Broadly applicable TCR-based therapy for multiple myeloma targeting the immunoglobulin J chain

Journal of Hematology & Oncology, vol. 16, pp. 16

Abstract

BACKGROUND: The immunoglobulin J chain (Jchain) is highly expressed in the majority of multiple myeloma (MM), and Jchain-derived peptides presented in HLA molecules may be suitable antigens for T-cell therapy of MM. METHODS: Using immunopeptidomics, we identified Jchain-derived epitopes presented by MM cells, and pHLA tetramer technology was used to isolate Jchain-specific T-cell clones. RESULTS: We identified T cells specific for Jchain peptides presented in HLA-A1, -A24, -A3, and -A11 that recognized and lysed JCHAIN-positive MM cells. TCRs of the most promising T-cell clones were sequenced, cloned into retroviral vectors, and transferred to CD8 T cells. Jchain TCR T cells recognized target cells when JCHAIN and the appropriate HLA restriction alleles were expressed, while JCHAIN or HLA-negative cells, including healthy subsets, were not recognized. Patient-derived JCHAIN-positive MM samples were also lysed by Jchain TCR T cells. In a preclinical in vivo model for established MM, Jchain-A1, -A24, -A3, and -A11 TCR T cells strongly eradicated MM cells, which resulted in 100-fold lower tumor burden in Jchain TCR versus control-treated mice. CONCLUSIONS: We identified TCRs targeting Jchain-derived peptides presented in four common HLA alleles. All four TCRs demonstrated potent preclinical anti-myeloma activity, encouraging further preclinical testing and ultimately clinical development.

Authors 14

1. Miranda H. Meeuwsen Aachen Department of Hematology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Hematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands

2. Anne K. Wouters Aachen Department of Hematology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Hematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands

3. Tassilo L A Wachsmann Aachen Department of Hematology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Hematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands

4. Renate S. Hagedoorn Aachen Department of Hematology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Hematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands

5. Michel G.D. Kester Aachen Department of Hematology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Hematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands

6. Dennis F.G. Remst Aachen Department of Hematology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Hematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands

7. Dirk M. van der Steen Aachen Department of Hematology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Hematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands

8. Arnoud H. de Ru Aachen Center for Proteomics and Metabolomics

   Leiden University Medical Center

   Affiliation as printed

   Center for Proteomics and Metabolomics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands

9. Els P. van Hees Aachen Department of Hematology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Hematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands

10. Martijn Kremer Aachen Department of Hematology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Hematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands

11. Marieke Griffioen Aachen Department of Hematology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Hematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands

12. Peter A. van Veelen Aachen Center for Proteomics and Metabolomics

    Leiden University Medical Center

    Affiliation as printed

    Center for Proteomics and Metabolomics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands

13. J.H. Frederik Falkenburg Aachen Department of Hematology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Hematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands

14. Mirjam H.M. Heemskerk corresponding Aachen Department of Hematology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Hematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. m.h.m.heemskerk@lumc.nl

    Department of Hematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands