Development of immunotherapy for brain metastasis (Review)

Abstract

Brain metastasis (BM) is associated with a poor prognosis, with the typical overall survival rate ranging from weeks to months in the absence of treatment. Although the concept of immune privilege in the central nervous system has eroded over time, the advent of immunotherapy has opened a new set of potential therapeutic options for patients with BM. Recently, immunotherapy has been demonstrated to confer survival advantages to patients with multiple malignancies commonly associated with BMs. Data from a number of clinical trials have demonstrated that immune checkpoint inhibitors are effective for patients with BM. In addition, cellular therapies, including the application of chimeric antigen receptors T-cell therapy and dendritic cell vaccine, have also been utilized in the treatment of BM. In the present review, preclinical and clinical evidence supporting the applicability of immunotherapy for the treatment of BMs from melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) were examined, where the challenges and safety of this treatment modality were also discussed. Contents 1. Introduction 2. Biology of brain metastases 3. Evidence of treatment with ICIs for patients with BMs 4. Cellular therapy for patients with BMs 5. Conclusions

Current Treatment Approaches and Global Consensus Guidelines for Brain Metastases in Melanoma

“…Investigators are also now exploring novel combinations of multimodal therapies in MBM patients. These ongoing trials are mostly combining triplet therapy consisting of IO and TT with other novel small molecule inhibitors ( 65 , 66 ). Current ongoing trials include: EMBRAIN-MEL (NCT03898908) combining Encorafenib plus Binimetinib before SRS; RadioCoBRIM (NCT03430947) combining vemurafenib plus cobimetinib after SRS; The phase III NIBIT-M2 study (NCT02460068) comparing the chemotherapy agent fotemustine alone versus combination fotemustine plus ipi alone or combination fotemustine plus ipi and nivo; And the phase II study combining vemurafenib and combimetinib with azetolizumab (NCT03625141).…”

Harnessing immunotherapy for brain metastases: insights into tumor–brain microenvironment interactions and emerging treatment modalities

“…STAT3 signaling bears significant impact on the microglia transformation from the proinflammatory/antitumor M1 phenotype to the anti-inflammatory/tumor-promoting M2 phenotype. This constitutes a key signal mediating BM’s immunosuppressive microenvironment [ 18 , 104 ]. The inflammatory factor IL-6 secreted by BM cells is an important upstream signal that activates the IL6R-JAK2-STAT3 signaling pathway and the potential target gene ARG1 of STAT3, thus inducing M2 polarization of microglia, which in turn induces MET and brain colonization of metastatic cells [ 103 ].…”