MBGE SEMINAR by Tolga Sütlü

Time: 14:30
Location: SCI 103

Speaker          :
Dr. Tolga Sütlü, Nanotechnology Research and Application Center, Sabancı University

Title                : Underdogs on the rise: TCR gene therapy gets a plot twist

Date                : September 27, 2018 Thursday
Time               : 14:30   
Cookie & Tea: 14:15 SCI 103 
Place               : SCI 103

Abstract         : In 1909, Paul Ehrlich was the first to propose in theory that the immune system had the potential to fight against tumors. Although it could not be confirmed at the time due to the lack of knowledge on the cellular and molecular details of the immune system, half a century later, Thomas and Burnet were able to formulate the “cancer immunosurveillance” theory. Accordingly, the development of any malignancy is under close surveillance by members of the immune system. Nevertheless, malignant cells obtain means to escape from the immune system and proliferate.

The technique of genetically introducing antigen-specific receptors, such as T cell receptors (TCRs) or chimeric antigen receptors (CARs), to redirect T cell-mediated immunity against tumor-associated antigens (TAAs) has delivered promising clinical results and CAR-T cell therapies have recently received clinical approval.  While CARs do have the ability to direct T and natural killer (NK) cell-mediated cytotoxicity, they can only target cell surface antigens and are blind to intracellular antigens. Alternatively, TCRs allow recognition of epitopes from both intracellular and cell surface antigens via Major Histocompatibility Complex (MHC) presentation. Nevertheless, this has so far only been tested in T cells.

Due to the heterodimeric structure of the TCR molecule, α and β chains introduced by gene delivery have a risk of mispairing with the endogenously expressed complementary β and α chains in T cells. This may give rise to TCRs of unpredictable specificity and cause iatrogenic autoimmunity. Despite the promise of TCR gene therapy, the mispairing problem constitutes a bottleneck in the development of effective and safe therapies.

In this study, we propose a paradigm shift by using NK cells for TCR gene therapy and aim to selectively target MHC-restricted epitopes of tumor-associated antigens. We show that the lentiviral delivery of TCR α/β genes into NK cells along with CD3 δ, γ, ε chains, but not necessarily CD3ζ, enables the surface expression of functional TCR complexes specific to a tyrosinase epitope (Tyr368-379) in complex with HLA-A2. These cells specifically and efficiently detect an antigenic epitope presented by MHC-I and robustly kill target cells in vitro and in vivo. This study underlines the value of NK cells as a resource that has similar cytotoxic capacity with T cells but present themselves unburdened from endogenous TCR expression.

Our strategy does not only have the potential to open up a whole new chapter in the field of cancer immunotherapy by enabling the targeting of intracellular antigens by NK cells but also provides a final and definitive solution for the mispairing problem observed in TCR gene therapy.

Keywords: T cell receptor, TCR gene therapy, Natural Killer cells, lentiviral vectors


Bio         : Tolga Sütlü is a graduate of Kadıköy Anadolu Lisesi and holds a B.Sc. degree in “Biological Sciences and Bioengineering” from Sabancı University. He got his Ph.D. in 2012 from Karolinska Institutet in “Medical Sciences”. In 2014, he joined Sabancı University and currently works at Sabancı University Nanotechnology Research and Application Center as a principal investigator funded by TÜBİTAK 2232, 3501, 1001 and 1007 programs.

His research focuses on immunology, specifically cancer immunotherapy. He is interested in design and optimization of biotechnological processes for personalized medicine approaches ranging from genetic modification of immune cells for tumor targeting to the development of immune cell-derived nanovesicles as a therapy approach and the production of monoclonal antibodies for cancer immunotherapy.

He is a founding partner of Vycellix, Inc. and serves as a board member for the Turkish Society of Immunology and the Molecular Biology Association of Turkey.