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

Abstract

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.

Personalized Neoantigen DNA Cancer Vaccines: Current Status and Future Perspectives

“…Also, granulocytemacrophage colony stimulating factor (GM-CSF) [36], IL-6 and TNF-alpha [37] have been applied as molecular adjuvants to modulate the plasmid DNA immune response upon vaccination. Another approach that enhances DNA vaccine immunogenicity has been observed from encoding APC binding molecules into the DNA plasmid, such as chemokine (C-C motif ) ligand 3 (CCL3) [38] and CCL19 [39], the latter describing the improved in vivo efficacy of plasmid DNA encoded neoepitopes in a murine model of colon carcinoma resulting from the CCL19-targeted approach. The adjuvants investigated in clinical and pre-clinical settings demonstrate that the use of molecular adjuvants enhances immunogenicity of DNA PCV´s and thereby vaccine efficacy and that this approach has promising clinical value.…”

“…The authors and colleagues have furthermore published a follow-up study that demonstrated how the addition of an APC-targeting molecule (chemokine CCL19, as described briefly in the prior paragraph) to a NeoAg DNA vaccine led to improved efficacy compared to NeoAg DNA without APC targeting [39]. This was evident from observations of APCtargeted NeoAg DNA effectively preventing subcutaneous tumor growth at a five-fold lower dose than the NeoAg DNA without APC targeting.…”