Memory potential, molecular characterization, and translational applications of the novel ThEO/TcEO T cell phenotype

新型 ThEO/TcEO T 细胞表型的记忆潜力、分子表征和转化应用

• 批准号: 9229761
• 负责人: Todd Bartkowiak
• 金额: $ 3.87万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-22 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9229761
• 关键词: Accounting; Address; Adoptive Transfer; Agonist; Antibodies; Antigens; Basic Science; Biological Markers; Boxing; CD8B1 gene; Cancer Immunology Science; Cell Therapy; Cells; Cessation of life; Clinic; Clinical; Clinical Research; Clinical Trials; Collaborations; Communities; Cytotoxic T-Lymphocyte-Associated Protein 4; Development; Diagnostic Neoplasm Staging; Disease; Disseminated Malignant Neoplasm; Education; Ensure; Flow Cytometry; Future; Goals; Human; Immune; Immune response; Immunobiology; Immunologic Memory; Immunologist; Immunotherapy; Knowledge; Longevity; Maintenance; Mediating; Memory; Mentors; Mentorship; Methods; Microarray Analysis; Modality; Modeling; Molecular; Mus; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Pathway interactions; Patients; Phenotype; Positioning Attribute; Process; Research; Research Personnel; Research Project Grants; Science; Scientist; Skin Cancer; System; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Therapeutic; Tissues; Toxic effect; Training; Tumor Immunity; Validation; Work; Writing; base; cancer immunotherapy; career; clinical phenotype; cytotoxic; cytotoxicity; doctoral student; experience; human disease; immunoregulation; insight; liver inflammation; long term memory; melanoma; neoplasm immunotherapy; novel; pre-clinical; pre-doctoral; programs; receptor; response; response biomarker; success; transcription factor; treatment response; trend; tumor; tumor immunology; Accounting; Address; Adoptive Transfer; Agonist; Antibodies; Antigens; Basic Science; Biological Markers; Boxing; CD8B1 gene; Cancer Immunology Science; Cell Therapy; Cells; Cessation of life; Clinic; Clinical; Clinical Research; Clinical Trials; Collaborations; Communities; Cytotoxic T-Lymphocyte-Associated Protein 4; Development; Diagnostic Neoplasm Staging; Disease; Disseminated Malignant Neoplasm; Education; Ensure; Flow Cytometry; Future; Goals; Human; Immune; Immune response; Immunobiology; Immunologic Memory; Immunologist; Immunotherapy; Knowledge; Longevity; Maintenance; Mediating; Memory; Mentors; Mentorship; Methods; Microarray Analysis; Modality; Modeling; Molecular; Mus; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Pathway interactions; Patients; Phenotype; Positioning Attribute; Process; Research; Research Personnel; Research Project Grants; Science; Scientist; Skin Cancer; System; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Therapeutic; Tissues; Toxic effect; Training; Tumor Immunity; Validation; Work; Writing; base; cancer immunotherapy; career; clinical phenotype; cytotoxic; cytotoxicity; doctoral student; experience; human disease; immunoregulation; insight; liver inflammation; long term memory; melanoma; neoplasm immunotherapy; novel; pre-clinical; pre-doctoral; programs; receptor; response; response biomarker; success; transcription factor; treatment response; trend; tumor; tumor immunology

Melanoma is an aggressive form of skin cancer that accounts for the majority of skin cancer related deaths. Newly developed therapeutic modalities, however, have offered hope in treating this once incurable disease. Advances in immunotherapy, particularly the approval of anti-CTLA-4 and anti-PD-1 therapy for melanoma and non-small-cell lung cancer have demonstrated the potential of immune modulation in not only treating, but curing metastatic cancers. The clinical success of these checkpoint blockade antibodies has expanded the potential of targeting other T cell co-receptor targets to potentiate robust anti-tumor immune responses that may afford greater clinical benefit. Use of agonist antibodies directed towards 4-1BB, a co-stimulatory receptor expressed on activated T cells, has proven effective in treating multiple tumor types in both murine systems and early human clinical trials. The exquisite potency of α4-1BB therapy in boosting anti-tumor immunity is due, in part, to 4-1BB-mediated programming of T cells to assume a highly cytotoxic phenotype driven by the T box transcription factor Eomesodermin (Eomes) and characterized by expression of the co-inhibitory receptor KLRG1. These Eomes+KLRG1+ CD8 (TcEO) and CD4 (ThEO) T cells mediate potent anti-tumor responses capable of complete tumor rejection. We hypothesize that this Eomes-driven ThEO/TcEO T cell phenotype represents a novel molecular program which forms stable immunologic memory despite maintenance of highly cytotoxic effector function and KLRG1 expression. By characterizing the unique pathways downstream of 4-1BB activation which create the ThEO program, we will establish the molecular basis for the exquisite cytotoxicity of these cells, as well as their paradigm-breaking capacity to express KLRG1 yet retain proliferative capacity and memory potential. Investigating the detailed memory phenotype of these cells, as well as their replicative capacity and longevity following antigenic rechallenge will deepen our understanding of 4-1BB agonist antibody immunobiology and provide insight into their translational value in a cell therapy setting. Finally, exploring the importance of ThEO phenotype T cells for mediating both the beneficial anti-tumor efficacy as well as the detrimental liver inflammation associated with 4-1BB agonist antibody will provide mechanistic insights as well as potential guiding biomarkers for future clinical studies. The proposed research project will provide extensive technical training in both basic and clinical research, scientific writing, collaboration, and lab management necessary to pursue a career as an independent investigator.

黑色素瘤是一种侵略性的皮肤癌，占皮肤癌相关的大多数死亡。 然而，新开发的治疗方式在治疗这种无法治愈的疾病方面给人带来了希望。 免疫疗法的进展，特别是抗CTLA-4和抗PD-1治疗的黑色素瘤和抗PD-1治疗 非小细胞肺癌已经证明了免疫调节的潜力，不仅在治疗中，而且还具有 固化转移性癌症。这些检查点阻断抗体的临床成功已扩大 将其他T细胞共受体靶标靶向潜在的强大抗肿瘤免疫反应的潜力 可能会带来更大的临床益处。使用针对4-1BB的激动剂抗体，这是一个联合刺激器接收器 在激活的T细胞上表示，已证明在两种鼠系统中都有效治疗多种肿瘤类型 和早期人类临床试验。 α4-1BB疗法的独家效力在增强抗肿瘤免疫史前 部分原因是T细胞的4-1BB介导的编程假设由T驱动的高度细胞毒性表型 盒转录因子Eomesodermin（EOMES），其特征是表达共抑制剂接收器 KLRG1。这些EOMES+ KLRG1+ CD8（TCEO）和CD4（THEO）T细胞介导潜在的抗肿瘤反应 能够完全排斥肿瘤。我们假设该Eomes驱动的Theo/Tceo T细胞 表型代表一个新型的分子程序，形成稳定的免疫记忆目的地 维持高度细胞毒性效应子功能和KLRG1表达。通过表征独特 4-1BB激活下游的途径，这创建了Theo程序，我们将建立分子 这些细胞的独家细胞毒性的基础，以及它们的范式破坏能力的表达能力 KLRG1仍保留增殖的能力和记忆潜力。研究的详细记忆表型 这些细胞，以及它们的复制能力和抗原补偿后的寿命将加深我们 了解4-1BB激动剂抗体免疫生物学，并在A中洞悉其翻译价值 细胞疗法设置。最后，探索Theo表型T细胞对介导的重要性 有益的抗肿瘤效率以及与4-1BB激动剂有关的有害肝感染 抗体将为未来的临床研究提供机械见解和潜在的指导生物标志物。 拟议的研究项目将在基础和临床研究，科学研究中提供广泛的技术培训 从事独立调查员的职业所必需的写作，协作和实验室管理。