DataSheet_1_Targeting neoantigens to APC-surface molecules improves the immunogenicity and anti-tumor efficacy of a DNA cancer vaccine.docx

IntroductionTumor-specific mutations generate neoepitopes unique to the cancer that can be recognized by the immune system, making them appealing targets for therapeutic cancer vaccines. Since the vast majority of tumor mutations are patient-specific, it is crucial for cancer vaccine designs to be compatible with individualized treatment strategies. Plasmid DNA vaccines have substantiated the immunogenicity and tumor eradication capacity of cancer neoepitopes in preclinical models. Moreover, early clinical trials evaluating personalized neoepitope vaccines have indicated favorable safety profiles and demonstrated their ability to elicit specific immune responses toward the vaccine neoepitopes.
MethodsBy fusing in silico predicted neoepitopes to molecules with affinity for receptors on the surface of APCs, such as chemokine (C-C motif) ligand 19 (CCL19), we designed an APC-targeting cancer vaccine and evaluated their ability to induce T-cell responses and anti-tumor efficacy in the BALB/c syngeneic preclinical tumor model.
ResultsIn this study, we demonstrate how the addition of an antigen-presenting cell (APC) binding molecule to DNA-encoded cancer neoepitopes improves neoepitope-specific T-cell responses and the anti-tumor efficacy of plasmid DNA vaccines. Dose-response evaluation and longitudinal analysis of neoepitope-specific T-cell responses indicate that combining APC-binding molecules with the delivery of personalized tumor antigens holds the potential to improve the clinical efficacy of therapeutic DNA cancer vaccines.
DiscussionOur findings indicate the potential of the APC-targeting strategy to enhance personalized DNA cancer vaccines while acknowledging the need for further research to investigate its molecular mechanism of action and to translate the preclinical results into effective treatments for cancer patients.

**引言**
肿瘤特异性突变可产生仅存在于该肿瘤的新表位（neoepitopes），此类新表位可被免疫系统识别，因此成为治疗性癌症疫苗的理想靶点。由于绝大多数肿瘤突变均为患者特异性的，因此癌症疫苗的设计需适配个体化治疗策略，这一点至关重要。质粒DNA疫苗已在临床前模型中证实了癌症新表位的免疫原性与肿瘤清除能力。此外，针对个体化新表位疫苗的早期临床试验显示，该类疫苗具有良好的安全性特征，且可诱导针对疫苗新表位的特异性免疫应答。
**方法**
本研究将经计算机模拟（in silico）预测的新表位与可结合抗原呈递细胞（antigen-presenting cell, APC）表面受体的分子（如趋化因子（C-C基序）配体19（CCL19））融合，设计出靶向APC的癌症疫苗，并在BALB/c同基因临床前肿瘤模型中评估其诱导T细胞应答与抗肿瘤功效的能力。
**结果**
本研究证实，向DNA编码的癌症新表位中添加APC结合分子，可提升新表位特异性T细胞应答水平与质粒DNA疫苗的抗肿瘤功效。针对新表位特异性T细胞应答的剂量反应评估与纵向分析表明，将APC结合分子与个体化肿瘤抗原递送相结合，有望提升治疗性DNA癌症疫苗的临床疗效。
**讨论**
本研究结果证实了靶向APC策略在优化个体化DNA癌症疫苗中的应用潜力，同时指出仍需开展进一步研究，以阐明其作用的分子机制，并将临床前研究结果转化为可用于癌症患者的有效治疗手段。