Development of in vitro models that test and predict immune-mediated adverse toxicities
(2023) KIMM01 20222Department of Immunotechnology
Educational programmes, LTH
- Abstract
- Cancer is a disease affecting many people where a possible treatment is immunotherapy. Immunotherapy has possible side effects called immune-related adverse events (irAEs) where cytokine release syndrome (CRS) is one. CRS differs in severity and an increased amount of cytokines are secreted. In this project, the aim was to explore key events of irAEs and to develop an assay to predict CRS. The effect of Proleukin, an IL-2 alternative, and ALT1, an antibody-based immunotherapy, on the activation of monocyte-derived dendritic cells (moDCs) and the surface expression of IL-2R was studied. Furthermore, an autologous BOEC:PBMC coculture was performed, stimulated with the immunotherapies and analyzed in a Luminex Discovery Assay.
The moDCs... (More) - Cancer is a disease affecting many people where a possible treatment is immunotherapy. Immunotherapy has possible side effects called immune-related adverse events (irAEs) where cytokine release syndrome (CRS) is one. CRS differs in severity and an increased amount of cytokines are secreted. In this project, the aim was to explore key events of irAEs and to develop an assay to predict CRS. The effect of Proleukin, an IL-2 alternative, and ALT1, an antibody-based immunotherapy, on the activation of monocyte-derived dendritic cells (moDCs) and the surface expression of IL-2R was studied. Furthermore, an autologous BOEC:PBMC coculture was performed, stimulated with the immunotherapies and analyzed in a Luminex Discovery Assay.
The moDCs were slightly activated when stimulated and one of the three IL-2 receptors (IL-2Rγ) had an enhanced expression. IL-2Rγ is a more common receptor subunit, compared to the other IL-2 receptor subunits, found in other cytokines and therefore expected to have a higher expression than the other IL-2R receptor subunits. The BOEC:PBMC coculture displayed enhanced concentrations of several cytokines for stimulation with the positive control. Stimulation with Proleukin resulted in a secretion profile similar to CRS at 4 h post stimulation whereas ALT1 did it at 24 h. Further research should be performed to further explore key events of irAEs and optimizing the assay such as mimicking patient administration of Proleukin. Furthermore, a moDC:T-cell coculture should be performed to explore the effect of activated moDCs on T-cells. The differentiation of BOECs and the autologous BOEC:PBMC coculture with healthy donors was successful however it should be performed with patient samples as a more severe CRS is expected. (Less) - Popular Abstract
- Cancer is a disease that affects many people with several ways to treat it. Immunotherapy is one of those treatments where the immune system of the patient is used to kill the cancer cells. Like all treatments, immunotherapies also have side effects. These side effects are caused by an excessive production and release of small proteins that regulate immune function in the body. The side effects can affect the body in many different ways with both mild symptoms including headache and nausea, as well as severe symptoms such as heart and respiratory failure. Due to the possibility of severe symptoms of the side effect, a method needs to be developed to test immunotherapies before entering clinical trials. The aim of this project was to... (More)
- Cancer is a disease that affects many people with several ways to treat it. Immunotherapy is one of those treatments where the immune system of the patient is used to kill the cancer cells. Like all treatments, immunotherapies also have side effects. These side effects are caused by an excessive production and release of small proteins that regulate immune function in the body. The side effects can affect the body in many different ways with both mild symptoms including headache and nausea, as well as severe symptoms such as heart and respiratory failure. Due to the possibility of severe symptoms of the side effect, a method needs to be developed to test immunotherapies before entering clinical trials. The aim of this project was to firstly, further explore how the side effect occurs in the body and secondly, to develop a method to predict the side effect on human cells outside of the body.
The project was performed using different immune cells, derived from healthy human blood. Two immunotherapies were added to the different immune cells to see if there was any change in a specific cell surface molecule which is known to be involved in the resulting side effects and also affects the activation of the immune cells. The level of small proteins that can be released and regulate immune function were also analyzed, in order to develop the method to predict the side effect. The results showed that the immunotherapies increased the presence of the cell surface molecule and increased the activation of the immune cells. The method of predicting the side effect was successful, showing increased levels of released small proteins. Based on the results, several future studies can be performed in order to further explore how the side effect occurs and to further develop the method to predict the side effect. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9110885
- author
- Aulin, Hanna LU
- supervisor
- organization
- course
- KIMM01 20222
- year
- 2023
- type
- H2 - Master's Degree (Two Years)
- subject
- language
- English
- id
- 9110885
- date added to LUP
- 2023-02-14 16:04:52
- date last changed
- 2023-02-14 16:04:52
@misc{9110885,
abstract = {{Cancer is a disease affecting many people where a possible treatment is immunotherapy. Immunotherapy has possible side effects called immune-related adverse events (irAEs) where cytokine release syndrome (CRS) is one. CRS differs in severity and an increased amount of cytokines are secreted. In this project, the aim was to explore key events of irAEs and to develop an assay to predict CRS. The effect of Proleukin, an IL-2 alternative, and ALT1, an antibody-based immunotherapy, on the activation of monocyte-derived dendritic cells (moDCs) and the surface expression of IL-2R was studied. Furthermore, an autologous BOEC:PBMC coculture was performed, stimulated with the immunotherapies and analyzed in a Luminex Discovery Assay.
The moDCs were slightly activated when stimulated and one of the three IL-2 receptors (IL-2Rγ) had an enhanced expression. IL-2Rγ is a more common receptor subunit, compared to the other IL-2 receptor subunits, found in other cytokines and therefore expected to have a higher expression than the other IL-2R receptor subunits. The BOEC:PBMC coculture displayed enhanced concentrations of several cytokines for stimulation with the positive control. Stimulation with Proleukin resulted in a secretion profile similar to CRS at 4 h post stimulation whereas ALT1 did it at 24 h. Further research should be performed to further explore key events of irAEs and optimizing the assay such as mimicking patient administration of Proleukin. Furthermore, a moDC:T-cell coculture should be performed to explore the effect of activated moDCs on T-cells. The differentiation of BOECs and the autologous BOEC:PBMC coculture with healthy donors was successful however it should be performed with patient samples as a more severe CRS is expected.}},
author = {{Aulin, Hanna}},
language = {{eng}},
note = {{Student Paper}},
title = {{Development of in vitro models that test and predict immune-mediated adverse toxicities}},
year = {{2023}},
}