Abstract
While the CNS has long been viewed as an immune-privileged environment, a paradigm shift in neuro-immunology has elevated the role of systemic immunotherapy for the treatment of metastatic disease. Increasing knowledge regarding the presence of a CNS lymphatic system and the physical and biochemical alteration of the blood brain barrier (BBB) by the tumor microenvironment suggests immune cell trafficking in and out of the CNS is possible. Emerging clinical data suggest immune checkpoint inhibitors (ICIs) can stimulate T cells peripherally to in turn have anti-tumor effects in the CNS. For example, anti-programmed cell death-1 (PD-1) monotherapy with pembrolizumab has shown intracranial response rates of 20–30% in patients with melanoma or non-small cell lung cancer (NSCLC) brain metastases. The combination of nivolumab and ipilimumab [anti-PD-1 and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)] showed an intracranial response rate of 55% in patients with melanoma brain metastases. More data are needed to confirm these response rates and to determine mechanisms of efficacy and resistance. While local therapies such as stereotactic radiosurgery (SRS), whole-brain radiation therapy (WBRT), and surgery remain current mainstays, ICIS offer potential decreased neurotoxicity. This review summarizes the biological rationale for systemic immunotherapy to treat CNS metastatic disease, existing clinical data on ICIs in this setting and ongoing clinical trials exploring areas of unmet need.
Highlights
Despite recent advances in cancer therapy, CNS metastasis remains a devastating complication for many solid organ cancer patients
The median progression-free survival (PFS) and overall survival (OS) were 5.5 and 6.5 months, respectively and only 1 patient discontinued therapy due to adverse events [22]. Another small series of 5 patients with asymptomatic non-small cell lung cancer (NSCLC) brain metastases treated with nivolumab showed activity in 3 patients: 1 complete response (CR), 1 partial responses (PRs), and 1 with stable disease for 10 weeks
This study showed a CNS response rate of 46% with the combination of nivolumab and ipilimumab vs. 20% with nivolumab alone
Summary
Despite recent advances in cancer therapy, CNS metastasis remains a devastating complication for many solid organ cancer patients. The median PFS and OS were 5.5 and 6.5 months, respectively and only 1 patient discontinued therapy due to adverse events [22] Another small series of 5 patients with asymptomatic NSCLC brain metastases treated with nivolumab showed activity in 3 patients: 1 CR, 1 PR, and 1 with stable disease for 10 weeks. The authors did not report CNS response or disease control rates, but reported median OS after the start of immunotherapy of 7.6, 7.2, 6.2, and 4 months for patients with melanoma, NSCLC, SCLC, and HNSCC, respectively They found that patients treated with immunotherapy alone had worse survival compared to combined modality therapy with radiation or surgery [29]. Ipilimumab 10 mg/kg q3W × 2 4 doses, 10 mg/kg q12W + fotemustine 100 mg/m2 q3W
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