Immunotherapy for pediatric brain tumors: past and present

Abstract

The field of cancer immunotherapy has progressed at an accelerated rate over the past decade. Pediatric brain tumors thus far have presented a formidable challenge for immunotherapy development, given their typically low mutational burden, location behind the blood-brain barrier in a unique tumor microenvironment, and intratumoral heterogeneity. Despite these challenges, recent developments in the field have resulted in exciting preclinical evidence for various immunotherapies and multiple clinical trials. This work reviews the history and advances in active immunotherapy, checkpoint blockade, and adoptive T-cell therapy for pediatric brain tumors, including ongoing clinical trials.

Keywords: brain tumor; immunotherapy; pediatric.

Figure 1.

Immune activation by cancer cell TSAs. Mutations occurring in the cancer cell genome are transcribed and translated into mutant proteins (“neoantigen”) that undergo digestion and processing onto MHC molecules for presentation to T cells via their specific TCR. Mutant proteins can also be released by the cancer cell for uptake and processing by APCs such as dendritic cells for immune activation. A similar process occurs for immune activation by TAAs except that self-antigens are being presented at high levels by tumor cells rather than novel or mutant proteins in the case of TSAs. Reproduced from Ajina et al, with permission.

Figure 2.

Negative checkpoint regulators. Simplified representation of stimulatory and inhibitor ligands and receptors at the T-cell surface. CTLA-4, PD1, Lag3, and Tim3 interact with ligands on tumor cells and antigen presenting cells (APCs) to produce an inhibitory effect on proliferation and cytotoxic effector function of the T cell. These regulators, as well as PDL1, are the targets blocked by checkpoint blockade therapeutics.

Figure 3.

Schematic of adoptive T-cell therapy. Immune cells, often T cells or NK cells, are taken from a patient and separated for expansion. Immune cells can then be manipulated ex vivo, including selection for activity against a particular immune stimulus, or introduction of a TCR or CAR. After ensuring successful manipulation, these cells are then re-introduced into the patient where they can exert cytotoxic effects on a tumor.