Kofoed Søren Vester, Barrio-Calvo Marina, Pavlidis Michail Angelos, Kleine-Kohlbrecher Daniela, Lausen Mads, Lunabjerg-Vestergaard Cherie, Viborg Nadia, Garde Christian, Rønø Birgitte, Friis Stine
Evaxion Biotech, Hørsholm, Denmark.
Cancer Immunol Immunother. 2025 Jul 24;74(9):276. doi: 10.1007/s00262-025-04120-1.
Plasmid DNA vectors are emerging as a versatile antigen delivery platform for personalized cancer vaccines. Here, we report a comprehensive preclinical evaluation of a modular DNA cancer vaccine that targets antigen-presenting cells and encodes tumor-specific antigens (TSAs), including neoantigens and endogenous retroviral (ERV) antigens. To specifically direct the TSAs to APCs, the chemokine C-C motif ligand 19 (CCL19) was incorporated, enhancing the magnitude and persistence of antigen-specific CD4+ and CD8+ T-cell responses. This resulted in strong anti-tumor activity in multiple murine models. Delivery via clinically relevant DNA methods, including electroporation and needle-free injection systems, further improved immune responses compared to standard syringe/needle injection. Pharmacokinetic and toxicological analyses of the CCL19 component demonstrated rapid systemic clearance and an absence of adverse effects, supporting its suitability for clinical application. The platform exhibited a favorable safety profile across repeated administrations at clinically relevant and escalated dosing regimens, including in combination with immune checkpoint blockade. Furthermore, in vitro and in vivo evaluation of multiple antigens confirmed consistent protein expression and sustained immunogenicity, irrespective of antigenic composition, underscoring the platform's robustness and translational potential for individualized cancer vaccine strategies. These findings demonstrate that the CCL19-targeted DNA vaccine platform is both immunologically potent and holds strong potential in personalized cancer therapy.
质粒DNA载体正成为一种用于个性化癌症疫苗的多功能抗原递送平台。在此，我们报告了一种模块化DNA癌症疫苗的全面临床前评估，该疫苗靶向抗原呈递细胞并编码肿瘤特异性抗原（TSA），包括新抗原和内源性逆转录病毒（ERV）抗原。为了将TSA特异性地导向抗原呈递细胞，引入了趋化因子C-C基序配体19（CCL19），增强了抗原特异性CD4+和CD8+ T细胞反应的强度和持久性。这在多个小鼠模型中产生了强大的抗肿瘤活性。与标准注射器/针头注射相比，通过临床相关的DNA方法（包括电穿孔和无针注射系统）进行递送进一步改善了免疫反应。对CCL19成分的药代动力学和毒理学分析表明其在体内迅速清除且无不良反应，支持其临床应用的适用性。该平台在临床相关和递增给药方案的多次给药中，包括与免疫检查点阻断联合使用时，都表现出良好的安全性。此外，对多种抗原的体外和体内评估证实，无论抗原组成如何，都能持续表达蛋白质并保持免疫原性，突出了该平台在个性化癌症疫苗策略方面的稳健性和转化潜力。这些发现表明，靶向CCL19的DNA疫苗平台在免疫方面具有强大效力，在个性化癌症治疗中具有巨大潜力。
