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: 9212116
• 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/9212116
• 关键词: Acute Lymphocytic Leukemia; Address; Affect; Antigen Targeting; Autologous; B lymphoid malignancy; B-Cell Lymphomas; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; CD19 Antigens; CD19 gene; CD20 Antigens; CD28 gene; CD8B1 gene; Cell physiology; 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; Light-Chain Immunoglobulins; 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; clinical application; experience; in vivo; lymphoid neoplasm; man; neoplastic cell; novel; phase 1 study; pre-clinical; prevent; public health relevance; response; success; targeted treatment; 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（由应用提供）：B细胞恶性肿瘤患者[非Hodgkin淋巴瘤（B-NHL），B-偶然淋巴细胞性白血病（B-CLL）和急性淋巴细胞白血病（B-all）]用CD20或CD20或CD20蚂蚁的响应T细胞反应T细胞。端植物。但是，靶向这些抗原并不能区分正常的B细胞和恶性B细胞，因此在有效的情况下，这种方法会引起深刻的B细胞性植物。因此，重要的是确定通过B细胞恶性肿瘤更有选择性地表达的靶标。 B-NHL和B-CLL细胞表达包含-或光链的单克隆免疫球蛋白（IGS）。作为原则的证明，我们实施了一项I期临床试验，该试验中传递/难治性+ b-cell恶性肿瘤的患者注入了工程设计的自体T细胞产品，该产品旨在表达针对人类IG的the of the the the the collight of Human Igs的汽车，并包含CD28 COTHIMIMANTORY ENDODONATION ENDODOMATONENDOMANEDOMAIN ENDODOMAIN（CAR.C.CD28.CD28T28T28T28）。该汽车将靶向正常和恶性细胞，但助长表达光链的正常B细胞​​的子集。这项研究目前正在进行中，并招募了10名患者。两名患者达到了完全反应，有4例患者经历了疾病稳定。尽管承诺，这项研究还显示出一些局限性，例如这些细胞的体内膨胀/持续性次优。我们发现了CD8茎的特定作用，当在表达CD28或4-1BB信号传导域中的汽车中掺入时，会大大增强其抗肿瘤作用。我们的中心假设是，将CD8驱动包含在CAR.（CAR..cd8.cd28）中，而不是CD28跨膜结构域和信号域，将增强VIVO中CAR-T细胞的膨胀和持久性，并促进更高的临床反应率。在拟议的第一阶段研究中，我们将解决CD8雄鹿在CAR信号传导中的机械作用，然后进行I期临床研究，其中每个患者将收到两个表达表达的T细胞产品 当前的CAR..CD28TM.CD28或新车。在完成这项第一名研究的完成后，我们将知道这款新型汽车是否可以代替当前用于成熟B细胞恶性肿瘤的CD19特异性汽车。我们还将临床上开发针对-链的特定汽车，以实施涵盖绝大多数B细胞成熟Malignancys患者的策略。