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Engaging immunosuppressive myeloid cells in the TME for the treatment of pancreatic cancer

让免疫抑制性骨髓细胞参与 TME 治疗胰腺癌

基本信息

批准号：
10178843
负责人：
Mikael Karlsson
金额：
$ 57.6万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-11 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10178843
关键词：
Agonist Anti-CD40 Antibodies Antibody Therapy Antigen Presentation Antitumor Response Binding Biological Assay Blocking Antibodies CD8-Positive T-Lymphocytes CTLA4 gene Cells Clinical Clinical Treatment Clinical Trials Combined Modality Therapy Cytotoxic T-Lymphocytes Data Development Disease Dose Engineering Evaluation Fc Receptor Flow Cytometry Genetically Engineered Mouse Goals Human IgG Receptors Immune Immune system Immunoglobulin G Immunotherapeutic agent Immunotherapy Inflammatory Innovative Therapy Interleukin-12 Knowledge Lead Malignant Neoplasms Malignant neoplasm of pancreas Mediating Methods Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells Natural Killer Cells Neoplasm Metastasis Oncology Operative Surgical Procedures PD-1/PD-L1 Pancreas Pancreatic Adenocarcinoma Pathway interactions Pattern recognition receptor Phenotype Property Proteins Radiation therapy Research Research Personnel Role Signal Transduction Specimen Structure T-Lymphocyte TNF gene TNFRSF5 gene Testing Therapeutic Translations Treatment Efficacy Tumor Antigens Tumor Immunity Tumor-associated macrophages Variant Work antibody engineering base cancer immunotherapy cancer therapy cell killing checkpoint therapy chemotherapy design exhaustion fighting immunosuppressive macrophages improved in vitro Assay in vivo in vivo evaluation innovation interest macrophage member neoplastic cell new therapeutic target novel pancreatic cancer model pancreatic cancer patients pancreatic neoplasm prevent receptor receptor binding recruit response standard of care success targeted treatment therapeutic candidate tumor tumor microenvironment tumor-immune system interactions

项目摘要

ABSTRACT Although the past decade was marked by the tremendous success of immunotherapeutics in oncology, few have provided significant benefit to patients with pancreatic cancer. The long-term goal of this project is to develop therapeutically useful immunotherapies for the clinical treatment of pancreatic cancer. The overall objectives in this application are to (i) characterize the role for MARCO in the TME, (ii) to evaluate the therapeutic efficacy of antibodies blocking this receptor, and (iii) improve antigen presentation within the pancreatic TME with a combination of Fc-enhanced antibodies targeting MARCO and CD40. Our central hypothesis is that pancreatic cancer repolarizes tumor associated macrophages to an M2 phenotype an this can be reversed through engagement of MARCO with antibodies, therefore promoting anti-tumor responses. The rationale for this project is that a determination of the immunosuppressive role of TAMs expressing MARCO in pancreatic cancer will likely offer a strong scientific framework whereby new immunotherapies can be developed. The central hypothesis will be tested by pursuing three specific aims: 1) Develop anti-human TAM antibodies for cancer immunotherapy and set up novel assays for large-scale evaluation of anti-TAM antibodies, 2) Define the role for MARCO in the polarization of TAMs in pancreatic cancer, and 3) Augment TAM repolarization in the pancreatic cancer TME using the Fc-enhanced CD40 agonist antibody 2141-V11, alone or in combination with anti- hMARCO antibodies.. Under the first aim, novel antibodies will be generated against human MARCO and optimized for Fc-receptor binding. In the second Aim, mice genetically engineered to express human MARCO will be studied for their role in the TME of pancreatic cancer. Following characterization immune cells expressing MARCO that can be targeted by antibody therapy, a panel of antibody variants will be tested to determine the Fc-requirements for optimal in vivo activity. MARCO expression and characterization of the immune microenvironment will also be evaluated in human pancreatic cancer specimens. Finally, in the third aim, we will use knowledge gained in Aims 1 and 2 to test novel combinations targeting the myeloid axis in pancreatic tumors. Here, the anti-tumor activity of the Fc-enhanced anti-CD40 antibody will be tested alone or in combination with anti-MARCO antibodies in pancreatic cancer models. The research proposed in this application is innovative, in the investigator’s opinion, because it focuses on defining novel pathways on myeloid cells contributing to the immune suppressive TME of pancreatic cancer, while identifying lead therapeutic candidates through Fc- engineering. The proposed research is significant because it is expected to provide strong scientific justification for the development of macrophage targeting immunotherapies. Ultimately, such knowledge has the potential of offering new opportunities for the translation of innovative therapies to the treatment of pancreatic cancer.

摘要