T cell receptor engineering for the treatment of RET fusion-positive NSCLC

RET fusions are a challenging subset of non-small cell lung cancers (NSCLC). Although initial efforts with multikinase inhibitors resulted in limited success, subsequent development of selective RET inhibitors has bolstered responses for patients harboring these genomic alterations. Despite these advances, patients with RET fusions eventually progress, highlighting the need for additional therapies. Immunotherapy has been inefficient in patients harboring RET fusions. However, RET fusions themselves may be immunogenic. T cells recognize proteins at the surface of cancer cells called antigens, upon which they can specifically destroy tumors. Importantly, fusions constitute a particularly immunogenic antigen type which could be the key to clinical responses. Although T cells harbor millions of different receptors capable of recognizing different antigens, they can be genetically-engineered to recognize an antigen of interest. As such, we hypothesize that RET fusions give rise to immunogenic antigens which can be effectively targeted by engineered T cells. To address our hypothesis, we will identify antigens derived from tumors harboring RET fusions, receptors capable of killing tumors with these antigens and engineer T cells to gain this ability. Our work could be of benefit to patients progressing on selective RET inhibitors. Our goal is to generate a library of TCRs which could be used off-the-shelf to target the two dominant RET fusions (KIF5B-RET=75%; CCDC6-RET=25%) in order to offer new therapeutic alternatives to the overwhelming majority of NSCLC patients harboring RET fusions.