By integrating genomic and in vitro functional analysis, this study uncovers tumor-intrinsic mechanisms of resistance to immunotherapies that target B cell maturation antigen (BCMA) or the orphan G-protein-coupled-receptor GPRC5D in multiple myeloma (MM), highlighting a pivotal role for mutations in the genes encoding BCMA and GPRC5D in driving clinical relapse. These insights provide crucial guidance for the selection of therapeutic strategies and the development of next-generation targeted immunotherapies in MM.
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References
Zhou, X. et al. BCMA loss in the epoch of novel immunotherapy for multiple myeloma: from biology to clinical practice. Haematologica 108, 958–968 (2023). This review article summarizes the existing data on BCMA loss after immunotherapy in MM.
Leblay, N. et al. Cite-Seq profiling of T cells in multiple myeloma patients undergoing BCMA targeting CAR T or BiTES immunotherapy. Blood 136, 11–12 (2020). This conference abstract describes the emergence of TNFRSF17 biallelic deletion from pre-existing subclones with monoallelic TNFRSF17 deletion during progression after anti-BCMA CAR T cell therapy.
Da Vià, M. C. et al. Homozygous BCMA gene deletion in response to anti-BCMA CAR T cells in a patient with multiple myeloma. Nat. Med. 27, 616–619 (2021). This study describes the selection of clones with homozygous TNFRSF17 deletion as an escape mechanism after anti-BCMA CAR T cell therapy and reports heterozygous TNFRSF17 loss or monosomy 16 as a potential risk factor for BCMA loss after targeted immunotherapy.
Samur, M. K. et al. Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma. Nat. Commun. 12, 868 (2021). This research article associates BCMA antigen loss through TNFRSF17 monoallelic deletion and a truncating mutation after anti-BCMA CAR T cell therapy with lack of response to subsequent infusion of CAR T cells.
Truger, M. S. et al. Single- and double-hit events in genes encoding immune targets before and after T cell-engaging antibody therapy in MM. Blood Adv. 5, 3794–3798 (2021). This research article reports that homozygous TNFRSF17 loss after anti-BCMA TCE therapy precluded a response to subsequent anti-BCMA therapies.
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This is a summary of: Lee, H. et al. Mechanisms of antigen escape from BCMA- or GPRC5D-targeted immunotherapies in multiple myeloma. Nat. Med. https://doi.org/10.1038/s41591-023-02491-5 (2023).
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Decoding antigen escape and multiple myeloma relapse after targeted immunotherapy. Nat Med 29, 2185–2186 (2023). https://doi.org/10.1038/s41591-023-02515-0
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DOI: https://doi.org/10.1038/s41591-023-02515-0
