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

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 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.