Abstract
The B-cell maturation antigen (BCMA) is currently being evaluated as promising tumor-associated surface antigen for T-cell-based immunotherapy approaches, such as CAR T cells and bispecific antibodies, in multiple myeloma (MM). Cytotoxic T cells bearing BCMA-specific T-cell receptors might further allow targeting HLA-presented antigens derived from the intracellular domain of BCMA. By analyzing a mass spectrometry-acquired immunopeptidome dataset of primary MM samples and MM cell lines for BCMA-derived HLA ligands, we identified the naturally presented HLA-B*18-restricted ligand P(BCMA)B*18. Additionally, P(BCMA)B*18 was identified on primary CLL samples, thereby expanding the range for possible applications. P(BCMA)B*18 induced multifunctional BCMA-specific cells de novo from naïve CD8+ T cells of healthy volunteers. These T cells exhibited antigen-specific lysis of autologous peptide-loaded cells. Even in the immunosuppressive context of MM, we detected spontaneous memory T-cell responses against P(BCMA)B*18 in patients. By applying CTLA-4 and PD-1 inhibition in vitro we induced multifunctional P(BCMA)B*18-specific CD8+ T cells in MM patients lacking preexisting BCMA-directed immune responses. Finally, we could show antigen-specific lysis of autologous peptide-loaded target cells and even MM.1S cells naturally presenting P(BCMA)B*18 using patient-derived P(BCMA)B*18-specific T cells. Hence, this BCMA-derived T-cell epitope represents a promising target for T-cell-based immunotherapy and monitoring following immunotherapy in B-cell malignancy patients.
Highlights
T-cell-based immunotherapies for multiple myeloma (MM) are on the advance, further improving the outcome of this still incurable disease
We identified two B-cell maturation antigen (BCMA)-derived human leukocyte antigen (HLA) class I-restricted ligands, both derived from its intracellular domain (Fig. 1a)
P(BCMA)B*18 could be identified in the immunopeptidome of 2/3 (67%) primary HLA-B*18+ chronic lymphocytic leukemia (CLL) samples[21]
Summary
T-cell-based immunotherapies for multiple myeloma (MM) are on the advance, further improving the outcome of this still incurable disease. BCMA-targeting CAR T cells showed promising results in heavily pretreated and refractory MM patients with an overall response rate of 81%7 Despite these encouraging results, potential toxicities and immense costs should be taken into account, in particular prior to application of such immunotherapy approaches in elderly and comorbid MM patients or larger patient cohorts at an earlier disease setting[14,15]. We characterized the naturally presented immunopeptidome of MM using a mass spectrometry (MS)-based approach and identified several novel MM-associated antigens[19] We evaluated this dataset for the presence of BCMA-derived peptides to provide a proof of concept for the feasibility to identify and target naturally presented Tcell epitopes from intracellular domains of highly promising tumor surface antigens
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