Intracranial antitumor responses of nivolumab and ipilimumab: a pharmacodynamic and pharmacokinetic perspective, a scoping systematic review

Abstract

Background Recently, two phase II trials showed intracranial activity of the immune checkpoint inhibitors nivolumab and ipilimumab in patients with melanoma brain metastases. However, it is generally assumed that large molecules like monoclonal antibodies nivolumab and ipilimumab cannot penetrate and pass an intact blood brain barrier (BBB). In this systematic review we provide a pharmacodynamic and pharmacokinetic consideration of the clinical activity of the immune checkpoint inhibitors nivolumab and ipilimumab in melanoma brain metastases. Methods Pubmed was systematically searched for prospective phase II and III studies on nivolumab and ipilimumab in melanoma brain metastases and cerebrospinal fluid (CSF) levels of nivolumab and ipilimumab. Results were discussed and a perspective on the pharmacodynamics and pharmacokinetics for the intracranial activity of these agents was given. Results Two phase II studies with the combination nivolumab and ipilimumab and one phase II study with ipilimumab monotherapy in melanoma brain metastases were included in this review. One article reported drug levels of nivolumab in CSF. Intracranial responses were achieved in 16 of 35 patients (46%; 95% confidence interval (CI) 29–63) in a phase II study cohort treated with nivolumab and ipilimumab. In a second phase II study in 94 patients, the rate of intracranial clinical benefit was 57% (95% CI 47–68). The CSF/serum ratio of nivolumab was 0.88–1.9% in a cohort of metastatic melanoma patients treated with nivolumab 1–3 mg/kg. Nivolumab concentrations ranged from 35 to 150 ng/ml in CSF of these patients, which is in the range of the half maximal effective concentration (EC50) of 0.64 nM. Conclusions Ipilimumab and nivolumab are active in melanoma brain metastases. Nivolumab penetrates into the CSF. Based on the described findings the general consensus that monoclonal antibodies do not penetrate into the central nervous system (CNS) and cannot have a direct intracranial effect needs to be reconsidered.

Meningeal lymphatic vessels regulate brain tumor drainage and immunity

“…However, evidence has emerged that CNS-derived soluble molecules and lymphocytes circulate through the healthy brain, and extensive cross-talk between the brain and the peripheral immune system exists under pathological conditions such as autoimmunity and infection. 4 To visualize this process, fluorescent tracer dye was injected into the gray matter from where it migrates out to the cervical lymph nodes (CLNs). 5 Subsequently, using a polarized macroscopic system, convective fluid fluxes with rapid interchange between cerebrospinal fluid (CSF) and interstitial fluid in the parenchyma were reported and named the "glymphatic" system based on its functional similarity to the lymphatic system in peripheral tissue, and on the important role of glial aquaporin-4 channels in the convective fluid transport.…”

Control and Toxicity in Melanoma Versus Other Brain Metastases in Response to Combined Radiosurgery and PD-(L)1 Immune Checkpoint Inhibition

“… 25 It has also been shown that nivolumab can penetrate the cerebrospinal fluid at effective concentrations, allowing for possible intracranial antigen response. 26 Some have called these effects an “in situ vaccine.” 27 To that end, we examined the distant intracranial control in our patients. Kaplan-Meier 1-year freedom from distant progression was 39%.…”

PD-1 Regulates GABAergic Neurotransmission and GABA-Mediated Analgesia and Anesthesia

“…We should also point out that half-life of Nivolumab in mouse is much shorter than that in human (3 days versus weeks) ( Wang et al., 2020a ). One systematic review found that benefits were observed with PD-1 blockade in melanomas with metastasis to the brain, and Nivolumab concentrations could reach from 35 to 150 ng/mL in CSF of these patients ( van Bussel et al., 2019 ). As tested in this study, this concentration range may be sufficient to affect neuronal activities.…”