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

项目摘要/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 显示出有限的反应。抗原提呈细胞(APC)是启动抗肿瘤免疫的关键，对于 ICB的疗效，并已知在乳腺癌中存在缺陷。重要的是，APC需要通过 CD40途径等途径，以促进抗肿瘤活性，而不是免疫耐受。我们 CD40激动剂与Flt3配体(Flt3L)有协同作用，Flt3L是一种促进 对抗原提呈很重要的DC1细胞的分化，以及蒽环类药物化疗对 在小鼠研究中根除三重阴性乳腺癌。在此基础上，我们假设结合 使用CD40激动剂和Flt3L进行化疗可增强抗原提呈并增加长期存活率 适应性免疫，从而改善三阴性乳腺癌(TNBC)疾病控制。为了 检验这一假设，我建议： 目的1：评估CD40激动剂与Flt3L联合应用的安全性、临床活性和免疫效果 和蒽环类化疗(三联疗法)治疗转移性TNBC(MTNBC)并鉴定 反应和抗性的生物标志物。我将担任CD40第一阶段试点试验的首席调查员 激动剂+Flt3L+聚乙二醇化阿霉素脂质体治疗mTNBC纵向组织样本将被 收集和分析以研究药效学、反应的生物标志物和耐药机制。 目的#2：利用同源和人源化的方法发现三胞胎治疗的应答和抵抗机制 小鼠模型，包括反映不同TNBC亚型的肿瘤。4T1-HA同基因模型将用于 研究CD40激动剂+Flt3L+聚乙二醇化阿霉素脂质体方案中的不同药物对 以及哪些免疫细胞类型是介导反应的，重点是CD8T细胞和Dc1细胞。我们 我还将利用同基因小鼠研究潜在的TNBC亚型如何影响三胞胎治疗的反应 和人性化的患者衍生的异种移植模型。 这项工作的结果将指导这种联合治疗在TNBC和其他实体肿瘤中的未来发展。 我是德克萨斯大学西南医学中心的助理教授和首席研究员 关于这项提议。我是一名乳腺癌内科肿瘤学家，致力于改善乳腺癌患者的预后。 通过免疫疗法。为了最有效地推动这一领域的发展，我计划整合对药物的临床调查 以患者组织为基础的翻译科学和临床前研究刺激抗原呈递。至 补充我在免疫监测方面的背景，这项建议详细说明了在 转译乳腺癌专家卡洛斯·阿特亚加博士和癌症免疫学家傅阳新博士。这是更远的 由专家咨询委员会、相关课程以及资源和支持环境提供支持 帮助我过渡到独立，成为一名专注于乳房免疫肿瘤学的内科科学家。

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.