Expected Paradigm Shift in Brain Metastases Therapy—Immune Checkpoint Inhibitors Vishal Jindal 1 & Sorab Gupta 2 Received: 8 November 2017 /Accepted: 11 January 2018 # Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract Brain metastasis (BM) is one of the dreadful complications of malignancies. The prognosis after BM is extremely poor and life expectancy is meager. Currently, our treatment modalities are limited to radiotherapy and surgical resection, which also has poor outcomes and leads to various neurological deficits and affects the quality of life of patients. New treatment modality, i.e., immune checkpoint inhibitors, has brought revolution in management of melanoma, renal cancer, and non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors basically enhance the immune response of the body to fight against cancers. Immune response in the brain is highly regulated; therefore, it is challenging to use immune-modulator drugs in BM. The microenviron- ment of BM is rich in cytotoxic T lymphocytes and which is the target of immune checkpoint inhibitors. Few studies have shown some hope regarding use of immune checkpoint inhibitors in management of BM. It works through inhibiting immune check point gates, i.e., CTLA-4 (cytotoxic T-lymphocyte-associated protein) and PD-1/PD-L1 (programmed cell death protein-1/ program death ligand-1). This article explains the basic mechanism of immune check point inhibitors, rationale behind their usage in BM, and some of the clinical studies which have shown the efficacy of immune check point inhibitors in BM. Keywords Brain metastasis . Ipilimumab . Immune checkpoint inhibitors . Pembrolizumab Introduction Brain metastasis (BM) is the devastating complication of ma- lignancies and a major cause of morbidity and mortality. BM is the most common intracranial tumors in adults and they constitute more than 50% of all intracranial tumors. From autopsy and clinical studies, it has been reported that inci- dence of BM among all cancers is in between 8.5 and 15% [1]. With advancement of diagnostic imaging, the detection rate of BM has been increased. With novel therapies of ma- lignances, survival of cancer patients improved which hastens the chances of developing BM [2]. Major treatment modalities which were available for BM are surgery, stereotactic radio- surgery, and whole brain radiation therapy. These therapies come with risk like neurological worsening, infection, intra- cranial hemorrhage, seizures, postoperative strokes, and de- cline in cognition [3] and there is a small benefit in survival [4]. Chemotherapy is not much successful in decreasing the cancer burden in the CNS. Newer chemotherapies like epider- mal growth factor receptor (EGFR) tyrosine kinase inhibitors and anaplastic lymphoma kinase (ALK) tyrosine kinase inhib- itors were unable to show significant results in BM [5–8]. Immune check point inhibitors have shown clinical activity in various cancers like lung cancers and melanoma. With that, some clinical trials on immunotherapy for BM and some case reports on immunotherapy in BM have led to courage to use these novel agents in management of BM. This review article will focus on explaining the molecular pathophysiology and clinical role of immune check point inhibitors in brain metastasis. Current Treatment Options for Brain Metastasis Surgical therapy and radiotherapy were the main treatment modalities before the targeted therapy and checkpoint * Vishal Jindal vishaljindal87@gmail.com Sorab Gupta Drsorabgupta@gmail.com 1 St. Vincent Hospital, 123 Summer Street, Worcester 01608, USA 2 Einstein Medical Center, 5501 Old York Rd, Philadelphia 19141, USA Molecular Neurobiology https://doi.org/10.1007/s12035-018-0905-3