Defining the Role of CD26 in Checkpoint Blockaded Induced Tumor Immunity

定义 CD26 在检查点阻断诱导肿瘤免疫中的作用

• 批准号: 10621564
• 负责人: Chrystal Mary Paulos
• 金额: $ 8.37万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-13 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10621564
• 关键词: Defining; Role; CD26; Checkpoint; Blockaded

Abstract: The objective of this MPI R21 is to support an important discovery found by this basic T cell immunologist and immune-therapist (Dr. Chrystal Paulos) and surgeon and scientist (Dr. David Neskey) research team in a Phase II clinical trial (NCT03021993) in patients with oral cavity squamous cell carcinoma (OCC). These patients were treated with Nivolumab as a novel neoadjuvant pre-surgical therapy at our institution (Hollings Cancer Center). Our unpublished work reveals that a remarkable 44% of patients responded to this therapy via pathological score. While promising, 56% of the patients remain unresponsive to this treatment. Our new data reveals that responders express higher CD26 (co-stimulatory molecule with enzyme activity) on tumor- infiltrating lymphocytes (TILs), while CD26 was far lower on TILs from non-responders. These data suggest that CD26 plays a critical role in the function and migration of antitumor T cells to the oppressive tumor microenvironment in patients responsive to PD-1 therapy. We propose to gain insight into CD26-expressing T cells in the tumor, positing that the enzymatic CD26 activity augments the function, migration and antitumor activity of human TILs (Aim 1) and that targeting this pathway can improve cancer immunotherapy in non- responders: an idea we will explore in Aim 2, using our highly clinically relevant OCC tumor models. Overall, the proposed research is expected to demonstrate that manipulation of the CD26 pathway may sufficiently induce durable immunity against advanced OCC tumors and rescue patients non-responsive to PD-1 therapy.

摘要： MPI R21的目标是支持这位基础T细胞免疫学家发现的一项重要发现，并 免疫治疗师(克里斯特尔·保罗博士)和外科医生兼科学家(大卫·内斯基博士)研究小组 口腔鳞状细胞癌患者的第二阶段临床试验(NCT03021993)。这些 在我们机构(霍林斯)，患者接受尼伏卢单抗治疗，作为一种新的术前辅助治疗 癌症中心)。我们未发表的研究表明，44%的患者对这种疗法的反应是通过 病理评分。虽然前景看好，但56%的患者对这种治疗仍然没有反应。我们的新数据 显示反应者在肿瘤上表达更高的CD26(具有酶活性的共刺激分子)- 浸润性淋巴细胞(TIL)，而CD26在无应答者TIL上的表达要低得多。这些数据表明 CD26在抗肿瘤T细胞的功能和向抑制性肿瘤的迁移中起关键作用 患者对PD-1治疗反应的微环境。我们建议深入了解CD26表达的T细胞 肿瘤中的细胞，假设酶的CD26活性增强了功能、迁移和抗肿瘤 人TIL的活性(Aim 1)及其靶向这一途径可以改善非肿瘤患者的肿瘤免疫治疗 响应者：我们将在Aim 2中探索一个想法，使用我们高度临床相关的OCC肿瘤模型。总的来说， 这项拟议的研究有望证明，对CD26通路的操纵可能足以 诱导对晚期OCC肿瘤的持久免疫，拯救对PD-1治疗无效的患者。