Immunotherapy with T cells: New strategies and improved designs

Abstract

Despite all the steps that have been made during the last decades towards the improvement of cancer treatment, for many patients the disease remains incurable. Moreover, the standard treatments such as irradiation, chemotherapy and surgery can cause a lot discomfort and unwanted side effects for patients. Currently, there are already several potential game-changing cancer immunotherapies implemented in clinical practice, and there are many more in different stages of preclinical and clinical development. While these will undoubtedly change treatment outcome for many cancer patients, unfortunately probably only a minor fraction of all cancer patients will benefit from these treatments. Therefore, further improvement of at-present used therapies, development of novel concepts as well as efforts to combine different treatments to increase overall efficacy is needed. In this thesis we aimed to advance immunotherapeutic strategies using αβ- or γδTCRs for tumor cell recognition. We developed a novel concept to purify and deplete αβTCR engineered T cells, a strategy that could contribute to improving the quality and safety of ex vivo manufactured αβTCR cell therapies. Furthermore, we improved in vitro and in vivo potency of T cells engineered with a γδTCR (TEG), by the introduction of an additional chimeric co-stimulation receptor. This will hopefully add to clinical efficacy of this cell product in the future, a strategy that might also be applicable to other cell therapies. Lastly, we introduced a novel concept to the fast-growing field of γδTCR mediated immunotherapy, with the development of a bispecific T cell engager by linking the extracellular domains of tumor-reactive γ9δ2TCRs to a CD3-binding moiety, creating gamma delta TCR anti-CD3 bispecific molecules (GABs). With the GABs we provide an alternative strategy to translate the promise of γδTCRs into anti-cancer therapy, with the potential to be a broadly applicable and off-the shelve therapy.