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Exploring omics-identified antigens and mRNA-lipid nanoparticle vaccines with alpha-galactosylceramide for multiple myeloma therapy

ABSTRACT: Introduction: Natural killer T (NKT) cells and CD8+ T cells are key in the immune response against multiple myeloma (MM), a largely incurable blood cancer. Immunization is a promising strategy to activate these T cell populations. To our knowledge, immunization with mRNA and α-galactosyl ceramide (αGC) have not been studied in MM, as knowledge on clinically relevant antigens in preclinical MM models is lacking. Methods: Transcriptomics and immunopeptidomics were used to identify candidate antigens for immunization in 5TMM models. Galsomes, lipid nanoparticles containing antigen mRNA and αGC were used to immunize 5T33MM bearing mice. This treatment was combined with a CD40 agonist. Tumor burden and activation of NKT cells and CD8+ T cells were studied using M-protein electrophoresis, cytospin, flow cytometry and ELISA. Results: Transcriptomics revealed survivin as a candidate antigen. Prime-boost Galsomes therapy targeting survivin significantly reduced M-protein levels despite low survivin-specific T cell responses. Further analysis showed potential T cell fratricide. Immunopeptidomics revealed HSP60, Idiotype, PICALM and EF1A1 as candidate antigens. Prime-boost therapy with Galsomes targeting these antigens reduced MM growth significantly when combined with a CD40 agonist, coinciding with significantly improved antigen presentation, co-stimulation and cytotoxicity of NKT cells and CD8+ T cells. Conclusion: These findings highlight the potential of Galsomes, an mRNA vaccine designed to activate CD8+ T cells and NKT cells, for MM therapy, and emphasize the importance of combinatorial approaches, addressing immune anergy for effective MM immunotherapies.

INSTRUMENT(S): timsTOF SCP

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Blood

SUBMITTER: Fabien Thery

LAB HEAD: Prof. Francis Impens

PROVIDER: PXD060156 | Pride | 2025-05-07

REPOSITORIES: Pride

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Immunopeptidomics identified antigens for mRNA-lipid nanoparticle vaccines with alpha-galactosylceramide in multiple myeloma therapy.

Van der Vreken Arne A Thery Fabien F Tu Chenggong C Mwangi Kevin K Meulewaeter Sofie S De Beck Lien L Janssens Edith E De Veirman Kim K Vanderkerken Karin K De Bruyne Elke E Franceschini Lorenzo L Impens Francis F Verbeke Rein R Lentacker Ine I Menu Eline E Breckpot Karine K

Journal for immunotherapy of cancer 20250429 4

<h4>Background</h4>Invariant natural killer T (iNKT) cells and CD8<sup>+</sup> T cells are key in the immune response against multiple myeloma (MM), a largely incurable blood cancer. Immunization is a promising strategy to activate these T cell populations. To our knowledge, immunization with messenger RNA (mRNA) and the iNKT agonist, α-galactosylceramide (αGC), has not been studied in MM, as knowledge on clinically relevant antigens in preclinical MM models is lacking.<h4>Methods</h4>Microarray ...[more]

PMID: 40300855

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Project description:Background Clinical success of T cell receptor (TCR) gene therapy has previously been demonstrated for NY-ESO-1 TCR gene therapy. To increase numbers of cancer patients that can be treated with TCR gene therapy we aimed to identify a novel set of high-affinity cancer specific TCRs targeting different cancer testis (CT) antigens in prevalent HLA class I alleles. Methods In this study, we selected based on publicly available gene expression databases the most promising CT genes to target. From these selected genes we identified by HLA peptidomics the naturally processed and presented HLA class I peptides. With these peptide-HLA tetramers were generated, and by single cell sorting CT specific CD8+ T cells were selected, and expanded from the allo-HLA repertoire of healthy donors. By several functional assays high avidity CT-specific T cell clones with safe recognition pattern were selected. To evaluate the potential for clinical application in TCR gene therapy, TCRs were sequenced and transferred into peripheral blood derived CD8+ T cells. Results In total we identified, 7 novel CT-specific TCRs that effectively target MAGE-A1, MAGE-A3, MAGE-A6 and MAGE-A9 in the context of human leukocyte antigen(HLA) -A1, -A2, -A3, -B7, -B35 and -C7. TCR gene transfer into CD8⁺ T cells resulted in efficient cytokine production and cytotoxicity of variety of different tumor types without detectable cross-reactivity. In addition, major in vivo antitumor effects of MAGE-A1 specific TCR engineered CD8⁺ T cells was observed in an orthotopic xenograft model for established multiple myeloma, in which bone marrow located tumor cells were completely eradicated after T cell injection. Conclusion The identification of 7 novel CT-specific TCRs, reactive against CT antigens presented in a variety of different HLA class I alleles, allows selection of therapeutic TCRs for an increased number of cancer patients, and will improve development of personalized TCR gene therapy.

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	CMB-1319.zip	Other
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