γδT cells play an important role in cancer immunosurveillance and are able to distinguish malignant cells from their healthy counterparts via their γδTCR. This characteristic makes γδT cells an attractive candidate for therapeutic application in cancer immunotherapy. Previously, we have identified a novel CD8α‐dependent tumor‐specific allo‐HLA‐A*24:02‐restricted Vγ5Vδ1TCR with potential therapeutic value when used to engineer αβT cells from HLA‐A*24:02 harboring individuals. αβT cells engineered to express this defined Vγ5Vδ1TCR (TEG011) have been suggested to recognize spatial changes in HLA‐A*24:02 present selectively on tumor cells but not their healthy counterparts. However, in vivo efficacy and toxicity studies of TEG011 are still limited. Therefore, we extend the efficacy and toxicity studies as well as the dynamics of TEG011 in vivo in a humanized HLA‐A*24:02 transgenic NSG (NSG‐A24:02) mouse model to allow the preparation of a first‐in‐men clinical safety package for adoptive transfer of TEG011. Mice treated with TEG011 did not exhibit any graft‐versus‐host disease‐like symptoms and extensive analysis of pathologic changes in NSG‐A24:02 mice did not show any off‐target toxicity of TEG011. However, loss of persistence of TEG011 in tumor‐bearing mice was associated with the outgrowth of extramedullary tumor masses as also observed for mock‐treated mice. In conclusion, TEG011 is well tolerated without harming HLA‐A*24:02+ expressing healthy tissues, and TEG011 persistence seems to be crucial for long‐term tumor control in vivo.
The population study of threatened species requires marking techniques that do not affect the survival of individuals. In this study, we evaluated the effectiveness of visible implant elastomer (VIE) in the identification and survival of individuals of the salamander Parvimolge townsendi. We compared three salamander groups under different treatments: intervened,
simulated intervention and control. No significant mortality differences were observed between groups (with two, none, and one individual, respectively), but implant migration was observe in four of 10 intervened individuals. Although VIE does not have a significant effect on survival, implant migration should be considered before use in population studies.
T cell engineering strategies offer cures to patients and have entered clinical practice with chimeric antibody-based receptors; abT cell receptor (abTCR)-based strategies are, however, lagging behind. To allow a more rapid and successful translation to successful concepts also using abTCRs for engineering, incorporating a method for the purification of genetically modified T cells, as well as engineered T cell deletion after transfer into patients, could be beneficial. This would allow increased efficacy, reduced potential side effects, and improved safety of newly to-be-tested lead structures. By characterizing the antigen-binding interface of a good manufacturing process (GMP)-grade anti-abTCR antibody, usually used for depletion of abT cells from stem cell transplantation products, we developed a strategy that allows for the purification of untouched abTCR-engineered immune cells by changing 2 amino acids only in the TCRb chain constant domain of introduced TCR chains. Alternatively, we engineered an antibody that targets an extended mutated interface of 9 amino acids in the TCRb chain constant domain and provides the opportunity to further develop depletion strategies of engineered immune cells.
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