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Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma

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  • Mehmet Kemal Samur

    (Dana Farber Cancer Institute
    Harvard T. H. Chan School of Public Health Boston
    Dana Farber Cancer Institute, Harvard Medical School)

  • Mariateresa Fulciniti

    (Dana Farber Cancer Institute, Harvard Medical School)

  • Anil Aktas Samur

    (Dana Farber Cancer Institute
    Harvard T. H. Chan School of Public Health Boston)

  • Abdul Hamid Bazarbachi

    (Dana Farber Cancer Institute, Harvard Medical School
    Albert Einstein College of Medicine)

  • Yu-Tzu Tai

    (Dana Farber Cancer Institute, Harvard Medical School)

  • Rao Prabhala

    (Dana Farber Cancer Institute, Harvard Medical School
    VA Boston Healthcare System)

  • Alejandro Alonso

    (Dana Farber Cancer Institute, Harvard Medical School)

  • Adam S. Sperling

    (Dana Farber Cancer Institute, Harvard Medical School)

  • Timothy Campbell

    (Bristol-Myers Squibb)

  • Fabio Petrocca

    (Bluebird Bio)

  • Kristen Hege

    (Bristol-Myers Squibb)

  • Shari Kaiser

    (Bristol-Myers Squibb)

  • Hervé Avet Loiseau

    (University Cancer Center of Toulouse Institut National de la Santé)

  • Kenneth C. Anderson

    (Dana Farber Cancer Institute, Harvard Medical School)

  • Nikhil C. Munshi

    (Dana Farber Cancer Institute, Harvard Medical School
    VA Boston Healthcare System)

Abstract

BCMA targeting chimeric antigen receptor (CAR) T cell therapy has shown deep and durable responses in multiple myeloma. However, relapse following therapy is frequently observed, and mechanisms of resistance remain ill-defined. Here, we perform single cell genomic characterization of longitudinal samples from a patient who relapsed after initial CAR T cell treatment with lack of response to retreatment. We report selection, following initial CAR T cell infusion, of a clone with biallelic loss of BCMA acquired by deletion of one allele and a mutation that creates an early stop codon on the second allele. This loss leads to lack of CAR T cell proliferation following the second infusion and is reflected by lack of soluble BCMA in patient serum. Our analysis suggests the need for careful detection of BCMA gene alterations in multiple myeloma cells from relapse following CAR T cell therapy.

Suggested Citation

  • Mehmet Kemal Samur & Mariateresa Fulciniti & Anil Aktas Samur & Abdul Hamid Bazarbachi & Yu-Tzu Tai & Rao Prabhala & Alejandro Alonso & Adam S. Sperling & Timothy Campbell & Fabio Petrocca & Kristen H, 2021. "Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma," Nature Communications, Nature, vol. 12(1), pages 1-7, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21177-5
    DOI: 10.1038/s41467-021-21177-5
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    Cited by:

    1. Fumou Sun & Yan Cheng & Visanu Wanchai & Wancheng Guo & David Mery & Hongwei Xu & Dongzheng Gai & Eric Siegel & Clyde Bailey & Cody Ashby & Samer Al Hadidi & Carolina Schinke & Sharmilan Thanendraraja, 2024. "Bispecific BCMA/CD24 CAR-T cells control multiple myeloma growth," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Frank Cichocki & Ryan Bjordahl & Jodie P. Goodridge & Sajid Mahmood & Svetlana Gaidarova & Ramzey Abujarour & Zachary B. Davis & Aimee Merino & Katie Tuininga & Hongbo Wang & Akhilesh Kumar & Brian Gr, 2022. "Quadruple gene-engineered natural killer cells enable multi-antigen targeting for durable antitumor activity against multiple myeloma," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Dongpeng Jiang & Haiwen Huang & Huimin Qin & Koukou Tang & Xiangru Shi & Tingting Zhu & Yuqing Gao & Ying Zhang & Xiaopeng Tian & Jianhong Fu & Weiwei Qu & Weilan Cai & Yang Xu & Depei Wu & Jianhong C, 2023. "Chimeric antigen receptor T cells targeting FcRH5 provide robust tumour-specific responses in murine xenograft models of multiple myeloma," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Maximilian Merz & Almuth Maria Anni Merz & Jie Wang & Lei Wei & Qiang Hu & Nicholas Hutson & Cherie Rondeau & Kimberly Celotto & Ahmed Belal & Ronald Alberico & AnneMarie W. Block & Hemn Mohammadpour , 2022. "Deciphering spatial genomic heterogeneity at a single cell resolution in multiple myeloma," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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