Abstract
Immune checkpoint inhibitors (ICI) based on anti-CTLA-4 (αCTLA-4) and anti-PD1 (αPD1) are being tested in combination with different therapeutic approaches including other immunotherapies such as neoantigen cancer vaccines (NCV). Here we explored, in two cancer murine models, different therapeutic combinations of ICI with personalized DNA vaccines expressing neoantigens and delivered by electroporation (EP). Anti-cancer efficacy was evaluated using vaccines with or without CD4 epitopes. Therapeutic DNA vaccines showed synergistic effects in different therapeutic protocols including established large tumors. Flow cytometry (FC) was utilized to measure CD8, CD4, Treg, and switched B cells as well as neoantigen-specific immune responses, which were also measured by IFN-γ ELIspot. Immune responses were augmented in combination with αCTLA4 but not with αPD1 in the MC38 tumor-bearing mice, significantly impacting tumor growth. Similarly, neoantigen-specific T cell immune responses were enhanced in combined treatment with αCTLA-4 in the CT26 tumor model where large tumors regressed in all mice, while monotherapy with αCTLA-4 was less efficacious. In line with previous evidence, we observed an increased switched B cells in the spleen of mice treated with αCTLA-4 alone or in combination with NCV. These results support the use of NCV delivered by DNA-EP with αCTLA-4 and suggest a new combined therapy for clinical testing.
Highlights
Developing innovative combination protocols to boost the efficacy of immune checkpoint inhibitors (ICI) is one of the challenges in cancer immunotherapy
We asked whether the M8 vaccine could improve the antitumor efficacy when administered in combination with αPD1 and/or αCTLA-4
Both anti CD4 and anti CD8 abolished anti-tumor activity induced by αCTLA-4/C20-IM (Fig. 4C). These results extend to the CT26 tumor model the combination of Neoantigen cancer vaccine (NCV) delivered by DNA-EP and αCTLA-4 and suggest that the protocol with ICI followed by NCV could be more effective
Summary
Developing innovative combination protocols to boost the efficacy of immune checkpoint inhibitors (ICI) is one of the challenges in cancer immunotherapy. Anti-CTLA-4 (αCTLA-4) and αPD1 are supposed to act at different levels, with the first promoting T cell activation at lymph nodes and the latter reactivating T cells in the tumor[24]. This conclusion is backed up by the large therapeutic advantage of combining αCTLA-4 and αPD1 therapy, even though efficacy comes at the expenses of severe adverse effects[25]. A predominant CD4+ response and a synergy with ICI were observed[27] External factors such as the microbiota can modulate the efficacy of a NCV expressed by a plasmid DNA and administered by electroporation (EP)[28]
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