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: 9908060
• 负责人: Todd Bartkowiak
• 金额: $ 7.84万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9908060
• 关键词: Address; Agonist; Antibodies; Antigens; Antitumor Response; Basic Science; Biological Markers; CD8B1 gene; Cell Compartmentation; Cell Therapy; Cells; Cessation of life; Clinic; Clinical; Clinical Research; Clinical Trials; Collaborations; Combination immunotherapy; Communities; Competence; Development; Disease; Disseminated Malignant Neoplasm; Education; Ensure; Flow Cytometry; Fruit; Future; Goals; Human; Immune; Immunobiology; Immunologic Memory; Immunologist; Immunotherapy; Knowledge; Longevity; Maintenance; Malignant Neoplasms; 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 cell therapy; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Therapeutic; Tissues; Toxic effect; Training; Tumor Immunity; Validation; Work; Writing; anti-4-1BB; anti-41BB therapy; anti-CTLA4; anti-PD-1; anti-PD1 therapy; anti-tumor immune response; cancer immunotherapy; career; cytotoxic; cytotoxicity; doctoral student; experience; human disease; immune checkpoint blockade; 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.

黑色素瘤是一种侵袭性皮肤癌，占皮肤癌相关死亡的大多数。 然而，新开发的治疗方式为治疗这种曾经无法治愈的疾病提供了希望。 免疫治疗的进展，特别是抗CTLA-4和抗PD-1治疗黑色素瘤的批准， 非小细胞肺癌的免疫调节不仅在治疗方面， 治疗转移性癌症这些检查点阻断抗体的临床成功扩大了 靶向其他T细胞共受体靶点以增强稳健的抗肿瘤免疫应答的潜力， 可以提供更大的临床益处。针对共刺激受体4-1BB的激动剂抗体的用途 在活化的T细胞上表达，已经证明在两种鼠系统中治疗多种肿瘤类型有效 和早期的人类临床试验。α4-1BB疗法在增强抗肿瘤免疫力方面的卓越效力是 部分原因是4- 1BB介导的T细胞编程，以呈现由T细胞介导的高度细胞毒性表型。 盒转录因子Eomesodermin（Eomes），其特征在于共抑制受体的表达 KLRG1.这些Eomes+ KLRG 1 + CD 8（TcEO）和CD 4（ThEO）T细胞介导强效抗肿瘤反应 能够完全排斥肿瘤。我们假设这种Eomes驱动的ThEO/TcEO T细胞 表型代表了一种新的分子程序，它形成稳定的免疫记忆， 维持高细胞毒性效应子功能和KLRG 1表达。通过描述独特的 4-1BB激活下游的途径，创造了ThEO程序，我们将建立分子 这些细胞的精致细胞毒性的基础，以及他们的范式突破能力，表达 KLRG 1仍保留增殖能力和记忆潜力。详细记忆表型的研究 这些细胞，以及它们在抗原再激发后的复制能力和寿命，将加深我们对它们的认识。 了解4-1BB激动剂抗体的免疫生物学，并提供深入了解其翻译价值， 细胞治疗设置。最后，探讨ThEO表型T细胞介导两种免疫应答的重要性。 有益的抗肿瘤功效以及与4-1BB激动剂相关的有害肝脏炎症 抗体将为未来的临床研究提供机制见解以及潜在的指导生物标志物。的 拟议的研究项目将提供广泛的技术培训，在基础和临床研究，科学 写作，协作和实验室管理必要的追求作为一个独立的调查员的职业生涯。