From mouse to human: Metabolic targeting of cancer with TEG-based immunotherapy

Abstract

The unconventional γδT cells share the property of innate and adaptive immunity that allows recognition of infected, stress-induced, and malignantly-transformed cells and undergo clonal expansion and memory formation. γδT cells recognize infected and tumor cells by sensing metabolic changes in these cells without the requirement of specific peptide representation on HLA molecules, making them applicable for a broader patient population compared to αβT cells. Despite their promising potential, clinical responses of adoptive transfer of ex vivo expanded unmodified γδT cells are relatively marginal due to the underestimated diversity in T cell functions and molecular activation modes. Considering these obstacles, we introduce the concept of TEGs: αβT cells engineered to express a defined γδTCR, where highly-tumor reactive γδTCR is introduced into αβT cell with superior proliferative capacity in cancer patients. Within the TEG concept, we have previously identified two distinct tumor-reactive γδTCRs: a γ9δ2TCR (TEG001) and a γ5δ1TCR (TEG011). To assess nonclinical efficacy-safety balance of these clinical candidates of TEG-based therapy for cancer treatment, selection of suitable preclinical models needs to be carefully considered and is critical prior to clinical translation. While in vitro assays provided some hints for efficacy and lack of toxicity, in vivo models are very valuable in studying the impact on the complete human hematopoietic compartments. This thesis focuses on bridging the path from the laboratory findings to first-in-men studies by studying the efficacy and safety balance of TEG001 and TEG011, in relevant preclinical mouse models and thereby highlighting their therapeutic potential prior to further clinical testing.