Kim Minji, Savsani Kush, Dakshanamurthy Sivanesan
College of Human Ecology, Cornell University, Ithaca, NY 14850, USA.
College of Humanities and Sciences, Virginia Commonwealth University, Richmond, VA 23284, USA.
Pharmaceuticals (Basel). 2023 Jun 27;16(7):932. doi: 10.3390/ph16070932.
Acute myeloid leukemia (AML) is a leading blood cancer subtype that can be caused by 27 gene mutations. Previous studies have explored potential vaccine and drug treatments against AML, but many were proven immunologically insignificant. Here, we targeted this issue and applied various clinical filters to improve immune response. KIT is an oncogenic gene that can cause AML when mutated and is predicted to be a promising vaccine target because of its immunogenic responses when activated. We designed a multi-epitope vaccine targeting mutations in the KIT oncogene using CD8+ and CD4+ epitopes. We selected the most viable vaccine epitopes based on thresholds for percentile rank, immunogenicity, antigenicity, half-life, toxicity, IFNγ release, allergenicity, and stability. The efficacy of data was observed through world and regional population coverage of our vaccine design. Then, we obtained epitopes for optimized population coverage from PCOptim-CD, a modified version of our original Java-based program code PCOptim. Using 24 mutations on the KIT gene, 12 CD8+ epitopes and 21 CD4+ epitopes were obtained. The CD8+ dataset had a 98.55% world population coverage, while the CD4+ dataset had a 65.14% world population coverage. There were five CD4+ epitopes that overlapped with the top CD8+ epitopes. Strong binding to murine MHC molecules was found in four CD8+ and six CD4+ epitopes, demonstrating the feasibility of our results in preclinical murine vaccine trials. We then created three-dimensional (3D) models to visualize epitope-MHC complexes and TCR interactions. The final candidate is a non-toxic and non-allergenic multi-epitope vaccine against KIT mutations that cause AML. Further research would involve murine trials of the vaccine candidates on tumor cells causing AML.
急性髓系白血病（AML）是一种主要的血液癌症亚型，可由27种基因突变引起。先前的研究探索了针对AML的潜在疫苗和药物治疗方法，但许多方法在免疫学上被证明无显著效果。在此，我们针对这一问题并应用各种临床筛选标准来改善免疫反应。KIT是一种致癌基因，突变时可导致AML，由于其激活时的免疫原性反应，预计是一个有前景的疫苗靶点。我们设计了一种针对KIT致癌基因突变的多表位疫苗，使用CD8 +和CD4 +表位。我们根据百分位数排名、免疫原性、抗原性、半衰期、毒性、IFNγ释放、致敏性和稳定性的阈值选择了最可行的疫苗表位。通过我们疫苗设计的全球和区域人群覆盖率观察数据的有效性。然后，我们从PCOptim-CD（我们基于Java的原始程序代码PCOptim的修改版本）中获得了用于优化人群覆盖率的表位。利用KIT基因上的24个突变，获得了12个CD8 +表位和21个CD4 +表位。CD8 +数据集的全球人群覆盖率为98.55%，而CD4 +数据集的全球人群覆盖率为65.14%。有5个CD4 +表位与顶级CD8 +表位重叠。在4个CD8 +和6个CD4 +表位中发现了与小鼠MHC分子的强结合，证明了我们的结果在临床前小鼠疫苗试验中的可行性。然后，我们创建了三维（3D）模型以可视化表位-MHC复合物和TCR相互作用。最终候选疫苗是一种针对导致AML的KIT突变的无毒且无致敏性的多表位疫苗。进一步的研究将涉及在导致AML的肿瘤细胞上对候选疫苗进行小鼠试验。
