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12 January 2018

Researchers in Japan have reported a potential new target for multiple myeloma (MM) immunotherapy.

Chimeric antigen receptors (CAR) are produced by combining the gene for an antibody that recognises a tumour antigen with the gene for a receptor on the surface of T cells. 

Writing in Nature Medicine, lead author Naoki Hosen emphasised that although CAR T-cell (CAR-T) therapy is one of the most successful therapeutic strategies for cancer, targeting appropriate antigens is very difficult because there is huge diversity within the proteins and between individual tumours.

The group investigated cancer-specific antigens specifically formed by protein modification during or after synthesis, such as glycosylation or conformational changes, an approach largely neglected in previous analyses.

The team screened more than 10,000 anti-MM monoclonal antibody (MAb) clones and identified MMG49 as an MM-specific mAb, specifically recognising a subset of integrin ß7 molecules, cell-surface receptors that facilitate cell-extracellular matrix adhesion.

MMG49 reacted to MM cells, but not other bone marrow cell types in MM patient samples, which led them to create a CAR that incorporates a fragment derived from MMG49.

The resulting MMG49 CAR-T was found to have anti-MM effects without damaging normal blood cells.

 “Our results also demonstrate that the active conformer of integrin beta 7 can serve as an immunotherapeutic target against MM, even though the expression of the protein itself is not specific to MM,” said co-author Yukiko Matsunaga.

“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.”

Source: Hosen N, Matsunaga Y, Hasegawa K et al. The activated conformation of integrin ß7 is a novel multiple myeloma–specific target for CAR T cell therapy. Nature Medicine 7 November 2017; doi:10.1038/nm.4431

Link: https://www.nature.com/articles/nm.4431

 

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