CAR-T cells: biology, concepts and principles

摘要

The development of new anti-tumor immunotherapy approaches has recently dramatically increased. Progresses made in molecular biology and the development of various genetic manipulation tools allow the "reprogrammation" of T cells in order to make them express a chimeric receptor including the variable part of an immunoglobulin capable of recognizing a tumor antigen along with the expression of molecules involved in T-lymphocyte activation signaling. Genetically modified T-cells, called "CAR (chimeric antigen receptors) -T cells", have yielded impressive clinical results in the treatment of relapsed or refractory lymphoid hematological malignancies after conventional treatments and are in development in solid tumors. Different generations of CAR-T cells have been developed and technological progress makes it possible to envisage modulations of gene constructs that could further optimize the efficacy and tolerance of CAR-T cells. The first challenge of these approaches concerns the identification of specific tumor antigen targets in order to limit the on-target/off-tumor effects and the loss of expression of the target. Approaches i) targeting several antigens or ii) limiting the duration of expression of CAR in lymphocytes or iii) destroying CAR-T cells by a suicide gene. Interesting approaches are the second objective of improvement concerns the accessibility of CAR-T cells to tumor sites and the control of the immune escape mechanisms of tumor cells to the cytotoxicity of CAR-T cells. This issue is currently under the way of search of innovative strategies that should improve the clinical effectiveness of CAR-T cells, especially in solid tumors.