New project aims to improve the efficacy and safety of CAR T therapies for solid tumors

Partners in the international consortium CAR T-REX announce the awarding of a highly competitive EIC Pathfinder Open grant, following the positive evaluation of their project entitled 'CAR T Cells Rewired to Prevent EXhaustion in the Tumour Microenvironment'. One of 57 projects selected amongst 858 submissions, with a total funding of €2.7M, CAR T-REX was recognized for its radical and ambitious vision to improve the efficacy and safety of CAR T-based solid tumor-targeted cell therapies.

• By combining innovative methods of genome editing and non-viral gene delivery, CAR T-REX will explore the engineering of transcriptional networks in Chimeric Antigen Receptor (CAR) modified T lymphocytes (i.e., CAR T cells), to selectively circumvent T-cell exhaustion upon activation in the tumour microenvironment (TME).
• CAR T-REX aims to (i) build novel auto-regulated genetic circuits controlled by microRNAs (miRNAs) in immune cells, (ii) employ a novel high-performance non-viral gene delivery platform for delivery of the synthetic miRNA constructs, (iii) select and benchmark the best-performing construct(s) in preclinical settings, and (iv) execute GMP-like manufacturing run(s) for the final CAR T product.
• CAR T-REX consortium brings together a multidisciplinary group of internationally recognized experts and companies across Europe. The project will start in June 2023 and run for 4 years.

Cell and gene therapies (CGT) are at the forefront of healthcare innovation, with the potential to transform the current therapy toolbox. Indeed, highly personalized (autologous) CAR T cell therapies have dramatically changed the treatment landscape, achieving partial or, in a significant number of cases, long-lasting full remission for patients with blood cancers. However, while CAR T cell therapies have shown remarkable efficacy for the treatment of specific hematological malignancies, broad clinical use is limited by multiple factors, including high manufacturing costs and significant side effects. Moreover, treatment of patients with solid tumors has thus far failed to demonstrate clinical benefit, with antigen heterogeneity, limited infiltration into tumor tissue and (especially) T cell exhaustion/loss of function, negatively impacting clinical outcomes. In this regard, CAR T-REX aims to explore a novel paradigm for the generation of improved CAR T cells. By combining non-viral gene delivery with precise genome editing of T cell autoregulatory pathways, CAR T-REX proposes a strategy to overcome the mechanisms by which solid tumors (and the immunosuppressive TME) "switch off" the anti-tumoural immune response, potentially extending the utility and safety of current CAR T technologies.

For an ever-growing number of cancer patients, the current treatment options fail to provide a clear therapeutic benefit. Hence there is an unmet clinical need, which could be addressed by unleashing the curative potential of T cell-based therapies. It has therefore been an honor and an energizing yet humbling opportunity to be able to bring together this consortium which we expect to majorly contribute to the therapy of solid tumors."

György Vereb, Head of Chair at the Faculty of Medicine, University of Debrecen

Rui A. Sousa, CEO of Stemmatters & Coordinator, explains: "CAR T-REX brings together a multidisciplinary team with unique expertise and capabilities in genome editing, non-viral gene delivery, immunology and T cell therapy, as well as Quality-by-Design methodologies and cGMP manufacturing, providing the right mix of skills needed to achieve the proposed goals. Stemmatters will ensure that processes are designed in compliance with harmonized quality standards and applicable regulatory requirements, as well as state-of-the-art methodologies, thus supporting a faster translation into the clinic setting".

Overall, the CAR T-REX consortium expects to lay the foundation of an improved technology, with potential for significant scientific and societal impact, with recent estimations on the incidence and mortality for 25 major cancers across 40 European countries revealing 4 million new cases (excluding non-melanoma skin cancer) and 1.9 million cancer-related deaths in 2020.