Immunotherapy in Medulloblastoma: Current State of Research, Challenges, and Future Perspectives

Abstract

Medulloblastoma (MB), a primary tumor of the central nervous system, is among the most prevalent pediatric neoplasms. The median age of diagnosis is six. Conventional therapies include surgical resection of the tumor with subsequent radiation and chemotherapy. However, these therapies often cause severe brain damage, and still, approximately 75% of pediatric patients relapse within a few years. Because the conventional therapies cause such severe damage, especially in the pediatric developing brain, there is an urgent need for better treatment strategies such as immunotherapy, which over the years has gained accumulating interest. Cancer immunotherapy aims to enhance the body’s own immune response to tumors and is already widely used in the clinic, e.g., in the treatment of melanoma and lung cancer. However, little is known about the possible application of immunotherapy in brain cancer. In this review, we will provide an overview of the current consensus on MB classification and the state of in vitro, in vivo, and clinical research concerning immunotherapy in MB. Based on existing evidence, we will especially focus on immune checkpoint inhibition and CAR T-cell therapy. Additionally, we will discuss challenges associated with these immunotherapies and relevant strategies to overcome those.

Subgroup-Specific Diagnostic, Prognostic, and Predictive Markers Influencing Pediatric Medulloblastoma Treatment

“…The challenge has always been overcoming the intricate system of barriers that complicates delivery and efficacy [ 102 ]. However, several immunotherapeutic approaches have reached clinical trials for MB, particularly immune checkpoint inhibitors that target the immunosuppressive brain tumor microenvironment [ 103 ]. To date, the most notable examples of effective immune checkpoint inhibitors are antibodies against cytotoxic-T-lymphocyte antigen 4 (CTLA-4) and the programmed cell death protein (PD-1) and its ligand PD-L1.…”

Digital expression profile of immune checkpoint genes in medulloblastomas identifies CD24 and CD276 as putative immunotherapy targets

“…Cancer immunotherapy using immune checkpoint (IC) blockade has shown promising results in treating solid tumors ( 7 , 8 ). Currently, PD-1, PD-L1, and CTLA4 are the best-established targets, already having FDA-approved monoclonal antibodies for the treatment of many different cancer types ( 9 ; 10 ). However, applying a single immune checkpoint blocker for these targets in CNS tumors, particularly medulloblastoma, did not attain the expected results in clinical trials, particularly in pediatric patients ( 11 – 13 ).…”

“…Additionally, the knowledge of the non-canonic checkpoints is still poorly described in medulloblastoma and could represent new promising targets for therapy ( 9 , 17 ). Hence, the immune checkpoint expression profile characterization in medulloblastomas is of utmost importance and could provide crucial cues for more effective and appropriate immune checkpoint blockade-based immunotherapy ( 10 , 17 ).…”

Prognostic role of indoleamine 2,3-dioxygenase 1 expression in solid tumors: A systematic review and meta-analysis

“…In the last decade, cancer immunotherapy has made significant progress with the application of immune checkpoint inhibitors (ICs). Cytotoxic T-lymphocyteassociated antigen 4 (CTLA-4), programmed death 1 (PD-1), and programmed cell death 1 ligand 1 (PD-L1) inhibitors had shown good safety and efficacy in various tumor types, including genitourinary oncology, gastrointestinal oncology, and hematologic tumor (1). It is reported that high mutational burden and PD-L1 expression of urothelial carcinoma made it more sensitive to immunotherapy (2,3), and several ICs had been approved to treat it (4).…”