Gene and Cell Therapy.

The general objective of the Gene and Cell Therapy group (GCTG) is the Improvement and Generation of Advanced Therapy Medicines for Cancer and Rare Diseases through the Combination of Gene Addition and Genomic Editing. In recent years, gene therapy (GT) has achieved unprecedented success in clinical trials for various previously incurable conditions. This has led to the approval of a total of 16 advanced therapy medicines (ATMPs) involving genetic modification. It is important to note that most of these GT-based medicines are based on introducing genetic material into target cells using viral vectors. In this direction, the overall goal of this group is to generate advanced therapy medicines based on genetic modification for the treatment of cancer and monogenic diseases. To achieve this goal, two main sub-lines will be pursued, aiming for the following scientific and technical impacts:

Improvement of Genetic Modification Tools

Improvement of Genetic Modification Tools with a Focus on Cancer and rare diseases. Despite the potential of viral vectors, there are still various efficacy and safety issues that hinder their use for many other pathologies. Therefore, an important objective is to refine the available viral vectors and, more importantly, implement new gene therapy (GT)
techniques based on genomic editing (GE) using non-viral systems. While viral vectors have shown good results, limitations persist related to their origin and their ability to alter the expression of oncogenes in specific cell types. Unlike traditional systems, GE allows for the creation or repair of mutations and the insertion of fragments up to 10 kb at a specific site efficiently enough to translate it to clinical applications. Consequently, GE can not only replace lentiviral vectors by inserting the transgene in a safer or better-expressing site but also enable novel therapeutic approaches impossible with traditional genetic modification systems.

The development of new therapeutic strategies

The development of new therapeutic strategies for currently untreated pathologies is crucial. Advances in the previous section will be utilized to create more effective and safer Advanced Therapy Medicinal Products (ATMPs) for treating conditions such as Pompe disease, lymphomas, and pancreatic cancer (which can be extended to other solid tumors).
These ATMPs will primarily involve ex vivo modification of T cells (lymphocyte engineering) and multipotent hematopoietic stem cells (HSCs).

• Lymphocyte engineering for cancer treatment: CAR-T cells

The GCTG has patented several tools for the development of improved CAR-T cells for the treatment of cancer. These technologies were the basis for the creation of LentiStem Biotech, the first Spanish Spin-off working on CAR-T cells. In addition, it is expected to reach first-in-human clinical trial approval by the end of 2024. This proposed clinical trial
has been financed by the ISCIII for the treatment of refractory type B Leukemias and Lymphomas and is led by Dra Inmaculada Herrera from H.U Reina Sofia (Córdoba). In addition, we are developing inducible 4th generation CAR-T cells for the treatment of Pancreatic cancer in collaboration with Dr Jose Antonio Salcedo (GENYO), Dr Juan Antonio Marchal (UGR), Dr Pedro Sierra and Dr Maria Rueda (H.U. Virgen de las Nieves), Dr Felipe Prosper (Clinica Universitaria de Navarra) y Dr Juan Bueren (CIEMAT). This project is financed by two National grants and the
TerAv network and use genome editing tools, inducible vectors (patented by the GCTG) and nanobodies to design more efficient and safer CAR-T cells for the treatment of solid tumors.

• Gene therapy for Pompe disease

The other objective of the GCTG is to use the new vectors and genome editing tools to generate an ATMP to treat Pompe disease. To tackle this objective, our first aim is to generate relevant cells and animal models were to study the efficacy and safety of the new ATMPs. This research line is led by Dr Pilar Muñoz and Fco Javier Molina Estevez and count with the support of National, Regional and Private grants, as well as with the help of patients association.