International Business Department           Liu Bojia           November 19, 2024

  In the fight against tumours, it is obviously not the best solution if we kill a thousand enemies but harm eight hundred. However, both traditional chemotherapeutic drugs and emerging immunotherapies may affect healthy cells in the body while targeting tumour cells, resulting in off-target injuries and adverse reactions.

  How to distinguish between tumour cells and healthy cells more accurately? This is a key challenge for researchers developing CAR-T cell therapies, which are genetically engineered immune cells with an engineered receptor called CAR (Chimeric Antigen Receptor) that targets specific antigens on the surface of the tumour cell, which is the key to the ability of these immune cells to recognise and eliminate tumour cells. However, non-tumour tissues may also express the same antigens, leading to non-tumour-targeted toxicity in patients.

  Recently, in the journal Nature, Dr Kole Roibal of the University of California, San Francisco (UCSF), in collaboration with 2024 Nobel Laureate in Chemistry Professor David Baker, described their development of a customisable receptor: the Synthetic Intra-membrane Protein Hydrolysis Receptor (abbreviated as SNIPR), which ensures that CAR-T cells are only activated in a specific environment -such as near tumours-are activated, thereby pinpointing cancer cells and reducing targeted non-tumour toxicity.

  The authors note that this technology is expected to lead to more precise and safer anti-cancer therapies, and that the same approach could also be used to develop novel targeted therapies for other types of diseases.

  Back in 2016, Dr Kole Roibal, co-corresponding author of the paper, and colleagues developed a class of sensors called synNotch receptors, which insert into cells and control their behaviour and function, for example by instructing T cells to perform a task such as finding cells with tumour antigen A, but only activating the killing program of the T cell if tumour antigen B is also present. In principle, the synNotch receptor is an engineered version of the natural receptor Notch, with one part reaching outside the cell to recognise a specific target - such as a tumour-specific antigen - and one part inside the cell, where the intracellular part is released into the nucleus when the receptor is activated to turn on or off specific genes -e.g. genes that express CAR. This approach can largely reduce off-target effects.

  The new SNIPR is an ‘upgraded’ version of the synNotch receptor, engineered so that the extracellular portion can be activated not only by cell-surface markers, but also by soluble ligands, which means that it is able to detect any free-floating molecules of interest in the cellular environment, such as immune signalling molecules in the tumour environment. immune signalling molecules in the environment.Upon binding of a SNIPR to a specific molecule, multiple receptors aggregate and undergo endocytosis, flipping inside the cell where pH-dependent cleavage occurs. Multiple SNIPRs inserted into a single cell can affect different genes or affect the same gene in different ways, altering the activity of the gene.

  Based on these principles, customised SNIPRs can ensure that cells perform specific tasks when they are in a particular environment, such as releasing drugs, activating immune responses or sending signalling molecules to other cells.

  In the Nature paper, the team inserted the newly designed SNIPR into CAR-T cells and specified that the SNIPR be activated by the soluble immune molecules TGF-β and VEGF. Levels of these two immune molecules are usually high around tumours. The SNIPR-equipped CAR-T cells turn on their anti-tumour activity only in the presence of TGF-β and VEGF, meaning that they do not initiate an immune response in areas of the body that are free of cancer cells.

  The study authors did a preliminary validation in a human-derived tumour mouse model and observed that the SNIPR-equipped CAR-T cells precisely attacked the tumours, shrinking the tumours without causing common CAR-T adverse effects such as weight loss and organ damage.

  Next, the research team said they plan to carry out clinical trials of CAR-T cells, and will also explore the use of SNIPR in different cell types to mediate communication between different cell types and interactions with the environment, leading to a wider range of applications.