A poly-neoantigen DNA vaccine synergizes with PD-1 blockade to induce T cell-mediated tumor control

Abstract

The combination of immune-stimulating strategies has the potency to improve immunotherapy of cancer. Vaccination against neoepitopes derived from patient tumor material can generate tumorspecific T cell immunity, which could reinforce the efficacy of checkpoint inhibitor therapies such as anti-PD-1 treatment. DNA vaccination is a versatile platform that allows the inclusion of multiple neoantigencoding sequences in a single formulation and therefore represents an ideal platform for neoantigen vaccination. We developed an anti-tumor vaccine based on a synthetic DNA vector designed to contain multiple cancer-specific epitopes in tandem. The DNA vector encoded a fusion gene consisting of three neoepitopes derived from the mouse colorectal tumor MC38 and their natural flanking sequences as 40 amino acid stretches. In addition, we incorporated as reporter epitopes the helper and CTL epitope sequences of ovalbumin. The poly-neoantigen DNA vaccine elicited T cell responses to all three neoantigens and induced functional CD8 and CD4 T cell responses to the reporter antigen ovalbumin after intradermal injection in mice. The DNA vaccine was effective in preventing outgrowth of B16 melanoma expressing ovalbumin in a prophylactic setting. Moreover, the combination of therapeutic DNA vaccination and anti-PD-1 treatment was synergistic in controlling MC38 tumor growth whereas individual treatments did not succeed. These data demonstrate the potential of DNA vaccination to target multiple neoepitopes in a single formulation and highlight the cooperation between vaccinebased and checkpoint blockade immunotherapies for the successful eradication of established tumors.

The Effect of Different Immunization Cycles of a Recombinant Mucin1-Maltose-Binding Protein Vaccine on T Cell Responses to B16-MUC1 Melanoma in Mice

“…Furthermore, the results of flow cytometry showed that the vaccine increased the proportion of CD4+ T and CD8+ T cells in the spleen and TME, suggesting the important role of CD4+ T and CD8+ T cells in antitumor immunity. Consistent with our results, Tondini et al and Tian et al evaluated CD4+ T and CD8+ T cells in vivo by injecting anti-CD4 and anti-CD8 antibodies in mice, and found that tumor regression was dependent on CD4+ T and CD8+ T cells [ 25 , 26 , 27 ]. Other experiments have also shown that increases in the numbers of CD4+ T and CD8+ T cells in the TME are closely related to tumor prognosis [ 28 , 29 , 30 , 31 ].…”

Identification of a neo-epitope dominating endogenous CD8 T cell responses to MC-38 colorectal cancer

“…Nevertheless, the previously described Adpgk epitope is beyond doubt relevant for vaccination-induced MC-38 tumor control as is observed by several groups, 28,32,33 including our own experimental data with specific DNA vaccination. 34 In addition, care should be taken with the origin of the MC-38 cell line, as different lines may contain other neo-epitopes.…”

A combination of PD‑1/PD‑L1 inhibitors: The prospect of overcoming the weakness of tumor immunotherapy (Review)

“…DNA vaccine induces Cytotoxicity of CD8 T cells. A single dose of DNA vaccine combined with anti-PD-1 treatment significantly delays tumor growth in tumor-bearing mice inoculated with MC38 colon cancer cell line and some of the tumors are cleared completely, with a cure rate of 25%, and this indicates that tumor vaccine works synergistically with immune checkpoint blocking therapy (28).…”