Biomaterial Database

An APRIL-based chimeric antigen receptor for dual targeting of BCMA and TACI in multiple myeloma. 2018

Lydia Lee, and Benjamin Draper, and Neil Chaplin, and Brian Philip, and Melody Chin, and Daria Galas-Filipowicz, and Shimobi Onuoha, and Simon Thomas, and Vania Baldan, and Reyisa Bughda, and Paul Maciocia, and Eva Kokalaki, and Margarida P Neves, and Dominic Patel, and Manuel Rodriguez-Justo, and James Francis, and Kwee Yong, and Martin Pule

Department of Haematology, University College London (UCL) Cancer Institute, London, United Kingdom.

B-cell maturation antigen (BCMA) is a promising therapeutic target for multiple myeloma (MM), but expression is variable, and early reports of BCMA targeting chimeric antigen receptors (CARs) suggest antigen downregulation at relapse. Dual-antigen targeting increases targetable tumor antigens and reduces the risk of antigen-negative disease escape. "A proliferation-inducing ligand" (APRIL) is a natural high-affinity ligand for BCMA and transmembrane activator and calcium-modulator and cyclophilin ligand (TACI). We quantified surface tumor expression of BCMA and TACI on primary MM cells (n = 50). All cases tested expressed BCMA, and 39 (78%) of them also expressed TACI. We engineered a third-generation APRIL-based CAR (ACAR), which killed targets expressing either BCMA or TACI (P < .01 and P < .05, respectively, cf. control, effector-to-target [E:T] ratio 16:1). We confirmed cytolysis at antigen levels similar to those on primary MM, at low E:T ratios (56.2% ± 3.9% killing of MM.1s at 48 h, E:T ratio 1:32; P < .01) and of primary MM cells (72.9% ± 12.2% killing at 3 days, E:T ratio 1:1; P < .05, n = 5). Demonstrating tumor control in the absence of BCMA, we maintained cytolysis of primary tumor expressing both BCMA and TACI in the presence of a BCMA-targeting antibody. Furthermore, using an intramedullary myeloma model, ACAR T cells caused regression of an established tumor within 2 days. Finally, in an in vivo model of tumor escape, there was complete ACAR-mediated tumor clearance of BCMA+TACI- and BCMA-TACI+ cells, and a single-chain variable fragment CAR targeting BCMA alone resulted in outgrowth of a BCMA-negative tumor. These results support the clinical potential of this approach.

UI	MeSH Term	Description	Entries
D008024	Ligands	A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed)	Ligand
D009101	Multiple Myeloma	A malignancy of mature PLASMA CELLS engaging in monoclonal immunoglobulin production. It is characterized by hyperglobulinemia, excess Bence-Jones proteins (free monoclonal IMMUNOGLOBULIN LIGHT CHAINS) in the urine, skeletal destruction, bone pain, and fractures. Other features include ANEMIA; HYPERCALCEMIA; and RENAL INSUFFICIENCY.	Myeloma, Plasma-Cell,Kahler Disease,Myeloma, Multiple,Myeloma-Multiple,Myelomatosis,Plasma Cell Myeloma,Cell Myeloma, Plasma,Cell Myelomas, Plasma,Disease, Kahler,Multiple Myelomas,Myeloma Multiple,Myeloma, Plasma Cell,Myeloma-Multiples,Myelomas, Multiple,Myelomas, Plasma Cell,Myelomas, Plasma-Cell,Myelomatoses,Plasma Cell Myelomas,Plasma-Cell Myeloma,Plasma-Cell Myelomas
D003602	Cytotoxicity, Immunologic	The phenomenon of target cell destruction by immunologically active effector cells. It may be brought about directly by sensitized T-lymphocytes or by lymphoid or myeloid "killer" cells, or it may be mediated by cytotoxic antibody, cytotoxic factor released by lymphoid cells, or complement.	Tumoricidal Activity, Immunologic,Immunologic Cytotoxicity,Immunologic Tumoricidal Activities,Immunologic Tumoricidal Activity,Tumoricidal Activities, Immunologic
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000074322	Antineoplastic Agents, Immunological	Antineoplastic agents containing immunological agents (e.g. MAbs). These pharmacologic preparations inhibit or prevent the proliferation of NEOPLASMS.	Antineoplastic MAbs,Antineoplastics, Monoclonal Antibodies,Antineoplastics, Monoclonal Antibody,MAbs, Antineoplastic,Monoclonal Antibodies, Antineoplastic,Antibodies Antineoplastics, Monoclonal,Antineoplastic Monoclonal Antibodies,Immunological Antineoplastic Agents,Monoclonal Antibodies Antineoplastics,Monoclonal Antibody Antineoplastics
D000076962	Receptors, Chimeric Antigen	Synthetic cellular receptors that reprogram T-LYMPHOCYTES to selectively bind antigens.	Chimeric Antigen Receptor,Chimeric T-Cell Receptor,Artificial T-Cell Receptors,Chimeric Antigen Receptors,Chimeric Immunoreceptors,Chimeric T-Cell Receptors,Antigen Receptor, Chimeric,Antigen Receptors, Chimeric,Artificial T Cell Receptors,Chimeric T Cell Receptor,Chimeric T Cell Receptors,Immunoreceptors, Chimeric,Receptor, Chimeric Antigen,Receptor, Chimeric T-Cell,Receptors, Artificial T-Cell,Receptors, Chimeric T-Cell,T-Cell Receptor, Chimeric,T-Cell Receptors, Artificial,T-Cell Receptors, Chimeric
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D045744	Cell Line, Tumor	A cell line derived from cultured tumor cells.	Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines
D051379	Mice	The common name for the genus Mus.	Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D053300	Tumor Necrosis Factor Ligand Superfamily Member 13	A member of tumor necrosis factor superfamily found on MACROPHAGES; DENDRITIC CELLS and T-LYMPHOCYTES. It occurs as transmembrane protein that can be cleaved to release a secreted form that specifically binds to TRANSMEMBRANE ACTIVATOR AND CAML INTERACTOR PROTEIN; and B CELL MATURATION ANTIGEN.	A Proliferation Inducing Ligand Protein,APRIL Protein,TALL-2 Protein,TNF- and APOL-Related Leukocyte Expressed Ligand 2 Protein,TALL 2 Protein,TNF and APOL Related Leukocyte Expressed Ligand 2 Protein