# Mechanisms of antigen escape from BCMA- or GPRC5D-targeted immunotherapies in multiple myeloma

Article · 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 and 8 more

- Archive id: doi:10.1038/s41591-023-02491-5
- Published: 2023-08-31
- Venue: Nature medicine
- DOI: https://doi.org/10.1038/s41591-023-02491-5
- PMID: 37653344
- PMCID: PMC10504087
- Citations: 338
- Source URL: https://doi.org/10.1038/s41591-023-02491-5
- PDF: https://europepmc.org/articles/PMC10504087/pdf
- Provenance: europepmc

## 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 reproduced under CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)._

Topics: [Cancer Immunotherapy](https://space-kitty.com/topics/cancer-immunotherapy)

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