Enhancing antigen presentation in triple negative breast cancers through CD40 agonist, Flt3 ligand, and anthracycline chemotherapy

通过 CD40 激动剂、Flt3 配体和蒽环类化疗增强三阴性乳腺癌的抗原呈递

• 批准号: 10349397
• 负责人: Sangeetha Meda Reddy
• 金额: $ 24.69万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-13 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10349397
• 关键词: 4T1; Address; Advisory Committees; Agonist; Anthracycline; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Bioinformatics; Breast; Breast Cancer Patient; CD8-Positive T-Lymphocytes; Cells; Clinical; Clinical Trials; Clinical Trials Design; Correlative Study; Data; Defect; Dendritic Cells; Development; Exhibits; FLT3 ligand; Foundations; Frequencies; Funding; Future; Growth Factor; Immune; Immune Tolerance; Immune response; Immunologic Markers; Immunologic Monitoring; Immunologics; Immunologist; Immunooncology; Immunotherapy; Individual; Investigation; Lead; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Medical Oncologist; Medical center; Mentorship; Mesenchymal; Modeling; Mus; Pathway interactions; Patients; Pharmacodynamics; Phase; Physicians; Pre-Clinical Model; Principal Investigator; Process; Randomized; Randomized Clinical Trials; Regimen; Research; Resistance; Resources; Safety; Scientist; Solid Neoplasm; Sterically Stabilized Liposome; Structure; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Testing; Therapeutic; Tissue Sample; Tissues; Training; Training Programs; Translational Research; Triplet Multiple Birth; Tumor Antigens; Tumor Immunity; Tumor Markers; Work; Yang; adaptive immunity; base; cancer subtypes; cancer therapy; cell type; chemotherapy; clinical biomarkers; clinical efficacy; clinical investigation; disorder control; efficacy study; experimental study; humanized mouse; immune checkpoint blockade; improved; improved outcome; malignant breast neoplasm; mouse model; novel; novel therapeutics; patient derived xenograft model; pharmacodynamic biomarker; pilot trial; pre-clinical; preclinical study; professor; resistance mechanism; response; response biomarker; success; supportive environment; synergism; tertiary lymphoid organ; therapy resistant; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor-immune system interactions; uptake

Project Summary / Abstract Despite the success of immune checkpoint blockade (ICB) in many tumor types, breast cancers have shown limited responses. Antigen presenting cells (APCs) are critical to initiate anti-tumor immunity and for efficacy of ICB, and are known to be defective in breast cancers. Importantly, APCs need to be activated through pathways such as the CD40 pathway in order to promote anti-tumor activity rather than immune tolerance. We demonstrated that CD40 agonists synergize with Flt3 ligand (Flt3L) which is a growth factor that promotes differentiation of DC1 cells which are important for antigen presentation, and anthracycline chemotherapy to eradicate triple negative breast cancers in mouse studies. Based on this, we hypothesize that combining chemotherapy with a CD40 agonist and Flt3L enhances antigen presentation and increases long-term adaptive immunity, thereby improving triple negative breast cancer (TNBC) disease control. In order to test this hypothesis, I propose: Aim #1: To assess safety, clinical activity, and immunologic efficacy of CD40 agonist in combination with Flt3L and anthracycline chemotherapy (triplet therapy) in patients with metastatic TNBC (mTNBC) and identify biomarkers of response and resistance. I will be Lead Principal Investigator on a phase 1 pilot trial of CD40 agonist + Flt3L + pegylated liposomal doxorubicin in patients with mTNBC. Longitudinal tissue samples will be collected and analyzed to study pharmacodynamics, biomarkers of response, and resistance mechanisms. Aim #2: To discover mechanisms of response and resistance to triplet therapy using syngeneic and humanized mouse models, including tumors reflecting different TNBC subtypes. 4T1-HA syngeneic model will be used to study how different agents in the CD40 agonist + Flt3L + pegylated liposomal doxorubicin regimen contribute to response and what immune cell types are mediating response, with a focus on CD8 T cells and DC1 cells. We will additionally study how underlying TNBC subtype impacts response to triplet therapy using syngeneic murine and humanized patient derived xenograft models. Results of this work will guide future development of this combination in TNBC and other solid tumors. I am an Assistant Professor at UT Southwestern (UTSW) Medical Center and the principal investigator on this proposal. I am a breast medical oncologist focused on improving outcomes of breast cancer patients through immunotherapy. To most effectively advance the field, I plan to integrate clinical investigation of agents stimulating antigen presentation with patient tissue based translational science and preclinical studies. To supplement my background in immune monitoring, this proposal details a training plan under the mentorship of translational breast cancer expert Dr. Carlos Arteaga and cancer immunologist Dr. Yang-Xin Fu. This is further supported by an expert advisory committee, relevant coursework, and the resources and supportive environment of UTSW to help me transition to independence as a physician scientist focused on breast immuno-oncology.

项目总结/摘要 尽管免疫检查点阻断（ICB）在许多肿瘤类型中取得了成功，但乳腺癌仍有 有限的反应。抗原提呈细胞（APC）对于启动抗肿瘤免疫和用于治疗肿瘤是至关重要的。 ICB的功效，并且已知在乳腺癌中是有缺陷的。重要的是，APC需要通过 在一些实施方案中，免疫耐受性是通过调节诸如CD 40途径的免疫途径来促进的，以促进抗肿瘤活性而不是免疫耐受。我们 证明了CD 40激动剂与Flt 3配体（Flt 3L）协同作用，Flt 3配体是一种生长因子， 分化的DC 1细胞，这是重要的抗原呈递，和蒽环化疗， 在小鼠研究中根除三阴性乳腺癌。基于此，我们假设， 使用CD 40激动剂和Flt 3L的化疗增强抗原呈递， 获得性免疫，从而改善三阴性乳腺癌（TNBC）疾病控制。为了 为了验证这个假设，我建议： 目的#1：评估CD 40激动剂与Flt 3L联合使用的安全性、临床活性和免疫学疗效 和蒽环类化疗（三联疗法）在转移性TNBC（mTNBC）患者中的应用，并确定 反应和抗性的生物标志物。我将担任CD 40 1期试点试验的首席研究员 激动剂+Flt 3L+聚乙二醇化脂质体多柔比星。纵向组织样本将 收集并分析以研究药效学、反应生物标志物和耐药机制。 目的#2：发现使用同基因和人源化的三联疗法的应答和抗性机制。 小鼠模型，包括反映不同TNBC亚型的肿瘤。4 T1-HA同基因模型将用于 研究CD 40激动剂+Flt 3L+聚乙二醇化脂质体阿霉素方案中的不同药物如何有助于 免疫应答和免疫细胞类型介导的应答，重点是CD 8 T细胞和DC 1细胞。我们 将另外研究潜在的TNBC亚型如何影响对使用同基因小鼠的三联疗法的应答。 和人源化患者来源的异种移植物模型。 这项工作的结果将指导这种组合在TNBC和其他实体瘤中的未来发展。 我是UT西南（UTSW）医学中心的助理教授和首席研究员 在这个提议上。我是一名乳腺肿瘤内科医生，专注于改善乳腺癌患者的预后。 通过免疫疗法。为了最有效地推进这一领域，我计划将药物的临床研究 利用基于患者组织的转化科学和临床前研究刺激抗原呈递。到 补充我在免疫监测方面的背景，该提案详细说明了在以下指导下的培训计划： 转化型乳腺癌专家卡洛斯阿特阿加博士和癌症免疫学家傅洋新博士。这进一步 由专家咨询委员会、相关课程以及资源和支持性环境提供支持 帮助我成为一名专注于乳腺免疫肿瘤学的医生科学家。