic pathways, microenvironment, post-transcriptional regulation, and immunotherapy. Within immunotherapy, strategies can include immunomodulatory drugs, oncolytic viral targeting, as well as passive, active, and adoptive immunotherapy approaches. Reprinted with permission from Gimple et al. (4).

Figure 3

Basic schema of the main immunotherapeutic modalities for targeting malignancies. In passive immunotherapy (A), antibodies are developed which bind specific tumor antigens and induce cellular-mediated phagocytosis or complement membrane attack complex-mediated cell death. In active immunotherapy (B), mononuclear cells are isolated from the patient’s blood then incubated with synthetic or biopsy-derived tumor antigens and activated before being transfused back into the patient in order to facilitate an anti-tumor T cell immune response. In adoptive immunotherapy (C), either tumor-infiltrating T cells are isolated from tumor biopsy, selected for their reactivity, and then transfused into a lymphodepleted patient, or T cells are isolated from blood, virally transduced to express a chimeric antigen receptor (CAR), and then transfused into a lymphodepleted patient.