Immunotherapy and brain metastasis in lung cancer: connecting bench side science to the clinic

Abstract

Brain metastases (BMs) are the most common form of intracranial malignant neoplasms in adults, with a profound impact on quality of life and traditionally associated with a dismal prognosis. Lung cancer accounts for approximately 40%–50% of BM across different tumors. The process leading to BMs is complex and includes local invasion, intravasation, tumor cells circulation into the bloodstream, disruption of the blood–brain barrier, extravasation of tumor cells into the brain parenchyma, and interaction with cells of the brain microenvironment, among others. Once the tumor cells have seeded in the brain parenchyma, they encounter different glial cells of the brain, as well as immune cells. The interaction between these cells and tumor cells is complex and is associated with both antitumoral and protumoral effects. To overcome the lethal prognosis associated with BMs, different treatment strategies have been developed, such as immunotherapy with immune checkpoint inhibitors, particularly inhibitors of the PD-1/PD-L1 axis, which have demonstrated to be an effective treatment in both non-small cell lung cancer and small cell lung cancer. These antibodies have shown to be effective in the treatment of BM, alone or in combination with chemotherapy or radiotherapy. However, many unsolved questions remain to be answered, such as the sequencing of immunotherapy and radiotherapy, the optimal management in symptomatic BMs, the role of the addition of anti–CTLA-4 antibodies, and so forth. The complexity in the management of BMs in the era of immunotherapy requires a multidisciplinary approach to adequately treat this devastating event. The aim of this review is to summarize evidence regarding epidemiology of BM, its pathophysiology, current approach to treatment strategies, as well as future perspectives.

Efficacy and safety of novel immune checkpoint inhibitor‐based combinations versus chemotherapy as first‐line treatment for patients with extensive‐stage small cell lung cancer: A network meta‐analysis

“…Different clinical trials and retrospective studies have evaluated the effect of ICI alone or in combination with other interventions in lung cancer patients with BM suggesting the efficacy of ICI in patients with BM was worse than those without BM. 51 In addition, data from recent studies of ICIs in patients with NSCLC having brain metastases supported the notion that the brain was an immune privileged site. 52 , 53 , 54 Similarly, the current study also showed no survival benefit from ICIs + CT versus CT in patients with BM, even with anlotinib in combination, which may be due to the small sample size of enrolled patients with BM.…”

“…The prognosis of ES‐SCLC with BM is dismal and only patients with asymptomatic BM or treated BM stable off steroids could be included in randomized controlled trials. Different clinical trials and retrospective studies have evaluated the effect of ICI alone or in combination with other interventions in lung cancer patients with BM suggesting the efficacy of ICI in patients with BM was worse than those without BM 51 . In addition, data from recent studies of ICIs in patients with NSCLC having brain metastases supported the notion that the brain was an immune privileged site 52–54 .…”