Dr Annie SCHMIDT (INSERM Nice)

The preclinical research project of Dr Alliana Schmid's team focuses on the treatment of pulmonary metastases from osteosarcoma by combinations of immunotherapy.

The aim of this project, which is unique in France, is to evaluate, in a preclinical model of pulmonary metastases from osteosarcoma - a cancer with a poor prognosis which particularly affects adolescents - the effects of a treatment combining two complementary immunotherapy strategies. The Eva pour la vie association is providing funding of 50,000 euros over 3 years, representing the entire cost of this project.
Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents with 150 new cases per year. Thanks to the progress of chemotherapy coupled with the optimization of surgical techniques, the cure rate reaches 60 to 70% for patients with non-metastatic osteosarcoma.

Unfortunately these tumors have a very strong propensity to metastasize, especially in the lungs. When diagnosing bone, lung metastases are already present in more than 20% of patients. Metastases indicate the severity of the disease. Indeed, patients with metastatic or recurrent bone respond poorly to current treatments and the cure rate in these patients has remained very low and unchanged for 30 years. It is therefore essential and essential to develop effective treatments for all these situations of therapeutic impasse and also to improve the quality of life of these young patients during and after the treatments.

Recognizing and eliminating cancer cells represent physiological functions of the immune system which are performed by specialized cells of the organism, leukocytes and in particular the population of T lymphocytes. The state of activation of T lymphocytes is permanently dependent on the balances between activating and inhibiting signals called immune checkpoints (activators or inhibitors). These immune checkpoints, which function as security locks, are essential both for optimizing the activation of T lymphocytes (activator checkpoints) and for preventing the risk of the immune system running away (inhibitory checkpoints). Cancer cells have developed multiple strategies to escape the immune system and in particular to deregulate inhibitory immune checkpoints in order to prevent the destruction of tumor cells by the immune system. The pharmaceutical industry has marketed antibodies and / or small chemical molecules which are capable of modulating some of these immune checkpoints and in fact making it possible to optimize the response of the immune system directed against the tumor.

Recent work in immuno-oncology has marked a major turning point in the understanding of the defense mechanisms of tumors against the immune system and have highlighted immune checkpoints as potential new therapeutic targets for antitumor. Treatments using this strategy in patients with metastatic melanoma have given extraordinary results in terms of cure and give new hope for other cancers. Today, therapies targeting immune checkpoints are given in many cancers, and are in clinical trial phase in osteosarcoma. The first results do not currently allow us to offer an effective treatment, in particular for the most aggressive osteosarcomas. It is therefore necessary to continue research research aimed at better understanding the interactions between cancer cells and immune cells involved in the progression of osteosarcomas.

The project funded by Eva Pour la vie (2017-2018, € 30,000) fits into this context. Its objective was to evaluate, in a preclinical model of pulmonary metastases from osteosarcoma, the effects of treatments combining two complementary immunotherapy strategies, one aimed at promoting selective recruitment of leukocytes in the tumor, the other aimed at neutralize 4 inhibitory immune checkpoints namely CTLA4, PD1, PDL1 and TIM3. This project consisted in testing different combinations of treatments with antibodies blocking inhibitory checkpoints (Ab anti-checkpoints) in the presence of fractalkine (FKN) allowing the recruitment of lymphocytes in the tumor.

Initially, the work carried out thanks to Eva pour la vie's first funding showed that the treatment of mice with FKN alone slowed the progression of pulmonary metastases from osteosarcoma by 40 to 60%, but over time , the animals eventually escaped treatment with FKN. However even though the mice metastasized in the presence of FKN, the mice were objectively in better shape than the untreated mice.

Regarding the treatments with blocking Ab at the PD1, PDL1, CTLA4 or TIM-3 checkpoints, the effects were on the one hand modest (at best a reduction of 5 to 30% in the progression of metastases) and on the other hand always lower. to those obtained with the FKN alone. In addition, we did not observe any cumulative effects of treatments combining anti-checkpoint Ab and FKN. The transcriptomic analysis of the tumors obtained in the different treatment situations (FKN + an inhibitory anti checkpoint Ab) indicated to us that the FKN had indeed enabled the recruitment of lymphocytes in the tumors but, and moreover, while certain obstacles had been lifted. by the Ac anti checkpoints, others were still active. Secondly, we associated treatment with FKN with several inhibitory anti-checkpoint antibodies. The results are disappointing since in all the combinations tested there were no more significant effects in terms of tumor reduction than FKN alone. Against all expectations, the transcriptomic analysis nevertheless revealed to us that in certain combinations, the 4 inhibitory checkpoints tested were neutralized.

The antibodies targeting CTLA4, PD1, PDL1 and TIM3 represented the first “wave” of commercialization of anti-immune checkpoint treatments. Today, antibody treatments targeting other inhibitory immune checkpoints are commercially available and in particular GAL9, LAG3 and Vista, and in fact represent new therapeutic hopes for osteosarcoma. In addition, all of our results led us to believe that the lymphocytes which were recruited into the tumor thanks to the FKN could, perhaps and also, present a defect of activation, limiting them in their capacity to destroy, cancer cells over time. This therefore led us to reconsider the combinations of immunotherapy that could be envisaged and in particular to test combinations of treatments associating FKN with blocking antibodies of inhibitory immune checkpoints and / or with stimulating antibodies of activating immune checkpoints. This study is in progress and is entirely carried out thanks to the second financial support provided by "Eva pour la Vie" (2019-2020, € 20,000)

The ultimate goal of our project being of course to offer as quickly as possible, to patients with metastatic bone, the most effective treatment possible and with the fewest side effects.

WE ALSO SUPPORT ..

Dr Christophe GROSSET (INSERM Bordeaux)

Since 2012, Dr Christophe Grosset has been studying hepatoblastoma, a liver tumor that affects very young children. Today, the main difficulty is to treat patients suffering from metastases or from an inoperable tumor resistant to treatment. With the support of the Eva pour la vie association, the team has set up a new model of hepatoblastoma in the chick embryo which makes it possible to test the effectiveness of new therapeutic molecules (such as microRNAs) and of facilitate the study of these tumors in the laboratory. It has also shown the value of a drug already used in the treatment of certain leukaemias, to treat children with very aggressive liver cancer.

Dr Fabienne MEGGETTO (INSERM Toulouse)

Dr Fabienne Meggetto is research director at INSERM Toulouse, within a team of excellence whose research work focuses on lymphomas in children. The Eva pour la vie association has decided to provide aid of 50,000 euros for the start of an ambitious and transversal project, which could make it possible to find new therapeutic avenues for lymphomas with a poor prognosis, but also, others. solid tumors such as neuroblastoma. ...

Dr Eddy PASQUIER (CNRS Marseille)

Dr Pasquier's research work mainly focuses on the repositioning of drugs which consists of testing, in new therapeutic indications, drugs already approved by the health authorities. The aim of this work is to identify new therapeutic targets for the most difficult to treat cancers and thus improve the care of patients suffering from these aggressive forms and refractory to treatment . In particular, pediatric cancers (neuroblastoma), brain tumors affecting children as well as adults (glioblastoma, medulloblastoma) as well as certain rare forms of cancer (angiosarcoma).



Dr Marie CASTETS (INSERM Lyon)

The work of the INSERM team co-directed by Dr Marie Castets (CR1 Inserm, HDR) and Dr Jean-Yves Blay (PUPH, HDR) focuses on cell death and cancers. Thanks to the support of Eva pour la Vie (55,000 euros) and other associations, this team is currently developing these lines of research on rhabdomyosarcomas, osteosarcomas and neuroblastomas ...



Dr Martin HAGEDORN (INSERM Bordeaux)

Since September 2014, Dr Martin Hagedorn has been leading a team of researchers (Caroline CAPDEVIELLE , Farah RAHAL, Justine CHARPENTIER and Mélissa MENARD) which devotes its research work to the identification of new therapeutic targets in brainstem tumors and to the improvement of its treatment methods. Work recognized by several European scientific teams & experts.



Dr Patrick AUGUSTE (INSERM Bordeaux)

For more than 20 years, this teacher-researcher has been working on cancer. And it's been almost 10 years since he went to kidney cancer or renal cell carcinoma. By joining the team of Dr Christophe Grosset (Inserm, MiRCaDe team), he wanted to use his experience and take a new step forward by working on childhood cancer. He is the initiator of an ambitious project, which involves several surgeons, doctors and international researchers, on the study of nephroblastoma (or Wilms tumor) in children, co-funded by the association Eva pour la vie and Aidons Marina ...



Prof. Sébastien PAPOT (University of Poitiers)

At the end of 2018, the Nouvelle Aquitaine region agreed to co-finance with Eva for life the research project "Biological and preclinical studies of new anticancer agents, including some targeting EZH2 / PRC2, in the treatment of highly proliferating hepatoblastoma", led by Prof. Papot and Dr Grosset. The Eva pour la Vie association covered up to 50% of the cost of the purchase of laboratory equipment (in the amount of € 9,000) necessary for the smooth running of this work.

Dr Max PIFFOUX (Center Léon Bérard, Lyon)

Doctor Max PIFFOUX - under the responsibility of the "Apoptosis and cancer" team coordinated by Aurélie DUTOUR at the CLB - is the scientific manager of the following research project: "Autophagic induction as a booster of response to immunotherapies: trial of a new therapeutic class, calorie restriction mimetics, in the pediatric osteosarcoma model ". Eva pour la vie & Aidons Marina have decided to co-finance the launch of this project, by providing a grant of 40,000 euros.

Dr Olivia FROMIGUE (Institut Gustave Roussy)

Resistance to treatment is a major clinical problem, in particular in the case of osteosarcomas, bone tumors affecting children or adolescents. Indeed, chemotherapy, associated with surgery, is the central pillar of current treatment. However, many osteosarcomas are or become resistant to these antiproliferative drugs. Recurrences and / or the appearance of metastases are then frequent. 2 out of 5 patients cannot be cured! Osteosarcoma is therefore a pediatric cancer with a poor prognosis for which it is absolutely necessary to identify ways to counteract resistance to treatment in order to improve the chances of recovery for patients.



Epidemiological research

If the development of therapeutic routes adapted to the child is essential (to try to save the children who today, remain without a therapeutic solution and / or to reduce the side effects), we do not forget an equally strong reality: over the past 50 years, the number of children affected by cancer has never declined. Much remains to be done in terms of prevention, both in terms of research and regulation. Eva pour la vie is actively involved by co-financing environmental studies. The first of these, HAPPI, aimed to have the KUDZU SCIENCE laboratory analyze dust samples taken in homes bordering vines - welcoming children or pregnant women - as well as in a primary school classroom.