The Role of Immune Checkpoint Inhibition in the Treatment of Brain Tumors

Abstract

The standard of care for malignant gliomas of the brain has changed very little over the last few decades, and does not offer a cure for these rare, but fatal, tumors. The field of immunotherapy has brought potent new drugs into the oncological armamentarium, and is becoming recognized as a potentially important arm in the treatment of glioblastoma for adults. Immune checkpoints are inhibitory receptors found on immune cells that, when stimulated, cause those immune cells to become quiescent. While this is a natural mechanism to prevent excessive inflammatory damage and autoimmunity in otherwise healthy tissues, cancer cells may utilize this process to grow in the absence of targeted immune destruction. Antibodies derived to block the stimulation of these negative checkpoints, allowing immune cells to remain activated and undergo effector function, are a growing area of immunotherapy. These therapies have seen much success in both the preclinical and clinical arenas for various tumors, particularly melanoma and nonsmall-cell lung cancer. Multiple clinical trials are underway to determine if these drugs have efficacy in glioblastoma. Here, we review the current evidence, from early preclinical data to lessons learned from clinical trials outside of glioblastoma, to assess the potential of immune checkpoint inhibition in the treatment of brain tumors and discuss how this therapy may be implemented with the present standard of care.

Keywords: Brain tumor; CTLA-4; Glioma; Immune checkpoint; PD-1.

Fig. 1

Immune checkpoint receptors and their cognate ligands can either inhibit or enhance the antitumor immune response. Major histocompatibility complex (MHC):antigen interaction with T cell receptor (TCR) provides either signal 1 for T-cell activation by antigen presenting cells (APCs) or subsequent recognition of tumor cells for cytolysis. Binding of costimulatory molecules B7-1 (CD80) or B7-2 (CD86) on APCs to CD28 on T cells provides signal 2 for amplification of MHC:antigen:TCR signaling. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) can sequester CD80/CD86 and transduce negative signals within the T cell. Programmed cell death 1 (PD-1) also inhibits T-cell effector function via distinct mechanisms when bound to its ligands (PD-L1 and PD-L2). Monoclonal antibodies targeting CTLA-4 and PD-1/PD-1/PD-L1/2 (first-generation immune checkpoint inhibitors) are currently approved for multiple tumor types and are currently being tested in clinical trials for malignant glioma. Other membrane-bound negative immune checkpoints include but are not limited to killer cell immunoglobulin-like receptors (KIRs), lymphocyte activation gene 3 (LAG-3), T-cell immunoglobulin mucin 3 (TIM-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and adenosine A2a receptor (A2aR). Indoleamine 2,3-dioxygenase (IDO) is a cytoplasmic protein that is the rate-limiting enzyme of tryptophan (Trp) to kynurenine (Kyn) pathway. IDO can negatively modulate T-cell responses by depleting the essential amino acid Trp and leading to the production of Kyn, which is a metabolite that can suppress T-cell function. Costimulatory receptors that enhance T-cell function upon ligand binding include inducible T-cell costimulator (ICOS), OX40 (CD134), 4-1BB, and glucocorticoid-induced TNFR family-related gene (GITR). CEACAM-1 = carcinoembryonic antigen-related cell adhesion molecule 1; PtdSer = phosphatidyl serine; PVR = poliovirus receptor (also known at CD155); ICOSL = ICOS ligand; OX40L = OX40 ligand; 4-1BBL = 4-1BB ligand; GITRL = GITR ligand; Gal-9 = galectin 9; HMG-B1 = high-mobility group protein B1

Fig. 2

Timing of occurrence and rates of immune-related adverse advents in clinical trials using ipilimumab 10 mg/kg (4 doses, every 3 weeks) [17, 77]. GI = gastrointestinal; LFTs = liver function tests

Fig. 3

Potential biomarkers for clinical response to programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade. From clinical trials outside of glioblastoma, CD8 T-cell infiltrate, PD-L1 expression, and high mutational burden have been described as distinct yet possibly overlapping predictors of clinical benefit to PD-1 pathway blockade. High tumor mutational burden has been associated with tumor defects in mismatch repair (MMR) proteins, mutations within the DNA polymerase epsilon gene (POLE), and environmental exposures (e.g., smoking in lung cancer and ultraviolet light in melanoma). PD-L1 can be upregulated on tumor cells via intrinsic oncogenic signaling pathways or extrinsically by infiltrating T cells through their release of interferon-γ (“adaptive immune resistance”). If a tumor lacks a pre-existing CD8 T-cell infiltrate, strategies to possibly generate one include administration of a tumor vaccine, radiation therapy, adoptive T-cell transfer, or local chemotherapy. PTEN = phosphatase and tensin homolog; PI3K = phosphatidylinositol 3-kinase; Akt = protein kinase B