Adoptive T cell therapy, in which antigen-specific T cells are generated ex vivo and transferred back into patients, is a promising strategy to treat cancer. Although CD19-targeting chimeric antigen receptor (CAR) T cells have shown remarkable results against acute lymphoblastic leukemia (ALL), many aspects of this technology remain to be improved. Regarding the therapeutic challenges, relapses have been observed in a large proportion of patients, many whose tumors expressed very low levels of target antigen. Second, clinical results remain poor in solid tumors, notably due to the lack of ideal targets, inefficient homing to the tumor site, limited T cell persistence and T cell dysfunction. Third, CAR therapies have been associated with toxicities, such as cytokine release syndrome (CRS) or cerebral edema. On the manufacturing side, the wide implementation of T cell therapy is limited by the use of randomly integrating vectors in autologous patient cells, which involves high cost and unavoidably a high variability of the final product.

Our laboratory is aimed at understanding the current limitations of CAR T cell therapy using innovative tumor models and functional genomics and overcoming these challenges by reprogramming T cells with the use of genome editing and synthetic receptors.

Active projects:

1) High Throughput Tool Development for Accelerated CAR Engineering
Recent studies have determined that not all CARs are created equal in terms of effector function, persistence, and antigen sensitivity. Our laboratory has developed powerful T cell editing tools which allow for high throughput screening of CAR constructs, as well as discovery of new CAR architectures with augmented effector functions, persistence and sensitivity to antigen density

2) Immunobiology of CAR T Cells in Solid Tumors
CAR T cells have shown poor therapeutic efficacy in solid tumors. To understand the challenges CAR T cells are facing in solid tumors we need mouse models that effectively recapitulate the complexities of the tumor microenvironment. Our lab is developing improved mouse models to investigate the interaction of CAR T cells with the different components of the solid tumor microenvironment and to identify mechanisms by which solid tumors induce dysfunction in CAR T cells.

3) Improvement of Gene-Edited Immune Cell Manufacturing for Clinical Trials
As immunotherapeutic strategies move toward more complex engineering and multiplexed editing, there is a growing need to optimize the manufacturing of CAR-engineered cells for the clinic. Our laboratory is focused on bolstering the efficiency of CAR T cell enrichment, improving the precision of T cell editing using novel tools developed in the lab. Finally, we are expanding our technologies to other immune cells and are optimizing gene editing protocols and CAR designs for NK cells.