iGEMMdev · Development and Characterisation of New Immunogenic GEMMs of Lung Cancer
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2017-01-01 → 2018-12-31
- EU contribution
- €183,455
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Development and Characterisation of New Immunogenic GEMMs of Lung Cancer
A few years ago, scientists demonstrated that our immune system could detect and eliminate tumour cells. Unfortunately, some tumours cells develop mechanisms that make them invisible to the immune system, and when this happens, the tumour grows and we talk about cancer. Scientists developed drugs which can block the mechanisms that allow the tumours cells to escape the immune system. When these drugs are given to patients with cancers, their immune system can detect the tumour again and eliminate it. The two scientists who developed the first drug that was capable of this are James Allison and Tasuku Honjo, and they received the Nobel Prize of Medicine in 2018 for this. This drug worked exceptionally well on some patients who were refractory to conventional therapies. Sadly though, for many patients, it did not work at all. Now many other similar drugs have been developed with the hope to cure all patients. They all block slightly different mechanisms which can be established by the tumour to escape the immune system. To understand how these drugs work and which ones will be the best to use for which patients, we have to use pre-clinical models. Because these drugs are working by changing the effect of the immune system on the tumour, we have to work with a whole animal where these systems are present. Unfortunately, the models which we have been using in the lab for years are not useful for studying this kind of therapy. Lung cancer in human has many mutations, and this is these mutations that the immune system can detect to recognise the tumour and to eliminate it. The mouse models of lung cancer we have been using so far have no mutations and therefore, could not be seen by the immune system making them useless to study immunotherapy. This project aimed to induce mutations in mouse lung tumours to make them more similar to their human counterpart and to make the immune system of these mice able to see the tumours.
Data: CORDIS, © European Union
Project objective
Many studies have recently archived a remarkable clinical efficacy of immunotherapeutic treatments in several cancers including non-small cell lung cancer (NSCLC). However, these approaches are not always successful and it is currently impossible to predict a therapeutic response or serious adverse event. These fundamental issues need to be addressed and, to recapitulate the complexity of interactions between immune cells and cancer, this has to be done in vivo. However, genetically engineered mouse models (GEMMs) of NSCLC do not mirror the genomic instability and the high mutations rate of their human counterparts. Consequently, these tumours rarely present neo-antigens that can induce an immune response, and are considered poorly immunogenic. To our knowledge, a genetically defined model of an immunogenic spontaneous tumour does not exist. Here, we propose to develop such an immunogenic GEMM (iGEMM).The leading mouse model of lung cancer is the GEMM Kraslsl-G12D/wtTrp53fl/fl (KP). We propose two strategies to induce either genomic instability or mutation rate in the KP model. 1) We will overexpress Mad2, a component of the mitotic spindle assembly checkpoint, to induce aneuploidy in KP tumours; 2) We will overexpress the cytidine deaminase Apobec3 to increase the mutation rate of KP tumours.The resulting immunogenic GEMMs (iGEMMs) will be characterised and used to assess new therapies that trigger an immune response and to address mechanisms which drive immunotolerance. iGEMMs will facilitate the investigation of currently available immunotherapies which will help predict clinical response to these therapies and investigation on alternative strategies to treat resistant lung tumours. All together, these investigations will provide novel information regarding the best strategies to cure NSCLC by modulation of the IS.
Original text from CORDIS.
Participants
- THE FRANCIS CRICK INSTITUTE LIMITED · LondonCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union