Alessia Potenza

Recent developments in genetic engineering of T cells

The development of genetic engineering technologies dramatically changed the landscape of Adoptive T cell therapy (ACT) for cancer making this treatment accessible to an unprecedent number of patients and tumor types. By inserting a chimeric antigen receptor or an exogeneous tumor reactive T cell receptor into patient’s T cells, the specificity can be precisely redirected toward selected tumor antigens. By permitting multiple gene disruption and targeted gene integration, genome editing tools have further increased the range of opportunities for ACT. With selected biotechnological tools and protocols, such as CRISPR/Cas9 and base editing, we could potentially endow T cells with the ability to infiltrate the tumor mass, recognize relevant tumor antigens, persist as memory cells, and resist the immunosuppressive signals present in the tumor microenvironment. This is of major importance in solid tumors, where exhaustion mechanisms, phenotypically resulting in the co-upregulation of multiple inhibitory receptors (IRs), impede the functional capacity of T lymphocytes against tumor cells. In liver metastases from colorectal and pancreatic cancers, we identified and harnessed the drivers of T cell exhaustion to enhance the potency of adoptively transferred T cells. After selection of the proper target antigen and the consequent identification of a panel of tumor-specific TCRs, we proved how TCR-redirected, IRs-disrupted T cells display a functional advantage in eliminating patient-derived tumor organoids in vitro and in vivo. Challenges and opportunities towards the generation of optimal T cell therapy products will be discussed.