DNA based neoepitope vaccination induces tumor control in syngeneic mouse models

Abstract Recent findings have positioned tumor mutation-derived neoepitopes as attractive targets for cancer immunotherapy. Cancer vaccines that deliver neoepitopes via various vaccine formulations have demonstrated promising preliminary results in patients and animal models. In the presented work, we assessed the ability of plasmid DNA to confer neoepitope immunogenicity and anti-tumor effect in two murine syngeneic cancer models. We demonstrated that neoepitope DNA vaccination led to anti-tumor immunity in the CT26 and B16F10 tumor models, with the long-lasting presence of neoepitope-specific T-cell responses in blood, spleen, and tumors after immunization. We further observed that engagement of both the CD4+ and CD8+ T cell compartments was essential to hamper tumor growth. Additionally, combination therapy with immune checkpoint inhibition provided an additive effect, superior to either monotherapy. DNA vaccination offers a versatile platform that allows the encoding of multiple neoepitopes in a single formulation and is thus a feasible strategy for personalized immunotherapy via neoepitope vaccination

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

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