Immunotherapy of brain metastases: breaking a “dogma”

Abstract

Until very few years ago, the oncology community dogmatically excluded any clinical potential for immunotherapy in controlling brain metastases. Therefore, despite the significant therapeutic efficacy of monoclonal antibodies to immune check-point(s) across a wide range of tumor types, patients with brain disease were invariably excluded from clinical trials with these agents. Recent insights on the immune landscape of the central nervous system, as well as of the brain tumor microenvironment, are shedding light on the immune-biology of brain metastases. Interestingly, retrospective analyses, case series, and initial prospective clinical trials have recently investigated the role of different immune check-point inhibitors in brain metastases, reporting a significant clinical activity also in this subset of patients. These findings, and their swift translation in the daily practice, are driving fundamental changes in the clinical management of patients with brain metastases, and raise important neuroradiologic challenges. Along this line, neuro-oncology undoubtedly represents an additional area of active investigation and of growing interest to support medical oncologists in the evaluation of clinical responses of brain metastases to ICI treatment, and in the management of neurologic immune-related adverse events. Aim of this review is to summarize the most recent findings on brain metastases immunobiology, on the evolving scenario of clinical efficacy of ICI therapy in patients with brain metastases, as well as on the increasing relevance of neuroradiology in this therapeutic setting.

Efficacy of Immune Checkpoint Inhibitors in Non-small-cell Lung Cancer Patients With Different Metastatic Sites: A Systematic Review and Meta-Analysis

“…We cannot exclude the potential efficacy of ICIs administrated as single agent in patients with brain metastases at present, and the superiority of combination therapy should be validated in larger trials. Currently, several ongoing trials have been investigating the efficacy and safety of ICIs combined with other treatment options in treating patients with brain metastases, such as chemotherapy and radiotherapy (52). We can expect more rigorous evidence for the choice of treatment regimens in the future.…”

“…Thus, there may be a selection bias to some extent. Up to date, several clinical trials are ongoing investigating ICIs in solid tumor with brain metastases (52). Further investigations are warranted to elucidate organ-specific tumor immune microenvironment, and more randomized trials are required to compare the efficacy of immunotherapy with conventional therapy based on metastatic sites.…”

Quantification of Scheduling Impact on Safety and Efficacy Outcomes of Brain Metastasis Radio- and Immuno-Therapies: A Systematic Review and Meta-Analysis

“…A summary of the studies considered is detailed in Table 1 ; a summary of covariate distributions is shown in Supplementary Figure 1 . The tumor types tested included brain metastases originating from melanoma ( N = 33), NSCLC ( N = 2), and pooled solid tumors (mainly melanoma and NSCLC, N = 5), which can be explained by the broad use of ICI drugs in the treatment of advanced melanoma and NSCLC combined with a high rate of brain metastases observed in these indications ( 62 ). Stereotactic RT regimens only were used in 29 studies; in the remaining 11 studies, conventional RT regimens were also considered.…”

Single-Cell Map of Diverse Immune Phenotypes in the Metastatic Brain Tumor Microenvironment of Non Small Cell Lung Cancer

“…Brain metastases represent an unmet medical need in current oncologic care. Given the poor prognosis of patients with brain metastases, particularly in lung adenocarcinoma patients, there is critical need to improve our understanding of the mechanisms underlying the pathogenesis as well as to identify novel targets for immune therapies [53][54][55] . Advances in singlecell RNA sequencing (scRNA-seq) have allowed for a comprehensive analysis of intra-tumoral heterogeneity and tumor immune microenvironment in various cancer types at primary sites 38,39,43,49,[56][57][58] .…”