Therapeutic implication of CD38 in CLL

CD38 在 CLL 中的治疗意义

基本信息

批准号：
10228566
负责人：
Asher A Chanan-Khan
金额：
$ 61.02万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-04 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10228566
关键词：
Activities of Daily Living Address Affect Affinity Aggressive Clinical Course Antitumor Response Apoptosis Applications Grants Architecture B-Cell Antigen Receptor B-Lymphocytes B-lymphocyte Cancer Binding Biochemical Biological Biology CD8-Positive T-Lymphocytes CD8B1 gene Categories Cell Surface Receptors Cell Survival Cell physiology Cells Chronic Lymphocytic Leukemia Clinical Clinical Trials Clone Cells Data Development Disease Disease Progression FDA approved Funding Goals Immune Immunity In Vitro Interleukin-10 Investigation Kinetics Knowledge Lead Lymphocyte Maintenance Malignant Neoplasms Malignant neoplasm of prostate Metabolism Molecular Monoclonal Antibodies Multiple Myeloma Mus NAD+ Nucleosidase Nature Non-Small-Cell Lung Carcinoma Pathway interactions Patients Pattern Phase II Clinical Trials Phosphorylation Population Process Prognosis Prognostic Marker Property Receptor Signaling Regulatory T-Lymphocyte Role Sampling Serum Signal Transduction Signaling Protein Surface Surface Antigens T cell clonality T cell receptor repertoire sequencing T cell response T-Cell Receptor T-Lymphocyte TNF gene Therapeutic Therapeutic Effect Time Transgenic Mice Uncertainty Waldenstrom Macroglobulinemia base cancer cell cell growth cell killing chronic lymphocytic leukemia cell clinical remission clinically relevant cytokine cytotoxic CD8 T cells hematopoietic tissue in vivo inhibitor/antagonist insight leukemia metabolic fitness mutant neoplastic cell novel phase 2 study prognostic receptor response small molecule inhibitor targeted treatment therapeutic target tumor tumor microenvironment

项目摘要

Project Summary The objective of this proposal is to decipher the mechanisms involved in CD38 signaling in patients with chronic lymphocytic leukemia (CLL, a B-cell cancer); how its increased expression drives an aggressive clinical course and whether its targeted therapeutic disruption can be beneficial for patients. CD38 is expressed on all hematopoietic tissues and functions as both an ecto-enzyme to regulate NAD metabolism and as a co-receptor to amplify signaling through the B-cell receptor (BCR) on B-cells and the T-cell receptor (TCR) on T-cells. Increased CD38 expression on CLL cells is associated with an unfavorable disease course in patients; resulting in shorter overall survival and time to treatment. While the role of CD38 as a negative prognostic marker in CLL has been established for over 2 decades, the therapeutic benefit to be derived by patients from its targeted inhibition, has, till date remained an open-ended subject. Much of this uncertainty has been due to lack of high-affinity, clinical-grade agents that can bind and inhibit CD38; thus, resulting in our inability to study the effects of CD38 disruption on CLL biology. Indeed, with the availability of Daratumumab, (Dara, anti-CD38 mAb, FDA-approved in multiple myeloma), as well as several other anti-CD38 mAbs and small molecule inhibitors in development, this issue will for the first time be appropriately addressed; by our group. Our preliminary data strongly indicates that targeting CD38 has a direct lethal effect on CLL cells, reduces the population of tumor-supportive T-regulatory cells (Tregs) and increases the quantity and functional capacity of tumor-specific CD8+ T-cells. These are novel observations and will be examined through the following aims where we will: 1. Determine the molecular processes of how CD38 activity in CLL cells promotes disease progression. 2. Elucidate the role of CD38 in the suppression of anti-tumor T-cell responses in vitro and in vivo. 3. Evaluate effects of Dara-based therapy in CLL patients on a phase II clinical trial. While the first two aims are highly mechanistic in nature, results from their completion will guide studies in Aim 3, where we will examine changes in CD38 enzymatic/receptorial activity and in the T-cell architecture in patients who are on Dara-based treatment (on an accompanying, but separately funded phase II study). Thus, our long-term goals are to understand the fundamentals of CD38 biology in the tumor cells themselves and in neighboring cells within the tumor microenvironment. Mechanistic insight into the processes engaged upon CD38 inhibition will propel more effective development of anti-CD38 treatments and no doubt lead to a paradigm shift- elevating CD38 from the category of a prognostic marker to a bonafide therapeutic target in CLL.

项目概要该提案的目的是破译 CD38 信号传导在患有以下疾病的患者中涉及的机制：慢性淋巴细胞白血病（CLL，一种 B 细胞癌）；它的表达增加如何驱动积极的临床过程以及其有针对性的治疗干扰是否对患者有益。 CD38 表达于所有造血组织，既作为调节 NAD 代谢的胞外酶，又作为共受体通过 B 细胞上的 B 细胞受体 (BCR) 和 T 细胞上的 T 细胞受体 (TCR) 放大信号传导。 CLL 细胞上 CD38 表达增加与患者的不利病程相关；导致总生存期和治疗时间缩短。而 CD38 的负面预后作用 CLL 标志物的建立已有 20 多年的历史，患者可以从以下方面获得治疗益处：迄今为止，其有针对性的抑制仍然是一个开放式主题。这种不确定性很大程度上是由于缺乏可以结合和抑制 CD38 的高亲和力、临床级药物；从而导致我们无法学习 CD38 破坏对 CLL 生物学的影响。事实上，随着 Daratumumab 的上市，（Dara，抗 CD38 mAb，FDA 批准用于治疗多发性骨髓瘤），以及其他几种抗 CD38 mAb 和小分子抑制剂正在开发中，这个问题将首次得到适当解决；由我们小组。我们的初步数据强烈表明，靶向 CD38 对 CLL 细胞具有直接致死作用，降低了肿瘤支持性 T 调节细胞 (Treg) 群体，并增加其数量和功能能力肿瘤特异性 CD8+ T 细胞。这些是新颖的观察结果，将通过以下目标进行检查我们将： 1. 确定 CLL 细胞中 CD38 活性如何促进疾病的分子过程进展。 2. 阐明CD38在体外和体内抑制抗肿瘤T细胞反应中的作用。 3. 在 II 期临床试验中评估基于 Dara 的疗法对 CLL 患者的效果。虽然前两个目标本质上是高度机械化的，完成它们的结果将指导目标 3 的研究，我们将检查接受治疗的患者 CD38 酶/受体活性和 T 细胞结构的变化基于 Dara 的治疗（在一项附带但单独资助的 II 期研究中）。因此，我们的长期目标了解肿瘤细胞本身和邻近细胞中 CD38 生物学的基础知识肿瘤微环境内。对 CD38 抑制过程的机制洞察将推动抗 CD38 疗法更有效的发展，无疑会导致范式转变 CD38 从预后标志物类别转变为 CLL 的真正治疗靶点。