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

项目概要：乳腺癌是女性最常见的癌症， 在美国，每年的死亡人数高达1000人，因此迫切需要新的和更有效的治疗方法。初始 在乳腺癌中使用免疫检查点抑制的经验已经证明了适度的反应，尽管 已观察到持久的反应。乳腺癌免疫治疗的关键障碍是 开发反应的预测性生物标志物和生物驱动的免疫治疗组合。 这项提案将调查将调查新的翻译方法，以克服免疫治疗- 乳腺癌的耐药性。在具体目标1中，我假设抑制细胞周期蛋白依赖性激酶（CDK） 4/6将导致雌激素受体（ER）阳性乳腺癌中肿瘤浸润淋巴细胞（TIL）的募集 癌症，并将导致更高的反应时，程序性细胞死亡配体1（PD-L1）抑制剂被添加。 这一目标将集中在ER阳性乳腺癌上，这是一种被认为是“非炎症”的乳腺癌亚型 或“免疫遗传性冷”，并且其中对单一药剂免疫检查点抑制的应答没有 表现出明显的反应。在《特定目标2》中，我假设， 免疫检查点抑制将上调缺氧诱导因子1（HIF 1）-α， 三阴性乳腺癌（TNBC）患者的免疫逃避基因。虽然TNBC似乎有一个 比ER阳性乳腺癌更多的“发炎”免疫表型，反应仍然是适度的， 迫切需要生物标志物以及合理的药物组合。本提案生成的数据 将允许我进行额外的研究，需要RO 1资金，包括验证这些生物标志物 更大规模研究中的途径，基于免疫疗法的新型组合，癌症的转化发现- 免疫细胞相互作用，并最终改善乳腺癌患者的预后。 约翰霍普金斯医院有几位实验室和临床研究人员， 环境进行我的研究，包括临床，行政和研究支持。我的背景 临床和转化乳腺癌研究，包括与实验室合作的经验 科学家和生物标志物的发展，使我能够成功地实现我的近期目标，包括培训 在癌症免疫学、免疫药物开发和生物信息学领域。为此，委员会建议， 在著名的癌症翻译研究者Elizabeth Jaffee博士和Vered Stearns博士的指导下， 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 (Dr. Leslie科普）和免疫治疗药物开发（Nilo Azad博士）。为了补充我的课程， 在约翰霍普金斯完成免疫学课程，并通过冷泉生物信息学研讨会 港口这个职业发展计划将使我获得必要的专业知识，最终成为一个 该领域的领导者，并为乳腺癌患者带来实践改变免疫为基础的范例。

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.