Immune Checkpoint Inhibitors in Brain Metastases: From Biology to Treatment

Abstract

Cancer immunotherapy has been a subject of intense research over the last several years, leading to new approaches for modulation of the immune system to treat malignancies. Immune checkpoint inhibitors (anti–CLTA-4 antibodies and anti–PD-1/PD-L1 antibodies) potentiate the host’s own antitumor immune response. These immune checkpoint inhibitors have shown impressive clinical efficacy in advanced melanoma, metastatic kidney cancer, and metastatic non–small cell lung cancer (NSCLC)—all malignancies that frequently cause brain metastases. The immune response in the brain is highly regulated, challenging the treatment of brain metastases with immune-modulatory therapies. The immune microenvironment in brain metastases is active with a high density of tumor-infiltrating lymphocytes in certain patients and, therefore, may serve as a potential treatment target. However, clinical data of the efficacy of immune checkpoint inhibitors in brain metastases compared with extracranial metastases are limited, as most clinical trials with these new agents excluded patients with active brain metastases. In this article, we review the current scientific evidence of brain metastases biology with specific emphasis on inflammatory tumor microenvironment and the evolving state of clinical application of immune checkpoint inhibitors for patients with brain metastases.

The Microenvironmental Landscape of Brain Tumors

“…nivolumab with radiotherapy in newly-diagnosed glioblastoma, NCT02617589, Phase III; nivolumab and/or ipilimumab versus bevacizumab in recurrent glioblastoma, NCT02017717, Phase III) (Preusser et al, 2015) and brain metastases (e.g. ipilimumab with either nivolumab or fotemustine in brain metastasis, NCT02460068, Phase III) (Berghoff et al, 2016). These studies collectively underscore the clinical potential of targeting the microenvironment, either through monotherapy or via rational combinations, as an alternative, integrated strategy for the management of different types of brain tumors.…”

Pembrolizumab-induced autoimmune encephalitis in a patient with advanced non-small cell lung cancer: A case report

“…Whether ICPis affect brain metastasis remains unclear (6,7). Some prospective trials are currently being conducted, and the results of a phase 2 trial of pembrolizumab for melanoma and NSCLC with brain metastasis (8) indicate that the brain lesions were responsive in 6 of 18 patients with NSCLC.…”

Immune Checkpoint Inhibitors in Melanoma: A Review of Pharmacokinetics and Exposure–Response Relationships

“…Monoclonal antibodies are very specific to their targets and provide a long-lasting effect, but they also have certain disadvantages in the context of immunotherapy. Their large size makes it difficult to access exhausted intratumoral T cells (at least for anti-PD1) and the use of antibodies can be challenging to treat tumours located at immune privileged sites such as the eye or the brain [27,28].…”