ABSTRACT Identifying accessible tumor antigens that are not expressed in vital organs would allow genetic engineering of CAR T cells to avoid dysfunction at tumor beds. We have identified an olfactory receptor (OR) expressed in a variety of human tumors, ranging from ~70% of intrahepatic cholangiocarcinomas and 39% of prostate cancers, to ~10% of NSCLCs, and generated CAR T cells that specifically target its extracellular domain. The long-term goal of these studies is to translate these CAR T cells. Here, we will advance the preclinical work needed to apply for IND approval for a first-in-human clinical trial conducted at Moffitt, using OR2H1 CAR T cells generated in our Cell Therapy Facility under GMP conditions. Our central hypothesis is that genetically engineered OR2H1 CAR T cells can effectively control the progression of established tumors of different histologies, without the unacceptable on-target, off-tumor effects of other targets expressed in vital tissues. In Specific Aim 1, we will demonstrate the effectiveness and specificity of targeting OR2H1+ PDX with CAR T cells in vivo. These studies will support a rationale for subsequent IND approval for OR2H1 CAR T cell administration in patients with tumors expressing OR2H1 at variable levels. In Specific Aim 2, we will define the superiority of XBP1-ablated OR2H1 CAR T cells. These studies will support a rationale for genetic engineering of OR2H1 CAR T cells, to empower them to resist metabolic restrictions and inhibitory signals at tumor beds. In Specific Aim 3, we will optimize a method to identify eligible patients for OR2H1 CAR T cell targeting. Our work could exert a profound effect in the field by supporting a first-in-human clinical trial using OR2H1- targeted CAR T cells against a variety of solid human tumors, which could have significant benefits in a broad range of cancer patients, with limited or negligible toxicity.