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 尽管在乳腺癌的治疗方面取得了重大进展，但该疾病的转移形式仍然存在 高致命性，5年总生存率仅为20%左右。即使使用新的、有针对性的 治疗如针对癌细胞表达的人表皮受体2（HER 2）的抗体， 70%的转移性疾病患者最终对治疗产生耐药性。Advances in cancer 使用免疫检查点阻断剂的免疫疗法已经表明，利用人体免疫系统的力量， 系统可以是对抗转移性癌症的有效策略。然而，只有一小部分患者 （~20%）对免疫检查点阻断剂有反应，其对乳腺癌的有效性仍然存在 不确定为了克服这些挑战，我们最近开发了一种多价双特异性纳米生物缀合物， 同时结合乳腺癌细胞上的HER 2受体和促吞噬作用的抑制剂（mBiNE） 在某些实施方案中，HER 2+分子可以在巨噬细胞上释放，以促进免疫系统对HER 2+乳腺癌的清除。的 目前的提议探索了使用mBiNE来促进抗肿瘤免疫应答并增强免疫应答。 免疫检查点阻断对转移性乳腺癌的有效性。该提案的目标1将 检查mBiNE是否激活针对以下的有效和广泛的抗原特异性抗肿瘤免疫应答： HER 2过表达转移性乳腺癌。对于目标2，我们将阐明 mBiNE诱导的肿瘤细胞吞噬作用促进了适应性巨噬细胞的交叉启动。 抗肿瘤免疫反应。最后，对于目标3，我们将研究mBiNE是否可以安全地组合 用抗PD 1疗法刺激先天性和适应性免疫应答， 免疫原性转移性乳腺癌。 一个广泛的培训和发展计划已提出的指导下， 多学科指导团队，由医生-科学家、肿瘤学家、免疫学家和肿瘤学家组成 生物学家我的主要导师，傅洋新博士，是一位内科医生科学家，也是公认的先天性心脏病专家。 肿瘤免疫;我的共同导师，温迪伍德沃德博士是众所周知的，她的临床前和临床工作， 侵袭性乳腺癌他们将加入我的指导委员会由博士欧文韦斯曼， 肿瘤免疫学的先驱;基思克努森博士，乳腺癌疫苗开发的领导者; 帕特里克胡，一个国际公认的癌症免疫治疗专家，谁将担任顾问。的 德克萨斯大学西南医学中心为我的研究提供了一个出色的环境， 职业发展。所有对拟议研究至关重要的资源和设备都是现成的 在校园里，我将有很多机会与癌症免疫疗法的领导者合作。 总之，建议的研究，培训和职业发展计划将确保我得到最好的 成为一名独立调查员。

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