Cancer Therapy: Preclinical Targeting Human B-cell Malignancies through Ig Light Chain–Specific Cytotoxic T Lymphocytes

Purpose: The variable regions of Ig (idiotype, Id) expressed by malignant B cells can be used as tumorspecific antigens that induce humoral and cellular immunity. However, epitopes derived from Id that stimulate human CD8þ T-cell immunity are incompletely characterized. Experimental Design: The clonal Ig VL of human myeloma cell line U266 and five primary B-cell tumors were sequenced, and peptides corresponding to the Ig VL region were tested for their ability to stimulate CTLs from 10HLA-A*0201–positive normal donors. The CTLs thus generated were tested against peptide-pulsed T2 cells and autologous tumor cells. Results: Fourteen peptides derived from Ig light chain (VL) of U266 and primary B-cell tumors were used to generate 68 CTLs lines that specifically produced IFN-g when cocultured with peptide-pulsed T2 cells. These CTLs lysed peptide-pulsed T2 cell as well as U266 or autologous tumor targets in an HLA class I–dependent manner. Sequence analysis revealed shared VL T-cell epitopes in U266 and primary B-cell tumors, not previously reported within Ig heavy chain (VH) sequences. Conclusion: This study thus identifies novel immunogenic CTLs epitopes from Id VL, suggests that they are naturally presented on the surface of B-cell malignancies, and supports their inclusion in nextgeneration Id vaccines. The ability to prime T cells derived from normal HLA-matched donors, rather than patients, may also have direct application to current strategies, designed to generate allogeneic tumorspecific T cells for adoptive transfer. Clin Cancer Res; 17(18); 5945–52. 2011 AACR.