In recent years, a variety of therapeutic approaches have been developed and tested that directly exploit the T-​cell mediated response against cancer, including:

• T-​cell engagers and activators (TEAs), which are antibody-​like molecules bringing T-​cells in close proximity with their targets leading to target cell killing.

• Chimeric antigen receptor (CAR) T-​cells, which are genetically engineered T-​cells that can recognize a surface antigen and directly attack and kill their targets.

Despite the success of engineered immunotherapies in B-​cell lymphomas, most patients receiving either type of therapy are not cured and will eventually relapse and show progressive disease. For diseases stemming from the myeloid compartment and for which there is a particularly high clinical need such as acute myeloid leukemia (AML), the difficulty in finding a suitable target antigen has so far hindered effective clinical application.

To better understand how T-​cells engage and kill their targets and why this process can succeed or fail, we combine the Manz laboratory’s expertise in TEA development and T-​cell engineering with the Schroeder laboratory’s expertise in long-​term live-​cell imaging and computational quantification of molecular and cellular dynamics. To this end, we will establish a live-​cell imaging platform for quantifying the interactions of T-​cells with their target cells in co-​cultures. Cell interaction dynamics and target cell killing will be quantified in relation to different molecular TEA and CAR T-​cell designs.

This will 1) allow a better understanding of how molecular design affects effector-​target cell interaction dynamics, killing specificity and efficacy, and 2) provide a platform for optimizing molecular TEA and CAR T-​cell design for improved T-​cell therapy. Ultimately, it will enable improvements in therapy design for patients in need of effective and safe engineered immune-​therapies against malignancies.