OR2H1 is an effective target for CAR T cells in human epithelial tumors

摘要 识别在重要器官中不表达的可接近的肿瘤抗原将允许遗传学上的治疗。 工程化CAR T细胞以避免肿瘤床的功能障碍。我们已经确定了一个嗅觉受体（OR） 在多种人类肿瘤中表达，范围从~70%的肝内胆管癌和39%的肝内胆管癌。 前列腺癌，约10%的NSCLC，并产生特异性靶向其细胞外结构域的CAR T细胞。 这些研究的长期目标是翻译这些CAR T细胞。在这里，我们将推进临床前工作， 需要申请IND批准在Moffitt进行的首次人体临床试验，使用OR 2 H1 CAR T细胞 在GMP条件下在我们的细胞治疗设施中产生。我们的核心假设是， 工程化的OR 2 H1 CAR T细胞可以有效地控制已建立的不同肿瘤的进展， 组织学，而没有在重要组织中表达的其他靶标的不可接受的中靶、脱瘤效应。 在具体目标1中，我们将证明用靶向OR 2 H1 + PDX的有效性和特异性。 体内CAR T细胞。这些研究将支持OR 2 H1 CAR T细胞的后续IND批准的基本原理 在具有以可变水平表达0 R2 H1的肿瘤的患者中施用。 在具体目标2中，我们将定义XBP 1消融的OR 2 H1 CAR T细胞的优越性。这些研究将 支持OR 2 H1 CAR T细胞基因工程的基本原理，使它们能够抵抗代谢 限制和抑制信号。 在具体目标3中，我们将优化一种方法，以确定符合OR 2 H1 CAR T细胞靶向条件的患者。 我们的工作可以通过支持使用OR 2 H1的首次人体临床试验在该领域产生深远的影响。 靶向CAR T细胞针对各种实体人类肿瘤，这可能在广泛的临床应用中具有显着的益处。 范围内的癌症患者，具有有限或可忽略的毒性。

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.