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- Title
Broadly applicable TCR-based therapy for multiple myeloma targeting the immunoglobulin J chain.
- Authors
Meeuwsen, Miranda H.; Wouters, Anne K.; Wachsmann, Tassilo L. A.; Hagedoorn, Renate S.; Kester, Michel G. D.; Remst, Dennis F. G.; van der Steen, Dirk M.; de Ru, Arnoud H.; van Hees, Els P.; Kremer, Martijn; Griffioen, Marieke; van Veelen, Peter A.; Falkenburg, J. H. Frederik; Heemskerk, Mirjam H. M.
- 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.
- Subjects
MULTIPLE myeloma; HISTOCOMPATIBILITY antigens; T cells; GENETIC vectors; MOLECULAR cloning; EPITOPES
- Publication
Journal of Hematology & Oncology, 2023, Vol 16, Issue 1, p1
- ISSN
1756-8722
- Publication type
Article
- DOI
10.1186/s13045-023-01408-6