Engineering synthetic adhesion receptors to enhance the sensitivity of therapeutic chimeric antigen receptors
Lead Research Organisation:
University of Oxford
Department Name: Sir William Dunn Sch of Pathology
Abstract
T cells are a type of white blood cell that continuously patrol the body in search of abnormal cells. They detect molecules called 'antigens' on these abnormal infected or cancerous cells using their T cell antigen receptors (TCRs). T cells are remarkably sensitive: they can become activated by the presence of a single antigen on a cell. This sensitivity is important because infectious organisms and cancer cells are very good at hiding from T cells by lowering the amount of antigen on their cell surface.
An exciting new treatment for cancer is to re-programme a patient's T cells to target their cancer. This is done by using genetic engineering to express chimeric antigen receptors (CARs) on T cells. CARs have a part that binds an antigen and a part derived from the TCR that send an activating signal into the T cell. They allows a patient's T cells to recognise and kill their cancer cells. This therapy is very effective for leukemias and lymphomas expressing high levels of certain antigens. However, many patients relapse when cancer cells emerge that have lower levels of antigen on their surface. One reason that this escape is possible is that CARs are much less sensitive than TCRs and so are unable to 'see' these new cancer cells. There is an urgent need to increase the sensitivity of CARs to prevent these relapses. More sensitive CARs would also allow CAR T cells to be used in treating a wider variety of cancers.
In this project we will use our understanding of why the TCR is so sensitive to improve the sensitivity of CARs. It is difficult for the relatively small TCR on the surface of T cells to 'find' what are also small target antigens on other cells. T cells use a specially-evolved adhesion receptor called CD2 that, when it binds to target cells, position the T cell and target cell membranes at precisely the right distance for the TCR to bind its target antigen. The allows the TCR to rapidly scan the other cell for antigens. We hypothesise that CD2 positions the membranes too closely for optimal scanning by CARs because they are bigger than the TCR. We will design and introduce into T cells enlarged forms of CD2 and test whether they improve the sensitivity of CARs. We will use electron microscopy to confirm that enlarging CD2 changes the distance between the T cell and the target cell membranes. This work should enable us to improve CAR T cell therapy by introducing enlarged forms of CD2 into the cells, thereby enabling them to recognise cancer cells with low levels of the antigen. In addition to improving existing CAR-T cell treatment for B cell cancers, this should allow new CAR-T cell treatments to be developed that eliminate cancers expressing low levels of target antigens.
An exciting new treatment for cancer is to re-programme a patient's T cells to target their cancer. This is done by using genetic engineering to express chimeric antigen receptors (CARs) on T cells. CARs have a part that binds an antigen and a part derived from the TCR that send an activating signal into the T cell. They allows a patient's T cells to recognise and kill their cancer cells. This therapy is very effective for leukemias and lymphomas expressing high levels of certain antigens. However, many patients relapse when cancer cells emerge that have lower levels of antigen on their surface. One reason that this escape is possible is that CARs are much less sensitive than TCRs and so are unable to 'see' these new cancer cells. There is an urgent need to increase the sensitivity of CARs to prevent these relapses. More sensitive CARs would also allow CAR T cells to be used in treating a wider variety of cancers.
In this project we will use our understanding of why the TCR is so sensitive to improve the sensitivity of CARs. It is difficult for the relatively small TCR on the surface of T cells to 'find' what are also small target antigens on other cells. T cells use a specially-evolved adhesion receptor called CD2 that, when it binds to target cells, position the T cell and target cell membranes at precisely the right distance for the TCR to bind its target antigen. The allows the TCR to rapidly scan the other cell for antigens. We hypothesise that CD2 positions the membranes too closely for optimal scanning by CARs because they are bigger than the TCR. We will design and introduce into T cells enlarged forms of CD2 and test whether they improve the sensitivity of CARs. We will use electron microscopy to confirm that enlarging CD2 changes the distance between the T cell and the target cell membranes. This work should enable us to improve CAR T cell therapy by introducing enlarged forms of CD2 into the cells, thereby enabling them to recognise cancer cells with low levels of the antigen. In addition to improving existing CAR-T cell treatment for B cell cancers, this should allow new CAR-T cell treatments to be developed that eliminate cancers expressing low levels of target antigens.
Technical Summary
T cells patrol the body in search of antigens derived from infectious organisms or cancer cells. They use their T cell antigen receptors (TCRs) to recognise peptide antigens on major-histocompatibility-complexes (pMHC). T cells have remarkable antigen sensitivity; they can become activated when recognising only a single pMHC. This high sensitivity is important because infectious organisms and cancers deploy evasion mechanisms to reduce the amount of antigen presented to T cells.
T cells are now engineered to recognise cancer antigens using chimeric antigen receptors (CARs). This therapy is approved to treat B cell cancers. However, many patients relapse with B cells that express low levels of the target antigen. It is now clear that CARs have a profound defect in antigen sensitivity; CARs require 100-1000-fold more antigen than the TCR to activate T cells. There is an urgent need to increase the sensitivity of CARs to prevent these relapses
The high antigen sensitivity of the TCR is partly a result of their adhesion receptor CD2 binding to its ligand CD58. The CD2/CD58 and TCR/pMHC complexes share a similar intermembrane distance of 14 nm. Therefore, many CD2/CD58 complexes are able to precisely align membranes to allow TCRs to efficiently bind the low numbers of pMHCs. Here, we hypothesise that CARs, which are larger than TCRs and target antigens that vary in size, will have different membrane alignment requirements that are not optimised by native CD2/CD58. Using an interdisciplinary approach that combines quantitative and synthetic biology and immunology, we will design novel adhesion receptors that optimise membrane alignment for existing and novel CARs to endow them with the same high antigen sensitivity as the TCR. This will improve existing CAR-T cell treatments for B cell cancers and should allow for new treatments to eliminate cancers expressing low levels of target antigens.
T cells are now engineered to recognise cancer antigens using chimeric antigen receptors (CARs). This therapy is approved to treat B cell cancers. However, many patients relapse with B cells that express low levels of the target antigen. It is now clear that CARs have a profound defect in antigen sensitivity; CARs require 100-1000-fold more antigen than the TCR to activate T cells. There is an urgent need to increase the sensitivity of CARs to prevent these relapses
The high antigen sensitivity of the TCR is partly a result of their adhesion receptor CD2 binding to its ligand CD58. The CD2/CD58 and TCR/pMHC complexes share a similar intermembrane distance of 14 nm. Therefore, many CD2/CD58 complexes are able to precisely align membranes to allow TCRs to efficiently bind the low numbers of pMHCs. Here, we hypothesise that CARs, which are larger than TCRs and target antigens that vary in size, will have different membrane alignment requirements that are not optimised by native CD2/CD58. Using an interdisciplinary approach that combines quantitative and synthetic biology and immunology, we will design novel adhesion receptors that optimise membrane alignment for existing and novel CARs to endow them with the same high antigen sensitivity as the TCR. This will improve existing CAR-T cell treatments for B cell cancers and should allow for new treatments to eliminate cancers expressing low levels of target antigens.