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

 描述(申请人提供)：B细胞恶性肿瘤患者[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)]对T细胞反应，重定向的T细胞由针对CD20或CD19抗原的嵌合抗原受体(CARS)重定向，并编码共刺激内域。然而，以这些抗原为靶点并不区分正常和恶性B细胞，因此这种方法在有效时会导致严重的B细胞再生障碍性疾病。因此，识别B细胞恶性肿瘤更有选择性地表达的靶点是重要的。B-非霍奇金淋巴瘤和B-CLL细胞表达含有-或-轻链的单抗免疫球蛋白。作为原则的证明，我们已经实施了一项I期临床试验，在该试验中，复发/难治性+B细胞恶性肿瘤的患者被注入自体T细胞产品，该产品旨在表达针对人免疫球蛋白-LIGH的CAR，并包含CD28共刺激内域(CAR..CD28TM.CD28)。这种CAR将针对正常和恶性的+细胞，但不包括表达轻链的正常B细胞亚群。这项研究目前正在进行中，它招募了10名患者。2例完全缓解，4例病情稳定。尽管前景看好，但这项研究也显示了一些局限性，如这些细胞在体内的扩增/持久性不佳。我们发现，CD8CD28的茎有一个特殊的作用，当它被整合到表达CD28或4-1BB信号域的汽车中时，显著增强了它们的抗肿瘤作用。我们的中心假设是，在CAR.(CAR...CD8.CD28)而不是CD28跨膜区和信号域中加入CD8CD8茎，将会增强CAR-T细胞在体内的扩增和持久性，并促进更高的临床应答率。在拟议的第一阶段研究中，我们将解决CD8CD8茎在CAR信号中的机制作用，然后进行第一阶段临床研究，在该阶段中，每个患者将获得两种T细胞产品，表达 当前CAR。.CD28TM.CD28或新CAR。.CD8.CD28使我们能够清楚地评估同一患者体内每个T细胞亚群的扩展/持久性。在完成这项首个人的研究后，我们将知道这种新型汽车是否可以取代目前用于治疗成熟B细胞恶性肿瘤的CD19特异性汽车。我们还将在临床前开发针对链的特定CAR，以便实施覆盖绝大多数B细胞成熟恶性肿瘤患者的策略。

 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.