- Title
- Monitoring patient response to pembrolizumab with peripheral blood exhaustion marker profiles
- Creator
- Graves, Moira; CelliMarchett, Giovana; van Zyl, Belinda; Tang, Denise; Vilain, Ricardo E.; van der Westhuizen, Andre; Bowden, Nikola A.
- Relation
- Frontiers in Medicine Vol. 6, no. 113
- Publisher Link
- http://dx.doi.org/10.3389/fmed.2019.00113
- Publisher
- Frontiers Research Foundation
- Resource Type
- journal article
- Date
- 2019
- Description
- Exhausted T cells are effector T cells that are silenced due to continuous T cell receptor (TCR) stimulation from persistent antigens. Characteristics of exhaustion include the increased expression of multiple inhibitory receptors such as programme death-1[PD-1], lymphocyte activation gene 3 [LAG-3], T cell Ig and mucin domain [TIM-3], the loss of effector cytokine secretion and altered transcriptional profile. The PD-1/PD-L1 interaction induces functional exhaustion of tumor-reactive cytotoxic T cells and interferes with anti-tumor T cell immunity. T cell exhaustion has been observed in metastatic melanoma patients where the exhaustion of tumor specific T cells suggests that tumor clearance has been impeded and contributed to tumor immune escape. Checkpoint immunotherapies are antibodies designed to block the interaction between the inhibitory receptors expressed on T cells and their respective ligands. Therapies such as anti-PD-1 (Pembrolizumab and Nivolumab) block these inhibitory receptors and are associated with a significant improvement in overall survival and progression free survival. However, only 20–40% of metastatic melanoma patients experience long-term benefit. In a cohort of 16 metastatic melanoma patients receiving pembrolizumab, blood was serially collected before each infusion (mean 8.3; range 1–12 cycles). The presence of inhibitory markers LAG-3, TIM-3, and PD-1 on the surface of T cells was examined and assessed in relation to patient response to identify if inhibitory markers can be used to differentiate responders from non-responders for Pembrolizumab. We confirmed that across a range of cycles (range 1–26) of pembrolizumab, PD-1 expression was significantly higher on CD4+ T cells from non-responders compared to responders and TIM-3 expressed on the surface of CD8+ T cells was significantly higher in non-responders compared to responders. This longitudinal data confirms previous studies that assessed single timepoints. This study provides preliminary evidence that PD-1 and TIM-3 may be predictive of non-responders when assessed over multiple treatment cycles.
- Subject
- melanoma; pembrolizumab; T cell exhuastion; PD-1; TIM-3; LAG-3; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1454683
- Identifier
- uon:44986
- Identifier
- ISSN:2296-858X
- Rights
- © 2019 Graves, CelliMarchett, van Zyl, Tang, Vilain, van der Westhuizen and Bowden. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
- Language
- eng
- Full Text
- Reviewed
- Hits: 2151
- Visitors: 2265
- Downloads: 115
Collections
Goal 3: Good Health and Well-Being
| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT02 | Publisher version (open access) | 1 MB | Adobe Acrobat PDF | View Details Download |