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.
We have had success in treating patients with hematological malignancies by using their own immune cells modified with a chimeric molecule that eliminates tumor cells but spare part of the immune B-lymphocytes. In this project we intend test in a Phase I clinical trial the safety, persistence and in vivo functionality of these cells that have ben further modified to persist longer after infusion into the patients.
