Selective targeting of multiple myeloma by B cell maturation antigen (BCMA)-specific central memory CD8+ cytotoxic T lymphocytes: immunotherapeutic application in vaccination and adoptive immunotherapy

Abstract

To expand the breadth and extent of current multiple myeloma (MM)-specific immunotherapy, we have identified various antigens on CD138+ tumor cells from newly diagnosed MM patients (n=616) and confirmed B-cell Maturation Antigen (BCMA) as a key myeloma-associated antigen. The aim of this study is to target the BCMA, which promotes MM cell growth and survival, by generating BCMA-specific memory CD8+ CTL that mediate effective and long-lasting immunity against MM. Here we report the identification of novel engineered peptides specific to BCMA, BCMA72–80 (YLMFLLRKI) and BCMA54–62 (YILWTCLGL), which display improved affinity/stability to HLA-A2 compared to their native peptides and induce highly functional BCMA-specific CTL with increased activation (CD38, CD69) and co-stimulatory (CD40L, OX40, GITR) molecule expression. Importantly, the heteroclitic BCMA72–80 specific CTL demonstrated poly-functional Th1-specific immune activities [IFN-γ/IL-2/TNF-α production, proliferation, cytotoxicity] against MM, which were correlated with expansion of Tetramer+ and memory CD8+ CTL. Additionally, heteroclitic BCMA72–80 specific CTL treated with anti-OX40 (immune agonist) or anti-LAG-3 (checkpoint inhibitor) display increased immune function, mainly by central memory CTL. These results provide the framework for clinical application of heteroclitic BCMA72–80 peptide, alone and in combination with anti-LAG3 and/or anti-OX40 therapy, in vaccination and/or adoptive immunotherapeutic strategies to generate long-lasting anti-tumor immunity in patients with MM or other BCMA expressing tumors.

Mass spectrometry-based identification of a B-cell maturation antigen-derived T-cell epitope for antigen-specific immunotherapy of multiple myeloma

“…We identified P(BCMA) B*18 as a highly immunogenic naturally presented epitope capable of inducing potent and multifunctional cytotoxic T-cell responses. This is in line with recent data reporting on the high immunogenicity of computationally predicted HLA*02-restricted T-cell epitopes derived from the extracellular surface domain of BCMA 32,33 . Our mass spectrometric approach further allowed us to validate P(BCMA) B*18 additionally as a target for CLL, for which plasma BCMA-levels were described as a prognostic factor 34 .…”

BCMA peptide-engineered nanoparticles enhance induction and function of antigen-specific CD8+ cytotoxic T lymphocytes against multiple myeloma: clinical applications

“…We recently identified a novel immunogenic heteroclitic BCMA 72-80 [YLMFLLRKI] peptide derived from human BCMA protein and reported its potential therapeutic application as a vaccine and adoptive T cell therapy. 17 The engineered heteroclitic BCMA 72-80 [YLMFLLRKI] peptide has a strong HLA-A2 binding affinity and stability with improved immunogenicity from its native BCMA 72-80 [VLMFLLRKI] peptide and induces robust BCMA-specific memory CD8 + CTL responses against MM cells. In this study, we have developed a strategy to further enhance BCMA-specific CTL generation and their antitumor activities, in order to achieve clinically significant responses.…”

Melflufen—A Novel Agent in the Treatment of Relapsed/Refractory Multiple Myeloma

“…Therefore, we are continuously looking for novel mechanisms of action that target fundamentally different aspects of tumor biology. In addition to B-cell maturation antigen (BCMA)-targeting strategies, including antibodies, but also excitingly chimeric antigen receptor T-cell (CAR-T) therapy, 6 we have several small molecule targets including the selective inhibition of nuclear export proteins (SINE), the best example of which is selinexor, and the inhibition of histone deacetylase, including panobinostat, which show promise. 7,8 Beyond these, there remains a challenge.…”