Immunophenotypic biomarkers to predict response and optimize immunotherapy-based combinations in breast cancer

项目摘要：乳腺癌是女性最常见的癌症，导致超过4万人患上乳腺癌 美国每年的死亡人数越来越多，因此迫切需要新的、更有效的治疗方法。首字母 免疫检查点抑制在乳腺癌中的经验表明反应温和，尽管 观察到了持久的反应。开发乳腺癌免疫疗法的一个关键障碍是 反应的预测生物标记物和生物驱动的免疫治疗组合的发展。 这项提案将调查将研究克服免疫疗法的新翻译方法- 乳腺癌中的耐药性。在特定目标1中，我假设细胞周期蛋白依赖性激酶(CDK)被抑制 4/6会导致雌激素受体(ER)阳性乳腺中肿瘤浸润性淋巴细胞(TIL)的募集 当加入程序化细胞死亡配体1(PD-L1)抑制剂时，将导致更高的反应。 这一目标将集中在ER阳性乳腺癌上，这是乳腺癌的一种亚型，被认为是“非炎症”的。 或“免疫遗传寒冷”，并且对单一免疫检查点抑制的反应没有 表现出显著的反响。在具体目标2中，我假设无论有没有化疗 免疫检查点抑制将上调缺氧诱导因子1(HIF1)-α及其下游 三阴性乳腺癌患者免疫逃逸基因的研究而TNBC似乎有一个 与ER阳性乳腺癌相比，免疫表型更“发炎”，反应仍然温和，具有预测性 生物标记物以及合理的药物组合是迫切需要的。从该提案中生成的数据 将允许我执行需要RO1资金的额外研究，包括验证这些生物标志物 更大研究中的途径，基于免疫疗法的新组合，癌症的翻译发现- 免疫细胞相互作用，并最终改善乳腺癌患者的预后。 约翰霍普金斯大学有几个实验室和临床研究人员，为我提供了一个理想的 进行我的研究的环境，包括临床、行政和研究支持。我的背景 从事乳腺癌的临床和转化性研究，包括与实验室合作的经验 科学家和生物标记物的开发，使我能够成功地实现我的眼前目标，包括培训 在癌症免疫学、免疫治疗药物开发和生物信息学领域。为此， 在伊丽莎白·贾菲博士和维瑞德·斯泰恩斯博士的指导下，著名的癌症翻译研究人员 分别是免疫学和乳腺癌，我已经组建了一个咨询委员会，包括生物信息学 (莱斯利·科普博士)和免疫疗法药物开发(尼洛·阿扎德博士)。为了补充我的课程，我计划 关于在约翰霍普金斯大学完成免疫学课程，以及通过冷泉举办生物信息学研讨会 港湾。这份职业发展计划将使我做好准备，获得最终成为一名 这是该领域的领先者，并为乳腺癌患者带来了改变基于免疫的范例的实践。

Project Summary: Breast cancer is the most common cancer in women and responsible for over 40 000 deaths in the United States each year, therefore novel and more effective therapies are urgently needed. Initial experience with immune checkpoint inhibition in breast cancer has demonstrated modest responses, although durable responses have been observed. A critical barrier in developing immunotherapies in breast cancer is the development of predictive biomarkers of response and biologically driven immunotherapy combinations. This proposal will investigate will investigate novel translational approaches to overcoming immunotherapy- resistance in breast cancer. In Specific Aim 1, I hypothesize that inhibition of cyclin dependent kinase (CDK) 4/6 will result in recruitment of tumor infiltrating lymphocytes (TILs) in estrogen receptor (ER) positive breast cancer, and will result in higher responses when a programmed cell death ligand 1 (PD-L1) inhibitor is added. This aim will focus on ER-positive breast cancer, a subtype of breast cancer that is considered “non-inflamed” or “immunogenetically cold”, and where responses to single agent immune checkpoint inhibition has not demonstrated significant responses. In Specific Aims 2, I hypothesize that chemotherapy with or without immune checkpoint inhibition will upregulate hypoxia inducible factor 1 (HIF1) -alpha, and downstream immune-evasion genes in patients with triple negative breast cancer (TNBC). While TNBC appears to have a more “inflamed” immune phenotype than ER-positive breast cancer, responses are still modest, and predictive biomarkers are urgently needed as well as rational drug combinations. The data generated from this proposal will allow me to perform additional research requiring RO1 funding, including validation of biomarkers of these pathways in larger studies, novel immunotherapy-based combinations, translational discovery of cancer- immune cell interactions, and ultimately improve outcomes for patients with breast cancer. Johns Hopkins houses several laboratory and clinical researchers, and provides me with an ideal environment to conduct my research, including clinical, administrative, and research support. My background in clinical and translational breast cancer research, including experience in collaborating with laboratory scientists and biomarker development, poise me to successfully obtain my immediate goals including training in the fields of cancer immunology, immunotherapeutic drug development, and bioinformatics. To this end, under the mentorship of Dr. Elizabeth Jaffee and Vered Stearns, renowned translational investigators in cancer immunology and breast cancer, respectively, I have assembled an advisory committee including bioinformatics (Dr. Leslie Cope), and immunotherapy drug development (Dr. Nilo Azad). To supplement my curriculum I plan on completing immunology courses at Johns Hopkins, and bioinformatics workshops through Cold Spring Harbor. This career development plan will poise me to obtain the expertise necessary to eventually become a leader in the field and bring practice changing immune-based paradigms for patients with breast cancer.