New Strategy For Multiple Myeloma Immunotherapy

Source: Osaka University

Summary: Researchers have uncovered a new strategy for treating multiple myeloma in which they showed an active conformer of a transmembrane protein can act as a therapeutic target.

In recent years, treating cancer with the help of monoclonal antibodies (mAb – antibodies made by clonal cells which are derived from a unique parent cell) has been one of the most successful therapeutic strategies for solid tumors and even blood cancers. One of the emerging technologies in mAb-based treatment is CAR-T (CAR stands for Chimeric Antigen Receptor and T for T-cells, a type of white blood cells). CARs are produced by combining – a gene for an antibody that recognizes tumor antigen and a gene for a receptor that resides on the surface of T cells. By inserting this new combo gene into a T-cell, it targets tumor precisely. Researchers from Osaka University have uncovered a new strategy for treating multiple myeloma (MM) in which they showed an active conformer of a transmembrane protein, integrin β7 can act as a therapeutic target. The study findings were published in the journal Nature Medicine.

Multiple Myeloma Treatment

MMG49 CAR T cells target the activated conformation of integrin b7 expressed on MM cells. Credit: Osaka University

Cancer-specific antigens which are formed by the protein modifications (glycosylation or conformational changes) during or after synthesis might have been missed in previous studies. In this study, the research team screened more than 10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb which can specifically recognize a subset of integrin Beta 7. In MM patient samples, MMG49 reacted only to MM cells but not other types of bone marrow cells. This led the researchers to design a CAR which can incorporate a fragment derived from MMG49. The resulting new MMG49 CAR T was found to have anti-MM effects without damaging normal blood cells.

Chimeric Antigen Receptor and T-cells Therapy

Outline of CAR T cell therapy. Credit: Osaka University

Study coauthor, Yukiko Matsunaga said, “Our results also demonstrate that the active conformer of integrin β7 can serve as an immunotherapeutic target against MM, even though the expression of the protein itself is not specific to MM”, “Therefore it’s highly plausible that there are other cancer immunotherapeutic targets that have yet to be identified in many cell-surface proteins that undergo conformational changes, even if the expression of the proteins themselves is not cancer-specific.”

Anti-myeloma activity

Anti-myeloma activity of MMG49 CAR T cells. Credit: Osaka University

More Information: Naoki Hosen et al, “The activated conformation of integrin β7 is a novel multiple myeloma–specific target for CAR T cell therapy”, Nature Medicine (2017). DOI: 10.1038/nm.4431

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