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

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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.

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Most cited references 24

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Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study

Shahneen Sandhu, Richard A Scolyer, Alexander M Menzies … (2018)

Nivolumab monotherapy and combination nivolumab plus ipilimumab increase proportions of patients achieving a response and survival versus ipilimumab in patients with metastatic melanoma; however, efficacy in active brain metastases is unknown. We aimed to establish the efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with active melanoma brain metastases.

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Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study.

Jedd Wolchok, Bart Neyns, Gerald P. Linette … (2010)

Ipilimumab is a human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 and has shown promising activity in advanced melanoma. We aimed to ascertain the antitumour efficacy of ipilimumab in patients with advanced melanoma. We undertook a randomised, double-blind, phase 2 trial in 66 centres from 12 countries. 217 patients with previously treated stage III (unresectable) or stage IV melanoma were randomly assigned a fixed dose of ipilimumab of either 10 mg/kg (n=73), 3 mg/kg (n=72), or 0.3 mg/kg (n=72) every 3 weeks for four cycles (induction) followed by maintenance therapy every 3 months. Randomisation was done with a permuted block procedure, stratified on the basis of type of previous treatment. The primary endpoint was best overall response rate (the proportion of patients with a complete or partial response, according to modified WHO criteria). Efficacy analyses were done by intention to treat, whereas safety analyses included patients who received at least one dose of ipilimumab. This study is registered with ClinicalTrials.gov, number NCT00289640. The best overall response rate was 11.1% (95% CI 4.9-20.7) for 10 mg/kg, 4.2% (0.9-11.7) for 3 mg/kg, and 0% (0.0-4.9) for 0.3 mg/kg (p=0.0015; trend test). Immune-related adverse events of any grade arose in 50 of 71, 46 of 71, and 19 of 72 patients at doses of 10 mg/kg, 3 mg/kg, and 0.3 mg/kg, respectively; the most common grade 3-4 adverse events were gastrointestinal immune-related events (11 in the 10 mg/kg group, two in the 3 mg/kg group, none in the 0.3 mg/kg group) and diarrhoea (ten in the 10 mg/kg group, one in the 3 mg/kg group, none in the 0.3 mg/kg group). Ipilimumab elicited a dose-dependent effect on efficacy and safety measures in pretreated patients with advanced melanoma, lending support to further studies at a dose of 10 mg/kg. Bristol-Myers Squibb. Copyright 2010 Elsevier Ltd. All rights reserved.

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Immunoglobulin G4: an odd antibody.

R Aalberse, S Stapel, J Schuurman … (2009)

Despite its well-known association with IgE-mediated allergy, IgG4 antibodies still have several poorly understood characteristics. IgG4 is a very dynamic antibody: the antibody is involved in a continuous process of half-molecules (i.e. a heavy and attached light-chain) exchange. This process, also referred to as 'Fab-arm exchange', results usually in asymmetric antibodies with two different antigen-combining sites. While these antibodies are hetero- bivalent, they will behave as monovalent antibodies in most situations. Another aspect of IgG4, still poorly understood, is its tendency to mimic IgG rheumatoid factor (RF) activity by interacting with IgG on a solid support. In contrast to conventional RF, which binds via its variable domains, the activity of IgG4 is located in its constant domains. This is potentially a source of false positives in IgG4 antibody assay results. Because regulation of IgG4 production is dependent on help by T-helper type 2 (Th2) cells, the IgG4 response is largely restricted to non-microbial antigens. This Th2-dependency associates the IgG4 and IgE responses. Another typical feature in the immune regulation of IgG4 is its tendency to appear only after prolonged immunization. In the context of IgE-mediated allergy, the appearance of IgG4 antibodies is usually associated with a decrease in symptoms. This is likely to be due, at least in part, to an allergen-blocking effect at the mast cell level and/or at the level of the antigen-presenting cell (preventing IgE-facilitated activation of T cells). In addition, the favourable association reflects the enhanced production of IL-10 and other anti-inflammatory cytokines, which drive the production of IgG4. While in general, IgG4 is being associated with non-activating characteristics, in some situations IgG4 antibodies have an association with pathology. Two striking examples are pemphigoid diseases and sclerosing diseases such as autoimmune pancreatitis. The mechanistic basis for the association of IgG4 with these diseases is still enigmatic. However, the association with sclerosing diseases may reflect an excessive production of anti-inflammatory cytokines triggering an overwhelming expansion of IgG4-producing plasma cells. The bottom line for allergy diagnosis: IgG4 by itself is unlikely to be a cause of allergic symptoms. In general, the presence of allergen-specific IgG4 indicates that anti-inflammatory, tolerance-inducing mechanisms have been activated. The existence of the IgG4 subclass, its up-regulation by anti-inflammatory factors and its own anti-inflammatory characteristics may help the immune system to dampen inappropriate inflammatory reactions.

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Author and article information

Contributors

Mark T. J. van Bussel:

ORCID: http://orcid.org/0000-0003-0048-6314

+31 (0)205129036 , m.v.bussel@nki.nl

Journal

Journal ID (nlm-ta): BMC Cancer

Journal ID (iso-abbrev): BMC Cancer

Title: BMC Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2407

Publication date (Electronic): 30 May 2019

Publication date PMC-release: 30 May 2019

Publication date Collection: 2019

Volume: 19

Electronic Location Identifier: 519

Affiliations

[1 ]GRID grid.430814.a, Division of Pharmacology, Netherlands Cancer Institute, Antoni van Leeuwenhoek, ; Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

[2 ]GRID grid.430814.a, Department of Medical Oncology & Clinical Pharmacology, Netherlands Cancer Institute, Antoni van Leeuwenhoek, ; Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

[3 ]GRID grid.430814.a, Department of Pharmacy & Pharmacology, Netherlands Cancer Institute – Antoni van Leeuwenhoek, ; Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

[4 ]ISNI 0000000120346234, GRID grid.5477.1, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Faculty of Science, , Utrecht University, ; Universiteitsweg 99, 3584 CG Utrecht, The Netherlands

[5 ]GRID grid.430814.a, Department of Neuro-oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek, ; Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

Author information

Mark T. J. van Bussel http://orcid.org/0000-0003-0048-6314

Article

Publisher ID: 5741

DOI: 10.1186/s12885-019-5741-y

PMC ID: 6543612

PubMed ID: 31146733

SO-VID: 3f7af485-f86a-4a3d-bdad-2c7a0c42ae83

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 7 January 2019

Date accepted : 22 May 2019

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: melanoma brain metastases,nivolumab,ipilimumab,neonatal fc receptor,pharmacodynamics,pharmacokinetics

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: melanoma brain metastases, nivolumab, ipilimumab, neonatal fc receptor, pharmacodynamics, pharmacokinetics

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

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Karger: Oncology

Most cited references 24

Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study

Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study.

Immunoglobulin G4: an odd antibody.

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