Induction of T Cell Immunity Using a Multipeptide Cocktail Containing XBP1, CD138 and CS1 Peptides in Smoldering Multiple Myeloma

Abstract 5039

Smoldering multiple myeloma (SMM) patients are at high risk for progression to active multiple myeloma (MM), making them candidates for novel immunotherapeutic strategies to prevent or delay disease progression. Among potential strategies, the ability to induce cytotoxic T lymphocytes (CTL) against multiple immunogenic epitopes provides a framework for overcoming major therapeutic challenges including heterogeneity of tumor associated antigen expression, frequent mutations of specific antigens, and variability of the human T-cell repertoire among individuals. In this study, we provide evidence that a cocktail of four immunogenic HLA-A2 specific peptides, heteroclitic XBP1 US_184–192, heteroclitic XBP1 SP_367–375, native CD138_260–268 and native CS1_239–247, induces specific CTL response in T cells from SMM patients. Following repeated rounds of multipeptide stimulation, we induced development of CD8⁺ CTL from SMM patients' T cells. The multipeptide specific-CTL demonstrated polyfunctional immune activities including high levels of IFN-g production, cell proliferation and cytotoxicity against MM cells in an HLA-A2 restricted manner. The multipeptide-specific CTL displayed increased memory (CD45RO⁺) and activated (CD69⁺) CD3⁺CD8⁺ T lymphocytes, suggesting that a multipeptide vaccine has the potential to induce durable memory by generating specific memory CTL with characteristics of effector T cells against MM cells. In addition, the multipeptide-specific CTL demonstrated peptide-specific responses to each of the relevant epitopes including heteroclitic XBP1 US_184–192, heteroclitic XBP1 SP_367–375, native CD138_260–268 and native CS1_239–247, but not against an irrelevant HLA-A2-specific MAGE-3_271–279 peptide in various functional assays including antigen-triggered CD137 (4-1BB) expression, IFN-g production and CD107a up-regulation. Therefore, these results suggest the potential of inducing a broad spectrum of immune responses against selected XBP1 unspliced, XBP1 spliced, CD138 and CS1 target antigens in SMM using multipeptide vaccination. In conclusion, these studies provide the framework for clinical trials of vaccination in patients with SMM to delay or prevent progression to active MM.