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

项目总结 今天，人们重新燃起了希望，即与各种癌症相关的死亡率将大幅降低。 基于新型免疫治疗药物的潜在成功，如嵌合抗原受体(CAR)- 表达T细胞。在某些情况下，免疫治疗剂的反应更强劲， 相对于传统的癌症化疗药物是持续的。 尽管这些成功--尽管在患者群体中非常参差不齐--但采用细胞疗法仍将存在 仅限于相对较小的一组患者，直到它的两个主要障碍被克服：(1)依赖 关于由于缺乏真正的，靶向的，肿瘤--癌细胞和健康细胞之间的狭隘分化 特异性标志物，以及(2)在所有患者中缺乏共同的靶向肿瘤生物标志物。 在这里，我们将利用癌细胞固有的酸性微环境和带负电的膜 通过使用pH(低)插入多肽(PHLIP)，一种选择性锚定在癌细胞表面的多肽，以 选择性地将非天然表位移植到癌细胞表面，以供同源识别和破坏 CAR-T细胞。 在结构迭代的每个阶段，将根据它们的化学物理性质来选择试剂， 募集CAR-T细胞、诱导对肿瘤细胞的选择性毒性和体内肿瘤的效果 针对性和有效性。拟议的工作将结合我们各自正在进行的研究领域 实验室：根据肿瘤固有的酸性将合成免疫诱导剂特异性地输送到肿瘤 (thévenin)，以及CAR-T免疫疗法的发现和临床测试(Snook)。 鉴于目前癌症免疫治疗模式亟需改进，我们预计 我们系统的成功开发有可能将治疗选择扩大到许多癌症患者， 因为它将允许(I)基于单一和共同的外源抗原的现成战略，(Ii)a 患者T细胞的标准化遗传操作，(Iii)简化治疗方法的临床评估 更多的人类肿瘤类型，以及(Iv)商业规模的这些治疗药物的生产 可行。

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.