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.

项目摘要 /摘要 尽管在许多肿瘤类型中，免疫检查点封锁（ICB）取得了成功，但乳腺癌仍具有 显示有限的响应。抗原呈递细胞（APC）对于启动抗肿瘤免疫和对 ICB的功效，已知在乳腺癌中有缺陷。重要的是，需要通过 诸如CD40途径之类的途径是为了促进抗肿瘤活性而不是免疫耐受性。我们 证明CD40激动剂与FLT3配体（FLT3L）协同作用，这是促进的生长因子 DC1细胞的分化对于抗原表现至关重要，蒽环类化疗至 在小鼠研究中消除三重阴性乳腺癌。基于此，我们假设结合 用CD40激动剂和FLT3L化学疗法可增强抗原表现并长期增加 自适应免疫，从而改善了三重阴性乳腺癌（TNBC）疾病控制。为了 测试这个假设，我建议： 目标＃1：评估CD40激动剂与FLT3L的安全性，临床活动和免疫学功效 转移性TNBC（MTNBC）患者的蒽环类化疗（三重疗法）并鉴定 反应和抗性的生物标志物。我将担任CD40 1阶段试验试验的首席研究员 MTNBC患者的激动剂 + FLT3L + PEGYPER的脂质体阿霉素。纵向组织样品将是 收集和分析以研究药效学，反应的生物标志物和耐药机制。 目标＃2：发现使用同步和人源化的反应机制和对三重疗法的抵抗力 小鼠模型，包括反映不同TNBC亚型的肿瘤。 4T1-HA合成模型将用于 研究CD40激动剂 + FLT3L +卵脂化脂质体阿霉素方案的不同药物如何有助于 反应以及哪些免疫细胞类型正在介导反应，重点是CD8 T细胞和DC1细胞。我们 还将研究潜在的TNBC亚型使用Syngeneic Murine影响对三重疗法的反应 和人源化患者衍生的异种移植模型。 这项工作的结果将指导TNBC和其他实体瘤中这种组合的未来发展。 我是UT西南（UTSW）医疗中心的助理教授和首席研究员 在此提案中。我是一名乳房医学肿瘤学家，专注于改善乳腺癌患者的预后 通过免疫疗法。为了最有效地推进该领域，我计划整合对代理的临床研究 通过基于患者组织的转化科学和临床前研究刺激抗原表现。到 补充我在免疫监控方面的背景，该提案详细介绍了在指导下的培训计划 翻译乳腺癌专家Carlos Arteaga博士和癌症免疫学家Yang-Xin Fu博士。这是进一步的 得到专家咨询委员会，相关课程以及资源和支持环境的支持 UTSW的旨在帮助我过渡到独立性的医生科学家，专注于乳房免疫肿瘤学。