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: 10704008
• 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/10704008
• 关键词: 4T1; Address; Advisory Committees; Agonist; Anthracycline; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Bioinformatics; Biological Markers; Breast; Breast Cancer Patient; CD8-Positive T-Lymphocytes; Cells; Clinical; Clinical Trials; Clinical Trials Design; Combination Drug Therapy; 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; Regimen; Research; Resistance; Resources; Safety; Scientist; Solid Neoplasm; Sterically Stabilized Liposome; 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; adaptive immunity; biomarker identification; cancer subtypes; cancer therapy; cell type; chemotherapy; 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; organizational structure; patient derived xenograft model; pilot trial; pre-clinical; preclinical study; professor; randomized, clinical trials; resistance mechanism; response; response biomarker; safety assessment; 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.

项目概要/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 表现出有限的反应。抗原呈递细胞（APC）对于启动抗肿瘤免疫和维持免疫至关重要。 ICB 的功效，并且已知在乳腺癌中存在缺陷。重要的是，APC 需要通过以下方式激活 CD40 途径等途径，以促进抗肿瘤活性而不是免疫耐受。我们 证明 CD40 激动剂与 Flt3 配体 (Flt3L) 协同作用，Flt3L 是一种生长因子，可促进 DC1细胞的分化对于抗原呈递很重要，并且蒽环类化疗 在小鼠研究中根除三阴性乳腺癌。基于此，我们假设结合 使用 CD40 激动剂和 Flt3L 进行化疗可增强抗原呈递并增加长期 适应性免疫，从而改善三阴性乳腺癌（TNBC）疾病控制。为了 检验这个假设，我建议： 目标#1：评估 CD40 激动剂与 Flt3L 联合使用的安全性、临床活性和免疫功效 和蒽环类化疗（三联疗法）治疗转移性 TNBC (mTNBC) 患者并确定 反应和抵抗的生物标志物。我将担任 CD40 第一阶段试点试验的首席研究员 激动剂 + Flt3L + 聚乙二醇化脂质体阿霉素治疗 mTNBC 患者。纵向组织样本将是 收集并分析以研究药效学、反应生物标志物和耐药机制。 目标#2：发现使用同基因和人源化三联疗法的反应和耐药机制 小鼠模型，包括反映不同 TNBC 亚型的肿瘤。 4T1-HA同系模型将用于 研究 CD40 激动剂 + Flt3L + 聚乙二醇化脂质体阿霉素方案中的不同药物如何促进 反应以及哪些免疫细胞类型介导反应，重点是 CD8 T 细胞和 DC1 细胞。我们 此外，还将研究潜在的 TNBC 亚型如何影响使用同基因小鼠的三联疗法的反应 和人源化患者来源的异种移植模型。 这项工作的结果将指导该组合在 TNBC 和其他实体瘤中的未来发展。 我是 UT 西南医学中心 (UTSW) 的助理教授和首席研究员 关于这个提议。我是一名乳腺肿瘤科医生，致力于改善乳腺癌患者的预后 通过免疫疗法。为了最有效地推进该领域，我计划整合药物的临床研究 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，该提案详细介绍了在指导下的培训计划 转化乳腺癌专家 Carlos Arteaga 博士和癌症免疫学家付阳新博士。这进一步 由专家咨询委员会、相关课程以及资源和支持环境支持 UTSW 的帮助我过渡到独立，成为一名专注于乳腺免疫肿瘤学的医师科学家。