Adoptively transferred T cells expressing recombinant chimeric antigen receptors (CAR T cells) have been approved for the treatment of several haematological malignancies. However, CAR T cell therapy for patients with solid tumours has shown limited benefit so far. One problem is the exhaustion of CAR T cells in the tumour microenvironment (TME). Current state-of-the-art strategies include the permanent modification of CAR T cells to (i) knock out negative regulators (e.g. PD1), or (ii) drive expression of molecules promoting efficacy upon CAR engagement (i.e. TRUCK concept). However, these strategies provide limited adaptation to the location of T cells, and, most importantly, do not limit the activation to the TME where exhaustion should be countered.
In this context, the CAR T-REX project attempts to tackle challenges related to the treatment of solid tumours, aiming at improving efficacy, safety, scalability and cost of therapies.
Genetic rewiring will be achieved through proprietary technology (from TargetGene, TG) to precisely insert artificial miRNAs under endogenous exhaustion-related “Driver” promoters to downregulate “Target” genes that cause exhaustion. These genetic modifications will be implemented using a novel high-performance peptide-based gene delivery platform (developed by Universidade de Santiago de Compostela, USC), allowing combination of several types of cargo. Rewired CAR T cells will be tested on preclinical breast and gastric carcinomas, including humanized animal models (by the Associated Partner University of Debrecen, UD-AP), and variants that eliminate tumours resistant to conventional 2nd and 3rd generation peers (without adverse events) will be developed and manufactured under GMP-like conditions (Stemmatters, STEM; and Leibniz Institute for Immunotherapy, LIT), thus accelerating the pathway towards clinical translation.
