Article ; Online: Broadly applicable TCR-based therapy for multiple myeloma targeting the immunoglobulin J chain.
Journal of hematology & oncology
2023 Volume 16, Issue 1, Page(s) 16
Abstract: Background: The immunoglobulin J chain (Jchain) is highly expressed in the majority ...
| 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. |
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| MeSH term(s) | Animals ; Mice ; Immunoglobulin J-Chains ; Multiple Myeloma/therapy ; Receptors, Antigen, T-Cell/genetics ; Alleles ; CD8-Positive T-Lymphocytes |
| Chemical Substances | Immunoglobulin J-Chains ; Receptors, Antigen, T-Cell |
| Language | English |
| Publishing date | 2023-02-27 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2429631-4 |
| ISSN | 1756-8722 ; 1756-8722 |
| ISSN (online) | 1756-8722 |
| ISSN | 1756-8722 |
| DOI | 10.1186/s13045-023-01408-6 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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