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