AXIS 2: ENGAGING EFFECTOR CELLS FOR CANCER THERAPY

CARMA: Adapting CAR T cell metabolism and activation to improve therapeutic efficacy:

Adoptive T-cell therapy using chimeric antigen receptor (CAR) technology has shown promise in the treatment of cancer, particularly hematological malignancies. However, challenges related to the persistence and functionality of CAR T cells limit their efficacy against solid tumors. Recent research highlights energy metabolism, in particular mitochondrial fitness and respiratory capacity, as key factors in CAR T cell efficacy and patient prognosis.

The CARMA project aims to develop a novel T cell activation method to produce CAR T cells with optimized metabolic profiles. Using an advanced optogenetic system, we can precisely control the dynamics and intensity of T cell stimulation to shape specific metabolic profiles with enhanced mitochondrial function.

By integrating optogenetics, cell biology, metabolism and onco-immunology, CARMA aims to generate CAR T cells with improved efficacy against solid tumors. In collaboration with neuro-oncologists at the Hôpital de la Timone, we are evaluating these cells in advanced preclinical models. This project has the potential to significantly advance adoptive cell immunotherapy.

In addition, we are exploring the potential of single-domain antibodies to generate multispecific CAR-T cells.

Multispecific immune modulators :

One of our main interests is to design effective multispecific immune cell mobilizers and modulators targeting different effector cells such as NK cells, T cells or macrophages. Their mechanisms of action and their ability to bypass any resistance mechanisms set up by tumor cells to evade their action are studied using 2D and 3D cell models in vitro, and their therapeutic efficacy in vivo in mouse models repopulated with human immune cells.

The exact mechanism by which the architecture of immune cell engager regulates the formation of immunological synapses, and hence the potency of these engagers, remains largely unexplored. Understanding the structure-function relationships between cell engager architecture and the formation and function of immunological synapses could accelerate the design of new cancer therapies.

As part of a consortium comprising biophysicists specializing in the measurement of mechanical forces applied to immune receptors, the design of pattern-controlled structures including lipid bilayers, and the national pioneer of DNA origami techniques, we are harnessing the power of DNA origami approaches to finely design and test a wide variety of immune cell engagers varying in valence, affinity, specificity, rigidity and size.