{"id":"doi:10.1038/s41591-023-02491-5","kind":"article","title":"Mechanisms of antigen escape from BCMA- or GPRC5D-targeted immunotherapies in multiple myeloma","authors":["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"],"author_count":33,"year":2023,"published":"2023-08-31","venue":"Nature medicine","cited_by":338,"doi":"10.1038/s41591-023-02491-5","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41591-023-02491-5","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41591-023-02491-5","updated":null,"pmid":"37653344","pmcid":"PMC10504087","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC10504087/pdf","abstract":"B cell maturation antigen (BCMA) target loss is considered to be a rare event that mediates multiple myeloma (MM) resistance to anti-BCMA chimeric antigen receptor T cell (CAR T) or bispecific T cell engager (TCE) therapies. Emerging data report that downregulation of G-protein-coupled receptor family C group 5 member D (GPRC5D) protein often occurs at relapse after anti-GPRC5D CAR T therapy. To examine the tumor-intrinsic factors that promote MM antigen escape, we performed combined bulk and single-cell whole-genome sequencing and copy number variation analysis of 30 patients treated with anti-BCMA and/or anti-GPRC5D CAR T/TCE therapy. In two cases, MM relapse post-TCE/CAR T therapy was driven by BCMA-negative clones harboring focal biallelic deletions at the TNFRSF17 locus at relapse or by selective expansion of pre-existing subclones with biallelic TNFRSF17 loss. In another five cases of relapse, newly detected, nontruncating, missense mutations or in-frame deletions in the extracellular domain of BCMA negated the efficacies of anti-BCMA TCE therapies, despite detectable surface BCMA protein expression. In the present study, we also report four cases of MM relapse with biallelic mutations of GPRC5D after anti-GPRC5D TCE therapy, including two cases with convergent evolution where multiple subclones lost GPRC5D through somatic events. Immunoselection of BCMA- or GPRC5D-negative or mutant clones is an important tumor-intrinsic driver of relapse post-targeted therapies. Mutational events on BCMA confer distinct sensitivities toward different anti-BCMA therapies, underscoring the importance of considering the tumor antigen landscape for optimal design and selection of targeted immunotherapies in MM.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Mechanisms of antigen escape from BCMA- or GPRC5D-targeted immunotherapies in multiple myeloma\" by Lee H, Ahn S, Maity R et al., https://doi.org/10.1038/s41591-023-02491-5, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"cancer-immunotherapy","name":"Cancer Immunotherapy","domain_slug":"medicine"}],"cited_in_dossiers":[]}