Periodic Reporting for period 1 - iGEMMdev (Development and Characterisation of New Immunogenic GEMMs of Lung Cancer)
Berichtszeitraum: 2017-01-01 bis 2018-12-31
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.
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.
Our objective was to improve the current transgenic mouse models of lung adenocarcinoma which are not immunogenic and therefore, do not enable the study of the interaction between tumour and immune system and do not offer the possibility of testing new drugs that aim to activate the anti-tumoural immune response. Because current models lake mutations in comparison with human lung cancer, our strategy was to increase the total number of mutations or to induce other genetic alterations which could lead to the presentation of neoantigens.
We developed and characterised three models of lung adenocarcinoma. From the two models that we had initially planned to generate, the KP-A3Bi model has not proven to be more immunogenic than the reference model of lung cancer in standard conditions. However, the immunogenic cell line we established from this model demonstrated that some clones within the KP-AB3i tumours can be recognised and controlled by the immune system. We are still working at finetuning this model to improve it. The second model, KP-M2, has just been developed and is still being characterised. We adapted our initial plan and added chemicals (carcinogens) to our transgenic models to increase the number of mutations in tumours. The U-A3Bi model resulting from this showed a partial response to immunotherapy. Altogether, this suggests that A3Bi (APOBEC3B) is an excellent candidate to induce mutations that are recognised by the immune system and therefore useful in the development of an immunogenic genetically engineered mouse model (or iGEMM) of lung cancer.
The characterisation of the two iGEMMs we planned to develop during this project will need more work before we can submit an article. In contrast, the transplant model and the conditional model we developed are both already used in 3 other projects which are expected to be published in high impact factor journals.
We developed and characterised three models of lung adenocarcinoma. From the two models that we had initially planned to generate, the KP-A3Bi model has not proven to be more immunogenic than the reference model of lung cancer in standard conditions. However, the immunogenic cell line we established from this model demonstrated that some clones within the KP-AB3i tumours can be recognised and controlled by the immune system. We are still working at finetuning this model to improve it. The second model, KP-M2, has just been developed and is still being characterised. We adapted our initial plan and added chemicals (carcinogens) to our transgenic models to increase the number of mutations in tumours. The U-A3Bi model resulting from this showed a partial response to immunotherapy. Altogether, this suggests that A3Bi (APOBEC3B) is an excellent candidate to induce mutations that are recognised by the immune system and therefore useful in the development of an immunogenic genetically engineered mouse model (or iGEMM) of lung cancer.
The characterisation of the two iGEMMs we planned to develop during this project will need more work before we can submit an article. In contrast, the transplant model and the conditional model we developed are both already used in 3 other projects which are expected to be published in high impact factor journals.
There were an estimated 3.5 million new cancer cases and 1.9 million cancer deaths in Europe in 2012 and 9.6 million deaths from cancer worldwide in 2018. Accordingly, the EU has emphasised cancer research within its H2020 program, highlighting the importance of cancer research. Immuno-oncology is an emerging and highly promising research area in the field of cancer therapy. Pre-clinical models which closely mimic the complexity of human cancers in terms of heterogeneity and mutation burden were lacking in the field. Both the transplant model and the conditional model of lung cancer we developed during this EU-funded project will benefit the field by bringing the possibility to investigate new treatments based on immunotherapy.
Our conditional model of lung cancer provides a tool to study immunological aspects of cancer but also resistance to treatment. It will be useful at different levels. It provides access to an immunologic cancer model other than subcutaneous transplant models which do not recapitulate the tumour microenvironment observed in the tissue where tumours develop. It can become standard in preclinical studies in lung cancer because: 1) Genomic alterations and consequent Intratumoural Heterogeneity (ITH) lead to more complex tumours and increase the difficulty to cure them because of subclones resistant to treatment. The model we developed mirrors this ITH allowing the study of its impact on drug resistance. 2) Therapies that aim to stimulate the immune system could lead to severe autoimmune toxicity. The opportunity to assess these possible toxicities on a relevant mouse model is crucial to limit patients risk exposure.
The models developed here will give new insights into the immunological aspects of lung cancer and consequently, will maximise the potentials of immunotherapies to cure cancer.
Our conditional model of lung cancer provides a tool to study immunological aspects of cancer but also resistance to treatment. It will be useful at different levels. It provides access to an immunologic cancer model other than subcutaneous transplant models which do not recapitulate the tumour microenvironment observed in the tissue where tumours develop. It can become standard in preclinical studies in lung cancer because: 1) Genomic alterations and consequent Intratumoural Heterogeneity (ITH) lead to more complex tumours and increase the difficulty to cure them because of subclones resistant to treatment. The model we developed mirrors this ITH allowing the study of its impact on drug resistance. 2) Therapies that aim to stimulate the immune system could lead to severe autoimmune toxicity. The opportunity to assess these possible toxicities on a relevant mouse model is crucial to limit patients risk exposure.
The models developed here will give new insights into the immunological aspects of lung cancer and consequently, will maximise the potentials of immunotherapies to cure cancer.