Development of Polyclonal Anti-tumor Therapy by Engineered Human T-cells

Cancer immunotherapy has revolutionized the oncology practice by providing an innovative solution for patients who were resistant to conventional therapy. Despite the promising beneficial effect of immunotherapies, their efficacy is still limited, mainly in solid tumors. Two main limitations of current immunotherapies are tumor antigen loss and lack of T cell persistence in the tumor microenvironment. We believe that polyclonality and polyfunctionality are two essential properties to address the shortcomings of current T cell therapies. We suggest overcoming these challenges by directly uncoupling tumor-reactive TCR repertoire from dysfunctional TILs and inserting it to new engineered T cells. Our methodology includes using established human TCR and peptide-MHC pairs, unique in vitro models for human T cell dysfunction, advanced synthetic biology and CRISPR engineering of primary human T cells. We will also use preclinical animal models to test our therapeutic approach for polyclonal TCR transfer. Successful completion of this project will elucidate the mechanism underlying TCR signalling and its involvement in T cell fate, which will open new avenues in immunotherapy and cancer treatment.