Combining Radiation Therapy with Immune Checkpoint Blockade for Central Nervous System Malignancies

Abstract

Malignancies of the central nervous system (CNS), particularly glioblastoma and brain metastases from a variety of disease sites, are difficult to treat despite advances in multimodality approaches consisting of surgery, chemotherapy, and radiation therapy (RT). Recent successes of immunotherapeutic strategies including immune checkpoint blockade (ICB) via anti-PD-1 and anti-CTLA-4 antibodies against aggressive cancers, such as melanoma, non-small cell lung cancer, and renal cell carcinoma, have presented an exciting opportunity to translate these strategies for CNS malignancies. Moreover, via both localized cytotoxicity and systemic proinflammatory effects, the role of RT in enhancing antitumor immune response and, therefore, promoting tumor control is being re-examined, with several preclinical and clinical studies demonstrating potential synergistic effect of RT with ICB in the treatment of primary and metastatic CNS tumors. In this review, we highlight the preclinical evidence supporting the immunomodulatory effect of RT and discuss the rationales for its combination with ICB to promote antitumor immune response. We then outline the current clinical experience of combining RT with ICB in the treatment of multiple primary and metastatic brain tumors. Finally, we review advances in characterizing and modifying tumor radioimmunotherapy responses using biomarkers and microRNA (miRNA) that may potentially be used to guide clinical decision-making in the near future.

Keywords: CTLA-4; PD-1; brain metastases; brain neoplasms; glioblastoma; immune checkpoint blockade; immunotherapy; radiotherapy.

Figure 1

Immunostimulatory effects of radiation therapy (RT) in combination with immune checkpoint blockade (ICB) in the CNS. RT and ICB work synergistically to create an immunogenic tumor microenvironment and promote systemic antitumor response. Anti-PD-1 and PD-L1 agents reduce tumor cell-mediated exhaustion signals to CD8⁺ CTLs, while anti-CTLA-4 agents block competing co-inhibitory activity of CTLA-4, resulting in increased and persistent T-cell activation. RT triggers immunogenic cell death (ICD) of tumor cells, displacement of calreticulin (CRT) to the cell surface, release of HMG-B1, increased MHC-I expression, and release of tumor-associated antigens (TAAs), with consequent increase in TCR repertoire of infiltrating T-cells. In addition, RT has stromal effects on the tumor microenvironment: increasing oxygenation, infiltration of TILs, and permeability of the blood–brain barrier (BBB), while decreasing interstitial fluid pressure. In combination with ICB, RT also reduces activity of T-regs and MDSCs. SRS, stereotactic radiosurgery; WBRT, whole brain radiation therapy; CTL, cytotoxic T-lymphocyte; PD-1/L1, programmed cell death protein 1/ligand 1; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DC, dendritic cell; TIL, tumor-infiltrating lymphocyte; TAA, tumor-associated antigen; MHC, major histocompatibility complex; TCR, T-cell receptor; MDSC, myeloid-derived suppressor cell; HMG-B1, high mobility group box 1.