Emerging Immunotherapies in the Treatment of Brain Metastases

Abstract

Brain metastases account for considerable morbidity and mortality in patients with cancer. Despite increasing prevalence, limited therapeutic options exist. Recent advances in our understanding of the molecular and cellular underpinnings of the tumor immune microenvironment and the immune evasive mechanisms employed by tumor cells have shed light on how immunotherapies may provide therapeutic benefit to patients. The development and evolution of immunotherapy continue to show promise for the treatment of brain metastases. Positive outcomes have been observed in several studies evaluating the efficacy and safety of these treatments. However, many challenges persist in the application of immunotherapies to brain metastases. This review discusses the potential benefits and challenges in the development and use of checkpoint inhibitors, chimeric antigen receptor T-cell therapy, and oncolytic viruses for the treatment of brain metastases. Future studies are necessary to further evaluate and assess the potential use of each of these therapies in this setting. As we gain more knowledge regarding the role immunotherapies may play in the treatment of brain metastases, it is important to consider how these treatments may guide clinical decision making for clinicians and the impact they may have on patients. IMPLICATIONS FOR PRACTICE: Immunotherapies have produced clinically significant outcomes in early clinical trials evaluating patients with brain metastases or demonstrated promising results in preclinical models. Checkpoint inhibitors have been the most common immunotherapy studied to date in the setting of brain metastases, but novel approaches that can harness the immune system to contain and eliminate cancer cells are currently under investigation and may soon become more common in the clinical setting. An understanding of these evolving therapies may be useful in determining how the future management and treatment of brain metastases among patients with cancer will continue to advance.

Keywords: Brain metastasis; Immunotherapy.

Figure 1

Immune checkpoint blockade for cancer immunotherapy. Checkpoint inhibitors are a class of immunotherapy drugs. Immune checkpoints normally function to prevent an immune response from overwhelming or attacking the host. These checkpoints are activated when T cells recognize and bind to proteins, also known as “checkpoints,” that they recognize on other cells such as antigen‐presenting cells, which in turn generate an “off” signal in the T cell. Well‐known protein pairings include B7 with CTLA‐4 and CD28, and PD‐1 with PD‐L1 and PD‐L2. Unfortunately, tumor cells can coopt this system by presenting checkpoints such as PD‐L1, allowing them to escape T‐cell–mediated immunity. Checkpoint inhibitors block the binding of T cells to checkpoint proteins, preventing the negative regulation of T‐cell responses and subsequently allowing the T cell to attack and destroy tumor cells. Abbreviations: APC, antigen‐presenting cell; CD, cluster of differentiation; CTLA‐4, cytotoxic T‐lymphocyte–associated antigen 4; MHC, major histocompatibility complex; PD‐1, programmed cell death protein 1; PD‐L1, programmed death‐ligand 1; TCR, T‐cell receptor.

Figure 2

CAR T‐cell therapy in cancer. In CAR T‐cell therapy, the T cells are isolated, and the remainder of the blood is returned to the body. These T cells, the primary killing cells of the adaptive immune system, are unable to recognize the cancer cells or fully destroy them. The isolated T cells are then genetically altered using viral vectors carrying genes encoding CARs that are subsequently expressed on the surface of modified T cells. These receptors allow the T cells to recognize and respond to the tumor cells, and these newly engineered CAR T cells are then multiplied to make millions of copies and reintroduced into the patient. There, CAR T cells continue to multiply, recognize and attach to specific antigens presented on the tumor cells to become activated, and proceed to kill the tumor cell. The CAR T cells remain in the body for a prolonged period to aid in destroying any remaining or new tumor cells that arise, allowing the patient to remain in remission. Abbreviation: CAR, chimeric antigen receptor.

Figure 3

Mechanism of cancer immunotherapy using oncolytic viruses. Oncolytic viral therapy involves harnessing and reprogramming a virus to target tumor cells. The benefit of this therapy is the virus's ability to differentiate normal healthy cells from tumor cells. In normal cells, the modified virus cannot reproduce and is eliminated, sparing the healthy cell and avoiding widespread infection. The virus is either directly injected into tumor lesions or homes to tumors after intravenous or intraventricular injection. Once the tumor cell is “infected,” it is then destroyed by oncolysis after viral replication and release, which triggers multiple antitumor processes: (a) release of viral and tumor particles that are then acquired by dendritic cells and presented to the host's T cells to instigate a systemic immune response; (b) release of new infectious viral particles to continue infection and oncolysis of remaining tumor cells; and (c) induction of local inflammation and reprogramming of the surrounding tumor microenvironment. Abbreviation: APC, antigen‐presenting cell.