A Phagocytosis Modulating Nanomedicine for Targeted Breast Cancer Immunotherapy

用于靶向乳腺癌免疫治疗的吞噬调节纳米药物

• 批准号: 10381905
• 负责人: Wen Jiang
• 金额: $ 25.34万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10381905
• 关键词: Antibodies; Antibody Therapy; Antigen-Presenting Cells; Antigens; Antitumor Response; Breast Cancer Cell; Breast Cancer Treatment; CD8-Positive T-Lymphocytes; Cancer Prognosis; Cancer Vaccine Related Development; Cells; Clinical; Collaborations; Combination immunotherapy; Cross Presentation; Cross-Priming; Cyclic GMP; Detection; Development Plans; Disease; Disseminated Malignant Neoplasm; Early treatment; Effectiveness; Ensure; Environment; Epidermal Growth Factor Receptor; Equipment; Generations; Goals; Human; Immune; Immune Targeting; Immune system; Immunocompetent; Immunologic Memory; Immunologist; Immunotherapy; Innate Immune Response; Interferon Type I; Interferon-alpha; Interferon-beta; Interferons; International; Intervention; Investigation; Lead; Mammary Neoplasms; Mediating; Medical center; Mentors; Mentorship; Messenger RNA; Metastatic breast cancer; Molecular; Mus; Nature; Normal tissue morphology; Oncologist; Pathway interactions; Patients; Pattern; Peptides; Phagocytes; Phagocytosis; Phagosomes; Physicians; Production; Program Development; Receptor Signaling; Research; Research Personnel; Research Training; Resistance; Resources; Scientist; Signal Transduction; Stimulator of Interferon Genes; Survival Rate; System; T cell response; T-Lymphocyte; Technology; Testing; Texas; Toll-like receptors; Toxic effect; Training; Tumor Antigens; Tumor Immunity; Tumor-Derived; Universities; Work; Yang; adaptive immune response; advanced breast cancer; anti-PD-1; anti-PD1 antibodies; anti-PD1 therapy; anti-tumor immune response; antitumor effect; breast cancer vaccine; calreticulin; cancer cell; cancer immunotherapy; career development; design; fighting; immune activation; immune checkpoint blockade; immune checkpoint blockers; immunogenic; macrophage; malignant breast neoplasm; mouse model; multidisciplinary; nanomedicine; neoplastic cell; novel; novel therapeutic intervention; overexpression; pre-clinical; receptor; research and development; response; targeted treatment; therapy resistant; tumor; tumor DNA; tumor immunology

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.

项目摘要 尽管在治疗乳腺癌方面取得了重大进展，但该疾病的转移形式仍然存在 高度致命的，5年的总生存率仅约20％。即使使用新的目标 癌细胞表达的人类表皮受体2（HER2）等抗体等疗法超过 70％的转移性疾病患者最终对治疗具有抵抗力。癌症的进展 免疫检查点阻滞剂的免疫疗法表明，利用人体免疫力 系统可以是对抗转移性癌症的有效策略。但是，只有一小部分患者 （〜20％）对免疫检查点阻滞剂的反应，其对乳腺癌的有效性仍然存在 不确定。为了克服这些挑战，我们最近开发了多价双特异性纳米偶联物 同时在乳腺癌细胞和促刺细胞上互动HER2受体的Envager（Mbine） 巨噬细胞上的分子促进免疫系统清除HER2+乳腺癌。这 当前的建议探讨了Mbine的使用来促进抗肿瘤免疫反应并增强 免疫检查点对转移性乳腺癌的有效性。提案的目标1将 检查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AIM 2，我们将阐明内部的先天机制 Mbine诱导的肿瘤细胞吞噬作用促进自适应的巨噬细胞 抗肿瘤免疫反应。最后，对于AIM 3，我们将调查Mbine是否可以安全地组合 使用抗PD1治疗来刺激先天性和适应性免疫反应对不良反应 免疫原性转移性乳腺癌。 在A的指导下提出了广泛的培训和发展计划 由医师科学家，肿瘤学家，免疫学家和肿瘤组成的多学科指导团队 生物学家。我的主要导师Yang-Xin Fu博士是医生的科学家，也是公认的先天专家 肿瘤免疫；我的联合学者温迪·伍德沃德博士以临床前和临床工作而闻名 积极的乳腺癌类型。他们将加入我的指导委员会，由欧文·韦斯曼博士（Irving Weissman）博士加入 肿瘤免疫学的先驱；乳腺癌疫苗开发领导者Keith Knutson博士；和博士 国际公认的癌症免疫疗法专家帕特里克·霍（Patrick Hwu）将担任顾问。这 德克萨斯大学西南医学中心为我的研究提供了一个杰出的环境 职业发展。所有对拟议研究至关重要的资源和设备都可以轻松获得 在校园里，我将有很多机会与癌症免疫疗法领导者进行合作。 拟议的研究，培训和职业发展计划一起确保我获得最好的 可以成为独立调查员的指导。

项目成果

Synthetic cationic helical polypeptides for the stimulation of antitumour innate immune pathways in antigen-presenting cells.

• DOI: 10.1038/s41551-024-01194-7
• 发表时间: 2024-04
• 期刊: Nature biomedical engineering
• 影响因子: 28.1
• 作者: DaeYong Lee;Kristin M Huntoon;Yifan Wang;M. Kang;Yifei Lu;Seongdong Jeong;Todd M Link;Thomas D Gallup;Y. Qie;Xuefeng Li;Shiyan Dong;B. R. Schrank;Adam J Grippin;A. Antony;Jonghoon Ha;Mengyu Chang;Yi An;Liang Wang;D. Jiang;Jing Li;A. Koong;John A Tainer;Wen Jiang;Betty Y S Kim