Unmet needs in T cell-based cancer therapies: opportunities for translational innovation

Abstract

Immunotherapies have greatly improved treatment options for patient suffering from a range of malignancies. After these novel, anti-cancer therapeutics like CART cells showed overwhelming clinical success in targeting hematological malignancies, the first promising signals are also seen for utilizing engineered immune cells for targeting solid tumors. However, despite numerous attempts, clinical efficacy in targeting solid tumors remains lacking. This is due to several reasons including a lack of targetable, tumor-specific antigens, immune-escape mechanisms in the more complex tumor microenvironment, tumor recurrence and metastases. In order to overcome these roadblocks, new approaches for targeting solid malignancies and improving existing immunotherapies are needed. Within this thesis, we describe and investigate multiple new strategies for utilizing γδT cells and their TCRs to improve the efficacy of T cell based immunotherapies in the field of oncology. First, we identify important TCR features dictating the behavior of tumor-reactive, Vγ9Vδ2T cells (Chapter 3). Next, we describe novel approaches for the recognition and targeting of either glioblastoma (Chapter 4) and colorectal cancer (Chapter 5) that provide potential for the development of future immunotherapies. Additionally, we identify a potential novel way to improve T-cells fitness upon in vitro expansion by investiganting on a alternative activation pathway (Chapter 6). Finally, we describe an approach to boost T cell infiltration in the tumor micro-environment in order to improve therapeutic efficacy of T cell based treatments for both hematological and solid tumors (Chapter 7). In Chapter 8 we conclude with a general discussion.