The recent approval by the American Federal Drug Agency (FDA) and the European Medicines Agency (EMA), of new immunotherapies for blood cancers have opened new hopes and avenues for the treatment of patient with cancer. Two new drugs, called YEScarta and Kymriah, use the patient’s own T-cells genetically engineered to express an artificial T- cell receptor able to target cancer cells. This form of immunotherapy is called Chimeric Antigen Receptor Therapy (CAR T). For the moment, the new CAR T therapies have only been endorsed for blood cancers that express the CD19 antigen. Clinical trials testing these agents demonstrated striking effect in patients with high rate of remission and in many cases even complete recovery. However, this new technology is not without his own drawbacks. Problem of toxicities are observed due to the targeting and killing of normal cells which also express the CD19 target antigen. Moreover, CAR T cell therapies have presented disappointing results with solid cancers. This inefficacy, is mainly due to CAR T inactivation by the tumour microenvironment. Currently, new CAR T cell therapies are evaluated using in vivo models that cannot determine efficiently their future performance when they will be translated to clinical trials. The AMIDE project aims at developing new innovative animal model for immunotherapy evaluation and to teat and validate new CAR T cell designs for their implementation toward clinical trials.
The emergence of immunotherapy is revolutionizing how we think and treat cancer patients. Indeed, immunotherapy has made such an impact upon cancer survival that it is already considered as the 4th pillar of cancer therapy (Europe new Horizon program). One particular cell-based immunotherapy, named Chimeric Antigen Receptor (CAR) T cell therapy, empowers the patient’s immune system to fight and eradicate cancer cells. CAR T cell therapy is based on the modification of the patients T-cell receptor (TCR) to recognize and destroy cancer cells through targeting of surface markers present on malignant cells. CAR-T-cell therapies have demonstrated successful and impressive clinical results in several type of haematological malignancies. However, this complex living medicinal product has the unique ability to self-amplify and persist in treated patients. Hence, CAR T cells have been associated with a unique set of acute toxicities with Cytokine Release Syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and on-target off-tumour effect. At first, CAR T cell therapies were directly evaluated in patients, bypassing preclinical validation traditionally employed prior to clinical development of therapeutics. This “on-human first” approach has led to treatment related safety and toxicity complications, often resulting in patient deaths. Thus, one major challenge facing the safe clinical implementation of CAR T cell-based therapies lies in the development of preclinical models that can more accurately model the human CAR T treatment paradigm. The AMIDE project is focused on the development of new preclinical animal model to evaluate and predict the efficacy and toxicities related to the development of new innovative CAR T cell therapies. The other objective of the project is to evaluate new innovative CAR T cell designs engineered to prevent off-targeting effect and T-cell exhaustion, two major issues affecting the CAR T cell technology.