Anti-CD19 Chimeric Antigen Receptor-Modified T Cells for Multiple Myeloma

Abstract

Multiple myeloma is a disease formed by malignant plasma cells that accumulate in the bone marrow. The lifetime risk of multiple myeloma in the U.S. is 1/140, making it the second most common hematologic malignancy and it was expected that 22,350 new cases to be diagnosed in the US in 2013 [1]. In the past decade, we have witnessed dramatic changes in the treatment of multiple myeloma. Proteasome inhibitors such as bortezomib and carfilzomib target the ubiquitin pathway, resulting in cytotoxic injury due to disruption of protein degradation in myeloma cells. When compared with melphalan–prednisone–lenalidomide (MPR), combine therapy with high-dose melphalan and stem-cell transplantation significantly prolonged progression-free survival among patients with multiple myeloma who were in the age group of 65 years or younger [2]. Discovery of anti-tumor efficacy of the graft vs. myeloma response, such as CAR T cell therapy seems likely to herald the beginning of a revolution in the treatment of multiple myeloma. Several observations have fostered optimism that more specific immunotherapeutic approach such as chimeric antigen receptors (CARs) modified autologous T cells might exhibit more potent anti-myeloma activity with less toxicity. Currently all ongoing CAR studies employ firstgeneration anti-CD19 CAR and a second-generation version, usually with CD28. In pre-clinical studies, anti-myeloma second-generation CARs are developed to target the Lewis Y antigen (Ley), B Cell Maturation Antigen (BCMA), cell surface glycoprotein CS1 and CD38. Ley is overexpressed in many epithelial malignancies. In a recent study, multiple myeloma cell lines were injected into a immunocompromised mice followed by the injection of anti-Ley CAR T cells that significantly exhibited prolonged survival and delayed development of symptomatic plasmacytomas [3]. The National Cancer Institute (NCI) has recently identified BCMA which is expressed on most multiple myeloma cells. Anti-BCMA CAR is a second-generation CD28-based CAR that showed quite favourable efficacy and toxicity profiles against multiple myeloma [4]. CS1 is over-expressed in multiple myeloma cells. The CD28-based anti-CS1 CAR-modified natural killer (NK) cells revealed cytotoxicity against multiple myeloma cell lines and prolonged survival in patients with multiple myeloma [5]. CD38 is a transmembrane glycoprotein and a second-generation 4-1BB-based anti-CD38 CAR was proved to be effective against multiple myeloma cell lines [6]. In a phase I/II study, anti-CD38 antibody daratumumab showed a remarkable efficacy for the treatment of patients with multiple myeloma [7]. The most clinical experience so far has been with anti-CD19 CARs that have been utilized in several phase I trials targeting B cell malignancies. Genetically engineered CARs that couple with an anti-CD19 single chain Fv domain to intracellular T-cell signalling domains of the T-cell receptor transmit cytotoxic T lymphocytes to antigen expressing cells. CAR–mediated T-cell responses can further be enhanced with the addition of a costimulatory domain. CD3 zeta domain has been used in CARmodified T cells that lead to the activation of T-cell signal and it has been referred as a first generation CAR. In recent competitive repopulation studies, CAR designs have been executed based on the addition of a single (second generation) or multiple co-stimulatory domains (third generation) [8]. In preclinical models, it has been found that antitumor activity and in vivo persistence of chimeric antigen receptors significantly increase with the inclusion of CD137 (4-1BB) signalling domain as compared with the inclusion of CD3-zeta chain alone [9]. CTL019 is a chimeric antigen receptor that includes a CD137 (4-1BB) signalling domain and is expressed with the use of lentiviral-vector technology for gene transfer and permanent T cell modification.