Transposon-Based, Targeted Ex Vivo Gene Therapy to Treat Age-Related Macular Degeneration (TargetAMD)

chain-specific ZFNs, followed by the introduction of tumorspecific TCR genes by lentiviral vectors. The original approach comprises four sequential steps of genetic manipulation and selection of engineered T-cells, and required approximately 40 days of culture. Within the SUPERSIST project and in view of a prompt clinical translation, we have recently simplified the editing protocol to retain the benefits of the original TCR gene-editing strategy while increasing its feasibility. This optimized gene-editing protocol can now be combined to T-cell activation and culture procedures that allow generating gene-edited T-cells with an early memory T-cell phenotype, which is associated to long-term persistence of the cells in several mouse models. These advances are instrumental to pave the way toward the development of a feasible and cost-efficient process supporting clinical testing of this new technology. In another fundamental advance made within the project, NKI has developed highly innovative TCR capture techniques that allow identifying novel tumor-reactive TCRs from primary clinical specimens. These studies have provided major new insights in the antigenic space targeted by the immune system in human tumors. These findings were reported in a top scientific journal and granted great attention by the scientific community, as they have substantial implications for understanding the process of cancer– directed immune response as well as improving the design and application of gene-based immunotherapy. Within the SUPERSIST summary, we will now exploit these technologies to widen the reach of TCR gene editing toward a broader range of neoplastic diseases. With the support of the SME partner MOLMED, the consortium will continue to perform the scale-up and optimization of gene-targeting protocols for both HSC and T-cells for the two gene therapy applications being developed. These processes will enable clinical testing of the new strategies. We are also designing an exploitation roadmap for SUPERSIST results, taking advantage of partnerships already established by consortium partners with leading biotech companies in the field, such as Sangamo BioSciences, for the development of ZFNs, and other big pharmas.