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

 描述（由申请方提供）：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）]患者对用嵌合抗原受体（CAR）重定向的T细胞产生应答，嵌合抗原受体（CAR）对CD 20或CD 19抗原具有特异性，并编码共刺激胞内域。然而，靶向这些抗原并不能区分正常和恶性B细胞，因此这种方法在有效时会导致严重的B细胞发育不全。因此，重要的是要确定目标表达的B细胞恶性肿瘤更有选择性。B-NHL和B-CLL细胞表达含有α-或β-轻链的单克隆免疫球蛋白（Ig）。作为原理的证明，我们已经实施了I期临床试验，其中患有复发性/难治性CD 28 + B细胞恶性肿瘤的患者被输注自体T细胞产物，所述自体T细胞产物被工程化以表达靶向人Ig的β-轻链的CAR，并且还含有CD 28共刺激胞内域（CAR.CD28TM.CD28）。这种CAR将靶向正常和恶性的IFN+细胞，但不影响表达IFN-轻链的正常B细胞亚群。该研究目前正在进行中，入组了10例患者。2例患者达到完全缓解，4例患者病情稳定。虽然有希望，但这项研究也显示了一些局限性，如这些细胞的次优体内扩增/持久性。我们发现了CD 8 β茎的特定作用，当其掺入表达CD 28或4-1BB信号传导结构域的汽车中时，显著增强其抗肿瘤作用。我们的中心假设是，在CAR. T中包含CD 8巨噬细胞柄（CAR. T. CD 8 +. CD 28），而不是CD 28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，并促进更高的临床应答率。在所提议的I期研究中，我们将解决CD 8巨噬细胞柄在CAR信号传导中的机制作用，然后进行I期临床研究，其中每个患者将接受两种表达CD 8巨噬细胞柄的T细胞产物。 CD 28或新的CAR.CD28TM.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/持续性。在完成这项首次人体研究后，我们将知道这种新型CAR是否可以取代目前用于成熟B细胞恶性肿瘤的CD 19特异性CAR。我们还将在临床前开发靶向β链的特异性CAR，以实施覆盖绝大多数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.