Targeting the Ig-light chains with CAR-T cells in lymphoid tumors

在淋巴肿瘤中使用 CAR-T 细胞靶向 Ig-轻链

• 批准号: 9020512
• 负责人: Gianpietro Dotti
• 金额: $ 56.93万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9020512
• 关键词: Acute Lymphocytic Leukemia; Address; Affect; Antigen Targeting; Autologous; B lymphoid malignancy; B-Cell Lymphomas; B-Lymphocytes; CD19 Antigens; CD19 gene; CD20 Antigens; CD28 gene; CD8B1 gene; Cells; Chronic Lymphocytic Leukemia; Clinical; Clinical Research; Clinical Trials; Disease; Disease remission; Engineering; Engraftment; Enrollment; Extracellular Protein; Future; Goals; Hematologic Neoplasms; Human; Humoral Immunities; Immune; Immunoglobulins; Impairment; In complete remission; Infusion procedures; Institutional Review Boards; Knowledge; Light; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Mature B-Lymphocyte; Modality; Molecular; Non-Hodgkin' s Lymphoma; Patients; Phase; Phase I Clinical Trials; Pre-Clinical Model; Receptor Signaling; Refractory; Relapse; Role; Safety; Signal Transduction; Structure; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Transmembrane Domain; antitumor effect; base; cancer cell; cellular engineering; chimeric antigen receptor; experience; in vivo; lymphoid neoplasm; man; neoplastic cell; novel; phase 1 study; prevent; public health relevance; response; success; targeted treatment; tumor; tumor growth; vector

 DESCRIPTION (provided by applicant): Patients with B-cell malignancies [non Hodgkin lymphoma (B-NHL), B-chronic lymphocytic leukemia (B-CLL) and acute lymphoblastic leukemia (B-ALL)] respond to T cells redirected with chimeric antigen receptors (CARs) specific for CD20 or CD19 antigens, and encoding costimulatory endodomains. Targeting these antigens, however, does not distinguish between normal and malignant B cells, so that this approach, when effective, causes profound B-cell aplasia. It is therefore important to identify targets expressed more selectively by B-cell malignancies. B-NHL and B-CLL cells express monoclonal immunoglobulins (Igs) that contain either - or -light chains. As a proof of principle, we hav implemented a phase I clinical trial in which patients with relapsed/refractory + B-cell malignancies are infused with autologous T-cell products engineered to express a CAR that targets the -light of human Igs, and also contains the CD28 costimulatory endodomain (CAR..CD28TM.CD28). This CAR would target normal and malignant + cells, but spares the subset of normal B cells that express the -light chain. This study is currently ongoing, and it enrolled 10 patients. Two patients achieved complete response and 4 patients experienced disease stabilization. Although promising, this study also shows some limitations such as the suboptimal in vivo expansion/persistence of these cells. We discovered a specific role of the CD8 stalk that when incorporated in CARs expressing either CD28 or 4-1BB signaling domains dramatically enhance their antitumor effects. Our central hypothesis is that the inclusion of the CD8stalk in the CAR. (CAR..CD8.CD28), rather than CD28 transmembrane domain and signaling domains, will enhance the expansion and persistence of CAR-T cells in vivo and promote higher rate of clinical responses. In the proposed phase I study we will address the mechanistic role of the CD8 stalk in CAR signaling, and then conduct a phase I clinical study in which each patient will receive two T-cell products expressing either the current CAR..CD28TM.CD28 or the new CAR..CD8.CD28 allowing us to clearly evaluate the expansion/persistence of each T-cell subset within the same patient. On completion of this first-in-man study we will know whether this novel CAR can substitute the CD19-specific CAR currently used for mature B-cell malignancies. We will also develop preclinically the specific CAR that targets the -chain in order to implement a strategy that covers the great majority of patients with B-cell mature malignancies.

 描述（由申请人提供）：患有 B 细胞恶性肿瘤 [非霍奇金淋巴瘤 (B-NHL)、B 慢性淋巴细胞白血病 (B-CLL) 和急性淋巴细胞白血病 (B-ALL)] 的患者对嵌合重定向的 T 细胞有反应然而，对 CD20 或 CD19 抗原具有特异性并编码共刺激内域的抗原受体 (CAR) 并不能区分这些抗原。正常和恶性 B 细胞之间存在差异，因此这种方法在有效时会导致严重的 B 细胞再生障碍性贫血，因此，识别 B-NHL 和 B-CLL 细胞表达单克隆免疫球蛋白的选择性靶标非常重要。 Igs）包含 - 或 - 轻链 作为原则证明，我们已经实施了一项 I 期临床试验，其中患有复发/难治性 + B 细胞的患者。恶性肿瘤被注入经过设计的自体 T 细胞产品，该产品可表达针对人类 Igs 的 β 光的 CAR，并且还包含 CD28 共刺激内域 (CAR..CD28TM.CD28)。该 CAR 将针对正常和恶性 β+。细胞，但保留了表达 λ-轻链的正常 B 细胞子集。这项研究目前正在进行中，并招募了 10 名患者。尽管有希望，但这项研究也显示出一些局限性，例如这些细胞的体内扩增/持久性不佳，我们发现了 CD8 茎在表达 CD28 或 4 的 CAR 中发挥的特定作用。 -1BB 信号结构域显着增强其抗肿瘤作用。我们的中心假设是 CAR 中包含 CD8茎。 (CAR..CD8.CD28)，而不是 CD28 跨膜结构域和信号传导结构域，将增强 CAR-T 细胞在体内的扩增和持久性，并促进更高的临床反应率。在拟议的 I 期研究中，我们将解决这一问题。 CD8 茎在 CAR 信号传导中的机制作用，然后进行 I 期临床研究，其中每位患者将接受两种表达以下任一者的 T 细胞产品： 现有的 CAR..CD28TM.CD28 或新的 CAR..CD8.CD28 使我们能够清楚地评估同一患者内每个 T 细胞亚群的扩增/持久性。我们将知道这种新型CAR是否可以替代目前用于成熟B细胞恶性肿瘤的CD19特异性CAR，我们还将按顺序开发针对l链的特异性CAR。实施覆盖绝大多数 B 细胞成熟恶性肿瘤患者的策略。