A Phagocytosis Modulating Nanomedicine for Targeted Breast Cancer Immunotherapy

项目摘要 尽管乳腺癌的治疗取得了重大进展，但这种疾病的转移形式仍然存在。 高致命性，5年总体存活率只有20%左右。即使使用新的、有针对性的 针对癌细胞表达的人类表皮受体2(HER2)的抗体等治疗方法 70%的转移性疾病患者最终会对治疗产生抵抗力。癌症研究进展 免疫检查点阻滞剂的免疫疗法表明，利用人体免疫的力量 系统可以成为对抗转移性癌症的有效策略。然而，只有一小部分患者 (约20%)对免疫检查点阻滞剂有反应，它们对乳腺癌的有效性仍然存在 不确定。为了克服这些挑战，我们最近开发了一种多价双特异性纳米生物结合物 同时与乳腺癌细胞上的HER2受体结合并促进吞噬作用的订阅者(MBiNE) 巨噬细胞上的分子有助于免疫系统清除HER2+乳腺癌。这个 目前的提案探索了使用mBiNE来促进抗肿瘤免疫反应和增强 免疫检查点阻断对转移性乳腺癌的疗效。该提案的目标1将 检测mBiNE是否激活有效和广泛的抗原特异性抗肿瘤免疫反应 HER2过表达转移性乳腺癌。对于目标2，我们将阐明 巨噬细胞通过mBiNE诱导的肿瘤细胞吞噬促进适应性的交叉启动 抗肿瘤免疫反应。最后，对于目标3，我们将调查mBiNE是否可以安全地组合 用抗PD1治疗来刺激先天和获得性免疫反应以对抗不良 免疫原性转移性乳腺癌。 一项广泛的培训和发展计划已在一个 由内科科学家、肿瘤学家、免疫学家和肿瘤专家组成的多学科指导团队 生物学家。我的主要导师傅阳新博士是一位内科科学家，也是公认的先天专家 肿瘤免疫；我的共同导师温迪·伍德沃德博士以她的临床前和临床工作而闻名 侵袭性类型的乳腺癌。他们将加入我的指导委员会，欧文·魏斯曼博士是一名 肿瘤免疫学的先驱；乳腺癌疫苗开发的领导者基思·克努森博士； 国际公认的癌症免疫治疗专家Patrick Hwu将担任顾问。这个 德克萨斯大学西南医学中心为我的研究和 职业发展。对拟议研究至关重要的所有资源和设备都是现成的 在校园里，我将有很多机会与癌症免疫治疗领域的领导者形成合作关系。 总而言之，拟议的研究、培训和职业发展计划将确保我获得最好的 可以成为一名独立调查员的导师。

Project Summary Despite significant advances in the treatment of breast cancer, the metastatic form of the disease remains highly lethal, with a 5-year overall survival rate of only around 20%. Even with the use of new, targeted therapies such as antibodies against the human epidermal receptor 2 (HER2) expressed by cancer cells, over 70% of patients with metastatic diseases eventually become resistant to therapy. Advances in cancer immunotherapy with immune checkpoint blockers have shown that harnessing the power of the body's immune system can be an effective strategy to fight metastatic cancer. However, only a small proportion of patients (~20%) respond to immune checkpoint blockers, and their effectiveness against breast cancer remains uncertain. To overcome these challenges, we recently developed a multivalent bispecific nanobioconjugate engager (mBiNE) that simultaneously engages HER2 receptor on breast cancer cells and pro-phagocytosis molecules on macrophages to facilitate the clearance of HER2+ breast cancer by the immune system. The current proposal explores the use of mBiNE to promote antitumor immune responses and to enhance the effectiveness of immune checkpoint blockade against metastatic breast cancers. Aim 1 of the proposal will examine whether mBiNE activates potent and broad antigen-specific antitumor immune responses against HER2 overexpressing metastatic breast cancer. For Aim 2, we will elucidate the innate mechanisms within macrophages by which mBiNE-induced tumor cell phagocytosis promotes the cross-priming of adaptive antitumor immune responses. Finally, for Aim 3, we will investigate whether mBiNE can be safely combined with anti-PD1 therapy to stimulate both the innate and adaptive immune responses against poorly immunogenic metastatic breast cancer. An extensive training and development program has been proposed under the guidance of a multidisciplinary mentoring team consisting of physician-scientists, oncologists, immunologists, and tumor biologists. My primary mentor, Dr. Yang-Xin Fu, is a physician scientist, and a recognized expert in innate tumor immunity; my co-mentor, Dr. Wendy Woodward is known for her preclinical and clinical work with aggressive types of breast cancers. They will be joined on my mentoring committee by Dr. Irving Weissman, a pioneer in tumor immunology; Dr. Keith Knutson, a leader in breast cancer vaccine development; and Dr. Patrick Hwu, an internationally recognized cancer immunotherapy expert, who will serve as an advisor. The University of Texas Southwestern Medical Center provides an outstanding environment for my research and career development. All of the resources and equipment critical to the proposed research are readily available on campus, and I will have many opportunities to form collaborations with leaders in cancer immunotherapy. Together, the proposed research, training and career development plan will ensure that I receive the best mentorship available to become an independent investigator.