Therapeutic implication of CD38 in CLL

CD38 在 CLL 中的治疗意义

• 批准号: 10683157
• 负责人: Asher A Chanan-Khan
• 金额: $ 56.51万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 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/10683157
• 关键词: Activities of Daily Living; Address; Affect; Affinity; Aggressive Clinical Course; Antitumor Response; Apoptosis; Applications Grants; Architecture; B-Cell Antigen Receptor; 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; 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 Cell; Receptor Signaling; Regulatory T-Lymphocyte; Role; Sampling; Serum; Signal Transduction; Signaling Protein; Sorting; 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; cancer cell; cell growth; cell killing; chronic T-cell leukemia; chronic lymphocytic leukemia cell; clinical remission; clinically relevant; cytokine; cytotoxic CD8 T cells; hematopoietic tissue; in vivo; inhibitor; insight; leukemia; metabolic fitness; mutant; neoplastic cell; novel; phase 2 study; prognostic; receptor; response; small molecule inhibitor; targeted treatment; therapeutic target; transmission process; tumor; tumor microenvironment; Activities of Daily Living; Address; Affect; Affinity; Aggressive Clinical Course; Antitumor Response; Apoptosis; Applications Grants; Architecture; B-Cell Antigen Receptor; 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; 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 Cell; Receptor Signaling; Regulatory T-Lymphocyte; Role; Sampling; Serum; Signal Transduction; Signaling Protein; Sorting; 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; cancer cell; cell growth; cell killing; chronic T-cell leukemia; chronic lymphocytic leukemia cell; clinical remission; clinically relevant; cytokine; cytotoxic CD8 T cells; hematopoietic tissue; in vivo; inhibitor; insight; leukemia; metabolic fitness; mutant; neoplastic cell; novel; phase 2 study; prognostic; receptor; response; small molecule inhibitor; targeted treatment; therapeutic target; transmission process; tumor; tumor microenvironment

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.

项目摘要 该提议的目的是解释患者患者CD38信号传导所涉及的机制 慢性淋巴细胞性白血病（CLL，A B细胞癌）；其增加的表达如何驱动激进的临床 当然以及其目标治疗性破坏是否对患者有益。 CD38在所有人上表达 造血组织和功能既是调节NAD代谢的过酶，又是共受体 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）扩增信号传导。 CLL细胞上的CD38表达增加与患者的不利疾病病程有关。 导致总体生存和治疗时间较短。而CD38作为负预后的作用 CLL中的标记已建立了20多年，患者从 它的目标抑制一直是迄今为止的开放式主题。这种不确定性大部分是由于 缺乏可以结合和抑制CD38的高亲和力的临床级药物；因此，导致我们无法学习 CD38破坏对CLL生物学的影响。确实，随着daratumumab的可用性（dara，anti-cd38） MAB，FDA在多发性骨髓瘤中批准），以及其他几种抗CD38 mAb和小分子 开发中的抑制剂，这个问题将首次适当解决；由我们的小组。我们的 初步数据强烈表明，靶向CD38对CLL细胞具有直接致命作用，减少了 肿瘤支持性T调节细胞（TREG）的种群，并增加了数量和功能能力 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 我们将在哪里：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。评估基于DARA的治疗对CLL患者对II期临床试验的影响。而前两个目标 本质上是高度机械的，其完成的结果将指导AIM 3中的研究，我们将在其中我们将 检查CD38酶促/受体活性的变化以及在ON的患者中的T细胞结构的变化 基于DARA的治疗（在随附但分别资助的II期研究中）。因此，我们的长期目标 要了解肿瘤细胞本身和邻近细胞中CD38生物学的基本面 在肿瘤微环境中。对CD38抑制过程中参与过程的机械洞察力将 推动抗CD38治疗的更有效发展，毫无疑问会导致范式升高 CD38从预后标记类别到CLL的真正治疗靶标。