Fig. 1
From: Control of CAR-T cell activity in space and time: the next level of anti-tumor action
Two novel synthetic biology approaches aim to overcome present limitations of CAR-T cell therapy. Upper panel (1): To overcome tumor microenvironment (TME) suppression of CAR-T cells in solid malignancies, Allen et al.1 developed circuits in which tumor-specific synthetic Notch (synNotch) receptors locally induced the production of IL-2 trigged by tumor antigens independent from TCR/CAR activation, thereby restricting IL-2 secretion to the tumor site and bypassing the suppressive effects of the TME. Subsequently, autocrine IL-2 signalling promoted CAR-T cell proliferation. This approach increased CAR-T cell infiltration and tumor clearance in immunocompetent models of pancreatic cancer and melanoma. Lower panel (2): Li et al.2 developed compact synthetic zinc finger transcriptional regulators (synZiFTRs) to control the transcription of therapeutically relevant genes in CAR-T cells using FDA-approved small molecule inducers. In this proof-of-principle study, it was shown that it is possible to instruct T cells by the use of such drugs to sequentially activate multiple cellular programs such as proliferation and antitumor activity. Studies performed in vitro in breast cancer cells and in vivo in immunodeficient mice showed that a sequential induction of superIL-2 (sIL-2, an enhanced version of IL-2 with stronger IL-2 receptor affinity) and CAR can be beneficial for the anti-tumor effect. Created with BioRender.com
