Mechanisms by which some multiple myelomas become resistant to certain T-cell therapies have been uncovered by an international team of scientists.
Multiple myeloma can be treated with CAR-T cells and bispecific T cell engagers (TCE), directed against one or both of two targets: BCMA, and GPRC5D. However, mutations in the myeloma cells can render these immunotherapies ineffective – allowing previously treatable cancers to adapt, escape treatment, and relapse.
The international team of researchers have led what is believed to be the first genomic study of intrinsic mechanisms of cancer cells that permit antigen escape in patients undergoing immunotherapy. The findings are published in Nature Medicine.
Senior author Dr Francesco Mauro said: “Recognising these mutations and gaining a clearer understanding of the resistance mechanisms to these potent immunotherapies is pivotal.
“This knowledge plays a crucial role in devising tailored strategies and making informed choices regarding the selection of products and targets for individual patients.”
The study involved 30 patients, and the researchers focused on changes that occurred in two potential targets on plasma cells: B cell maturation antigen (BCMA) and G-protein coupled receptor family C group 5 member D (GPRC5D).
The team identified distinct and novel mutations in myeloma cells that are responsible for resistance to anti-BCMA and anti-GPRC5D immunotherapies.
One group of mutations they found affected the extracellular domain of BCMA. This impeded the binding of the immunotherapies, without exerting any influence on the protein’s expression or downstream signalling pathways.
This revealed the proportion of patients with myeloma who experience relapse due to antigen escape is more extensive than initially anticipated.
The authors say identifying these mutational events underscores the need to screen patients for these variants.
“Detailed characterisation of these binding interactions will permit the rational design of next-generation T-cell redirecting agents and inform the optimal sequencing and combination of these immune-therapeutic approaches,” they add.
Lee H, Ahn S, Maity R, Leblay N, Ziccheddu B, Truger M, Chojnacka M, Cirrincione A, Durante M, Tilmont R, Barakat E, Poorebrahim M, Sinha S, McIntyre J, M Y Chan A, Wilson H, Kyman S, Krishnan A, Landgren O, Walter W, Meggendorfer M, Haferlach C, Haferlach T, Einsele H, Kortüm MK, Knop S, Alberge JB, Rosenwald A, Keats JJ, Rasche L, Maura F, Neri P, Bahlis NJ. (2023) “Tumor Intrinsic Mechanisms of Antigen Escape to Anti-BCMA and Anti-GPRC5D Targeted Immunotherapies in Multiple Myeloma.” Nature Medicine, doi: 10.1038/s41591-023-02491-5
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