Off-the-shelf CAR-T Therapy via Tumor-Selective Immuno-engagers

项目摘要 今天，人们重新燃起了希望，与各种癌症类型相关的死亡率将大大降低 基于新型免疫抑制剂的潜在成功，如嵌合抗原受体（CAR）- 表达T细胞。在某些情况下，来自免疫抑制剂的应答更强， 相对于传统的癌症化疗药物， 尽管取得了这些成功--尽管在患者群体中非常不平衡--过继细胞疗法仍将继续存在。 仅限于相对较小的患者亚组，直到克服其两个主要障碍：（1）依赖 由于缺乏真正的、可靶向的肿瘤细胞， 特异性标志物，和（2）在所有患者中缺乏共同的可靶向肿瘤生物标志物。 在这里，我们将利用固有的酸性微环境和负电荷的癌细胞膜 通过使用pH（低）插入肽（pHLIP），一种选择性锚定在癌细胞表面上的肽， 选择性地将癌细胞的表面与非天然表位移植，用于被同源抗原识别和破坏， CAR-T细胞。 在结构迭代的每个阶段，将基于其化学物理性质选择试剂， 招募CAR-T细胞、诱导对癌细胞的选择性毒性和体内肿瘤的功效 目标和功效。拟议的工作将结合联合收割机领域正在进行的研究，在我们各自的 实验室：基于其固有酸性将合成免疫增强剂特异性递送至肿瘤 (Th evenin），以及CAR-T免疫疗法（Snook）的发现和临床试验。 鉴于迫切需要改善目前的癌症免疫模式，我们预计， 我们系统的成功开发具有将治疗选择扩展到许多癌症患者的潜力， 因为它将允许（i）基于单一和共同的外源抗原的现成策略，（ii） 对患者T细胞的标准化遗传操作，（iii）对治疗的简化临床评估， 更大的人类肿瘤类型的集合，以及（iv）以商业上可接受的规模生产这些治疗剂。 可行的

PROJECT SUMMARY Today, there is renewed hope that mortality associated with various cancer types will be dramatically reduced based on the potential success of novel immunotherapeutic agents, such as chimeric antigen receptor (CAR)- expressing T cells. In some cases, the response from immunotherapeutic agents has been more robust and sustained relative to traditional cancer chemotherapeutics. Despite these successes – albeit very uneven across patient populations – adoptive cell therapy will remain confined to a relatively small subgroup of patients until two of its major hurdles are overcome: (1) the reliance on narrow differentiation between cancer and healthy cells due to the lack of bona fide, targetable, tumor- specific markers, and (2) the lack of common targetable tumor biomarkers among all patients. Here, we will exploit the inherent acidic microenvironment and negatively charged membranes of cancer cells by using the pH(Low) Insertion Peptide (pHLIP), a peptide that selectively anchors onto cancer cell surfaces, to selectively graft the surface of cancer cells with a non-native epitope for recognition and destruction by cognate CAR-T cells. At each stage of structural iterations, agents will be selected based on their chemico-physical properties, efficacy in recruiting CAR-T cells, induction of selective toxicity towards cancer cells, and in vivo tumor targeting and efficacy. The proposed work will combine areas of ongoing research in our respective laboratories: specific delivery of synthetic immuno-engager agents to tumors based on their inherent acidity (Thévenin), and discovery and clinical testing of CAR-T immunotherapy (Snook). Given the critical need to improve on current cancer immunotherapeutic modalities, we anticipate that the successful development of our system has the potential to extend treatment options to many cancer patients, as it would allow for (i) off-the-shelf strategies based on a single and common exogenous antigen, (ii) a standardized genetic manipulation of patients' T cells, (iii) streamlined clinical evaluation of therapies for a larger set of human tumor types, and (iv) the production of these therapeutics at a scale that is commercially viable.