Van der Vreken Arne, Thery Fabien, Tu Chenggong, Mwangi Kevin, Meulewaeter Sofie, De Beck Lien, Janssens Edith, De Veirman Kim, Vanderkerken Karin, De Bruyne Elke, Franceschini Lorenzo, Impens Francis, Verbeke Rein, Lentacker Ine, Menu Eline, Breckpot Karine
Department of Biomedical Sciences Brussels, Translational Oncology Research Center, Vrije Universiteit Brussel, Brussels, Belgium
VIB-UGent Center for Medical Biotechnology, VIB, Ghent, Belgium.
J Immunother Cancer. 2025 Apr 29;13(4):e010673. doi: 10.1136/jitc-2024-010673.
Invariant natural killer T (iNKT) 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 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.
Microarray data and immunopeptidomics (imPep) 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 iNKT cells and CD8 T cells were studied using M-protein electrophoresis, flow cytometry and ELISA.
RNA transcripts 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. ImPep 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, costimulation and cytotoxicity of iNKT cells and CD8 T cells.
These findings highlight the potential of Galsomes, an mRNA vaccine designed to activate CD8 T cells and iNKT cells, for MM therapy, and emphasize the importance of combinatorial approaches, addressing immune anergy for effective MM immunotherapies.
不变自然杀伤T（iNKT）细胞和CD8 T细胞在针对多发性骨髓瘤（MM）的免疫反应中起关键作用，MM是一种基本上无法治愈的血癌。免疫接种是激活这些T细胞群体的一种有前景的策略。据我们所知，尚未在MM中研究过用信使核糖核酸（mRNA）和iNKT激动剂α-半乳糖神经酰胺（αGC）进行免疫接种，因为缺乏关于临床前MM模型中临床相关抗原的知识。
利用微阵列数据和免疫肽组学（imPep）在5TMM模型中鉴定用于免疫接种的候选抗原。使用含抗原mRNA和αGC的脂质纳米颗粒免疫携带5T33MM的小鼠。这种治疗与一种CD40激动剂联合使用。使用M蛋白电泳、流式细胞术和酶联免疫吸附测定（ELISA）研究肿瘤负荷以及iNKT细胞和CD8 T细胞的激活情况。
RNA转录物显示生存素是一种候选抗原。尽管生存素特异性T细胞反应较低，但靶向生存素的初免-加强脂质纳米颗粒疗法显著降低了M蛋白水平。进一步分析显示存在潜在的T细胞自相残杀现象。免疫肽组学显示热休克蛋白60（HSP60）、独特型、磷酯酰肌醇结合网格蛋白组装蛋白（PICALM）和真核延伸因子1α1（EF1A1）为候选抗原。当与CD40激动剂联合使用时，用脂质纳米颗粒靶向这些抗原的初免-加强疗法显著降低了MM的生长，这与iNKT细胞和CD8 T细胞的抗原呈递、共刺激和细胞毒性显著改善相吻合。
这些发现突出了脂质纳米颗粒（一种旨在激活CD8 T细胞和iNKT细胞的mRNA疫苗）在MM治疗中的潜力，并强调了联合方法的重要性，即解决免疫无反应性以实现有效的MM免疫治疗。
