From mouse to human

Summary

Despite the surmounting clinical responses from immunotherapy against cancer, only some cancer patient populations benefit from the treatment. This is the consequence of our rather limited understanding of how to better engineer a balance between the targeted killing of malignant cells while protecting their healthy counterparts. Within this context, T cells are a major player which facilitates cellular immunity against different foreign proteins, including malignantly-transformed cells. If this delicate balance of cancer immunosurveillance failed, multiple reasons are accountable for tumor development. Reasons for immune escape are as follows, e.g., loss of antigens, because tumor-reactive T cells became anergic or deleted, or immune cells are kept outside the established immunosuppressive tumor microenvironment. To overcome these hurdles, better understanding of the interplay between the immune system, cancer cells, and healthy tissues is crucial for developing effective cancer immunotherapy options to offer better outcome for patients. With this perspective, multiple cancer immunotherapies have been developed in laboratories. However, a critical step in clinical translation is to substantially reduce the gap between laboratory findings and clinical exploration of novel therapeutic candidates. This thesis focuses on bridging the path from the laboratory findings to first-in-men studies by studying the efficacy and safety balance of two novel therapeutic candidates of cancer immunotherapy, namely αβT cells Engineered to express a defined γδTCR (TEG), expressing two distinct γδTCRs: a tumor-reactive γ9δ2TCR (TEG001) and a tumor-reactive γ5δ1TCR (TEG011).

In conclusion, a careful choice of relevant preclinical models and appropriate study designs are pivotal to assess the efficacy-safety balance to support the successful translation of cell-based immunotherapy into the clinic. Within this context, I bridged the gap from preclinical development of different TEG formats to first-in-men studies. While 2D and 3D models provided some hints for efficacy and lack of toxicity, in vivo models are very valuable in studying the impact on the complete human hematopoietic compartment and studying important parameters that impact persistence, even in the absence of the appropriate target molecule. Within the limitation of our preclinical mouse models, we could proficiently assess the efficacy-safety profile of both TEG001 and TEG011 against hematological malignancies and hereby provide sufficient nonclinical evidence prior to first-in-men studies, in which TEG-based therapy may have beneficial effects for cancer patients. As a result, TEG001 is currently tested in a first-in-men study (clinical trial registration NTR6541).

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