Phase I Study of Intraventricular Administration of Rituximab in Patients With Recurrent CNS and Intraocular Lymphoma

Rubenstein, James L.; Fridlyand, Jane; Abrey, Lauren E.; Shen, Arthur; Karch, Jon; Wang, Endi; Issa, Samar; Damon, Lloyd E.; Prados, Michael D.; McDermott, Michael; O’Brien, Joan M.; Haqq, Chris; Shuman, Marc A.

doi:10.1200/jco.2006.09.7311

Cited by 300 publications

(206 citation statements)

References 22 publications

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“…The current study demonstrates that approximately 0.1% of systemically administered daclizumab reaches the intrathecal compartment, consistent with other monoclonal antibodies such as rituximab 17, 18. The observed rise in serum and CSF IL‐2 levels provides evidence for the ability of daclizumab to inhibit consumption of IL‐2 by activated T cells14 in both systemic and intrathecal compartments.…”

Section: Discussionsupporting

confidence: 82%

Pharmacodynamic effects of daclizumab in the intrathecal compartment

Komori

Kósa

Stein

et al. 2017

Ann Clin Transl Neurol

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ObjectiveIt was previously demonstrated that daclizumab therapy normalizes cellular cerebrospinal fluid (CSF) abnormalities typical of multiple sclerosis (MS) in the majority of treated patients. However, CSF cells represent only the mobile portion of intrathecal immune responses. Therefore, we asked whether daclizumab also reverses compartmentalized inflammation and if not, whether residual inflammation correlates with clinical response to the drug.MethodsForty MS patients treated with an intravenous or subcutaneous injection of daclizumab were followed for up to 16 years in two open‐label clinical trials. MRI contrast‐enhancing lesions (CELs), clinical scales, and CSF biomarkers quantified residual disease.ResultsRapid decreases in CELs, sustained throughout the observation period, were observed with daclizumab treatment. Daclizumab therapy induced modest but statistically significant (P < 0.0001) decreases in CSF levels of T‐cell activation marker CD27 and IgG index. Interleukin 2 (IL‐2) CSF levels increased from baseline levels during treatment, consistent with reduced IL‐2 consumption by T cells, as a consequence of daclizumab's saturation of high‐affinity IL‐2 receptors. CSF levels of IL‐12p40, chitinase‐3‐like protein‐1 (CHI3L1), chemokine C‐X‐C motif ligand 13, and neurofilament light chain (NFL) were also significantly reduced by daclizumab. Among them, inhibition of CHI3L1 correlated with inhibition of NFL and with lack of disease progression.InterpretationThese observations confirm daclizumab's direct pharmacodynamics effects on immune cells within central nervous system tissues and identify inhibition of CSF biomarkers of myeloid lineage as a stronger determinant of reduction in clinical MS activity than inhibition of biomarkers of adaptive immunity.

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Section: Discussionsupporting

confidence: 82%

Pharmacodynamic effects of daclizumab in the intrathecal compartment

Komori

Kósa

Stein

et al. 2017

Ann Clin Transl Neurol

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“…5,6,12 Unfortunately, IV rituximab is poorly effective against CNS-PTLD because of low penetrance across the blood-brain barrier. [13][14][15] In this study, only 3 of 14 patients were responsive to the IV rituximab-based treatments, which was consistent with the reports. 6,7 Recently, a few studies demonstrated that intrathecal administration of rituximab was an effective and safe method for pediatric CNS-PTLD.…”

supporting

confidence: 82%

Intrathecal rituximab for EBV-associated post-transplant lymphoproliferative disorder with central nervous system involvement unresponsive to intravenous rituximab-based treatments: a prospective study

Sun

Zhang

et al. 2015

Bone Marrow Transplant

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“…Greater understanding of FOXP1 isoform heterogeneity may help to identify therapy-resistant DLBCL clones, as elevated FOXP1 is linked to resistance in response to both CHOP-R and rituximab monotherapy in lymphoma. 19,21,22,41 Abundant Ex6bS transcript expression in GC-DLBCL cell lines lacking FOXP1 S protein expression suggests posttranscriptional regulatory mechanisms may also regulate FOXP1 S protein expression in DLBCL. Alternate exon-specific miRNA activity, in addition to the previously report-P.J.…”

Section: Discussionmentioning

confidence: 99%

N-terminally truncated FOXP1 protein expression and alternate internal FOXP1 promoter usage in normal and malignant B cells

et al. 2016

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Strong FOXP1 protein expression is a poor risk factor in diffuse large B-cell lymphoma and has been linked to an activated B-cell-like subtype, which preferentially expresses short FOXP1 (FOXP1 S ) proteins. However, both short isoform generation and function are incompletely understood. Here we prove by mass spectrometry and Nterminal antibody staining that FOXP1 S proteins in activated B-cell-like diffuse large B-cell lymphoma are N-terminally truncated. Furthermore, a rare strongly FOXP1-expressing population of normal germinal center B cells lacking the N-terminus of the regular long protein (FOXP1 L ) was identified. Exon-targeted silencing and transcript analyses identified three alternate 5ʹ non-coding exons [FOXP1-Ex6b(s), FOXP1-Ex7b and FOXP1-Ex7c], downstream of at least two predicted promoters, giving rise to FOXP1 S proteins. These were differentially controlled by B-cell activation and methylation, conserved in murine lymphoma cells, and significantly correlated with FOXP1 S protein expression in primary diffuse large B-cell lymphoma samples. Alternatively spliced isoforms lacking exon 9 (e.g. isoform 3) did not encode FOXP1 S , and an alternate long human FOXP1 protein (FOXP1 AL ) likely generated from a FOXP1-Ex6b(L) transcript was detected. The ratio of FOXP1 L :FOXP1 S isoforms correlated with differential expression of plasmacytic differentiation markers in U-2932 subpopulations, and altering this ratio was sufficient to modulate CD19 expression in diffuse large B-cell lymphoma cell lines. Thus, the activity of multiple alternate FOXP1 promoters to produce multiple protein isoforms is likely to regulate B-cell maturation.

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Phase I Study of Intraventricular Administration of Rituximab in Patients With Recurrent CNS and Intraocular Lymphoma

Abstract: These results suggest that intrathecal rituximab (10 to 25 mg) is feasible and effective in NHL involving the CNS.

Cited by 300 publications

References 22 publications

Pharmacodynamic effects of daclizumab in the intrathecal compartment

Pharmacodynamic effects of daclizumab in the intrathecal compartment

Intrathecal rituximab for EBV-associated post-transplant lymphoproliferative disorder with central nervous system involvement unresponsive to intravenous rituximab-based treatments: a prospective study

N-terminally truncated FOXP1 protein expression and alternate internal FOXP1 promoter usage in normal and malignant B cells

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