Co‐inhibitory blockade while preserving tolerance: checkpoint inhibitors for glioblastoma

Abstract

Summary The introduction of immunotherapy with checkpoint receptor blockade has changed the treatment of advanced cancers, at times inducing prolonged remission. Nevertheless, the success rate of the approach is variable across patients and different tumor types, and treatment is often accompanied by severe immune-related side effects, suggesting the importance of co-inhibitory pathway for both prevention of autoimmunity and failure of tumor rejection. A better understanding of how to uncouple anti-tumor activity from loss of self-tolerance is necessary in order to increase the therapeutic efficacy of checkpoint immunotherapy. In this review, we describe basic concepts of T cell exhaustion that occur in cancer, highlighting the role of co-inhibitory receptors in contributing to this process while preventing immunopathology. By providing an overview of the current therapeutic success and immune-related burden of secondary effects of checkpoint immunotherapy, we illustrate the “double-edged sword” related to interference with immune-regulatory pathways. Finally, since achieving tumor rejection while preserving self-tolerance is particularly important for the central nervous system, we analyze the case for checkpoint immunotherapy in glioblastoma, the most common adult brain tumor.

Costimulatory checkpoint SLAMF8 is an independent prognosis factor in glioma

“…Blockade of coinhibitory checkpoint molecules such as CTLA‐4, PD‐1, and PD‐L1 has resulted in breakthroughs for multiple malignancies, including glioma . However, checkpoint blockade has therapeutic benefit only for subsets of glioma . Treatment by checkpoint blockade is often accompanied by inflammation that is responsible for immune‐related side effects such as dermatitis, colitis, inflammatory endocrinopathies, and even fatal cerebral edema .…”

“…However, checkpoint blockade has therapeutic benefit only for subsets of glioma . Treatment by checkpoint blockade is often accompanied by inflammation that is responsible for immune‐related side effects such as dermatitis, colitis, inflammatory endocrinopathies, and even fatal cerebral edema . Given the limited regenerative capacity of neuronal tissue, adverse events from CNS inflammation of brain parenchyma are particularly deleterious .…”

Introduction to checkpoint inhibitors and cancer immunotherapy

“…The interaction between the CD28 costimulatory receptor and its ligands CD80 (B7‐1) and CD86 (B7‐2) fulfilled many requirements for the costimulatory signal envisioned by Lafferty and Cunningham (see this issue). However, the discovery of CTLA‐4 as a CD28 homolog that possessed potent inhibitory functions, dramatically changed our perception of the two signal model . We now appreciate that there are a number of inhibitory (coinhibitory) as well as stimulatory (costimulatory) second signals that can modulate T cell receptor (TCR)—mediated T signals.…”

“…First, further work is needed to understand the extent to which inhibitory checkpoints provide redundant or unique functions, and whether there is a hierarchy in the orchestration of their signals. For example, coinhibitory receptors can be coexpressed on T cells, and coblockade of the inhibitory receptors PD‐1 and CTLA‐4, or PD‐1 and Tim‐3, or PD‐1 and TIGIT, or PD‐1 and Vista can lead to better tumor clearance than blockade of each alone. It is not yet clear whether synergy results from coblockade on the same cell or different cells.…”

“…Some checkpoint receptors such as Tim‐3 are expressed on myeloid cells as well as T cells, suggesting roles on innate and adaptive immunity. Finally, inhibitory checkpoint blockade carries the risk of autoimmune adverse events, given the roles of inhibitory checkpoint molecules in T cell tolerance . A better understanding of how to uncouple anti‐tumor activity from loss of self tolerance is necessary to increase therapeutic efficacy of checkpoint blockade.…”