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Role of natural killer cells in the therapeutic efficacy of oncolytic measles virus

 

 

Funding: European Regional Development Fund (ERDF) “On Implementation of Activity 1.1.1.2 “Post-doctoral Research Aid” of the Specific Aid Objective 1.1.1 “To increase the research and innovative capacity of scientific institutions of Latvia and the ability to attract external financing, investing in human resources and infrastructure” of the Operational Programme “Growth and Employment”

 

Project Title: „Role of natural killer cells in the therapeutic efficacy of oncolytic measles virus”

Project Nr.: 1.1.1.2/VIAA/2/18/292

Period: 36 month (1st October 2018 – 30 st September 2021)

Project costs: 133 806,00 EUR

Project implementer: Dr.rer.nat. Rūta Veinalde

Oncolytic viruses (OVs) are emerging as a multimodal, clinically relevant therapeutic option for cancer treatment. Stimulation of anti-tumor immunity of the host is one of the mechanisms of action of OVs. Natural killer (NK) cells are cytotoxic lymphocytes which are involved in recognition of malignant and virus-infected cells. The role of NK cell activation in OV therapy remains controversial. In this project molecular mechanisms of NK cell activation in the context of oncolytic measles virus (MV) infection will be investigated. Moreover, the role of the NK cell activity in MV therapy will be examined depending on the tumor microenvironment, specifically the MHC-I status. Based on the obtained results, options for rational NK cell modulation during MV therapy will be investigated with the aim to develop novel combination treatment strategies with increased therapeutic efficacy.

Information published 01.10.2018.

 

Progress of the project

1 October 2018 - 31 December 2018

During the initiation phase of the project a primary melanoma cell line collection (11 cultures in total) available at the BMC has been validated for expression of melanoma specific markers on mRNA level using RT-PCR. Validated melanoma cell lines have been compared for susceptibility to oncolytic measles virus (oMV) infection using fluorescence microscopy. Cytotoxic effects of oMV in the same cultures have been assessed by a colorimetric cell viability assay. Based on these results two of the melanoma cell lines have been selected for further experiments. Protocols for human natural killer (NK) cell isolation from full blood of healthy donors and cultivation in vitro have been established. The two previously selected primary melanoma lines have been shown to be susceptible to IL-2 primed NK cell killing using a lactate dehydrogenase release assay. Furthermore, production of a laboratory grade oMV at the BMC for further experiments has been started.

Information published 28.12.2018.

 

Progress of the project

1 January 2019 – 31 March 2019

During this peridod production of a laboratory grade oncolytic measles virus (oMV) at the BMC has been finished. A protocol for natural killer (NK) cell isolation from human peripheral blood mononuclear cells has been optimised. NK cell isolation based on negative selection using magnetic beads has been determined to be the most appropriate for the planned applications. Experiments to compare NK cell-mediated killing of oMV-infected and uninfected primary melanoma cells (in two different cell lines) have been performed. In one of the cell lines a tendency for increased NK cell killing of oMV-infected melanoma cells has been observed, while in the other cell line this effect has not been detected. To confirm these results, a protocol to measure NK cell mediated cytotoxicity in real time using a digital bio-imaging system has been prepared.

Also, experiments to assess the direct impact of oMV on the activation status of NK cells have been performed. Results demonstrate that incubation of NK cells in the presence of an increasing amount of oMV leads to slightly elevated expression levels of the early activation marker CD69 on the surface of NK cells.

Finally, protocols to assess the impact of oMV infection on the dendritic cell and NK cell crosstalk are being prepared in collaboration with the Laboratory of Immunology at the National Cancer Institute in Vilnius, Lithuania.

Information published 29.03.2019.




Mājas lapas izstrādi finansēja ERAF 2.1.1.2. aktivitātes projekts Nr. 2010/0196/2DP/2.1.1.2.0/10/APIA/VIAA/004 "Latvijas biomedicīnas pētījumu integrācija Eiropas zinātnes telpā".