A gorilla adenovirus vaccine targeting tumor neoepitopes enhances the activity of anti–PD-1 therapy.
Major Finding: A gorilla adenovirus vaccine targeting tumor neoepitopes enhances the activity of anti–PD-1 therapy.
Concept: Treatment with both vaccine and PD-1 blockade supports neoantigen-specific effector and stem-like CD8+ T-cell accumulation.
Impact: This treatment combination overcomes PD-1 blockade resistance and improves immunotherapy efficacy.
PD-1 blockade induces the proliferation of Tcf1+ stem-like CD8+ T-cell (TSTEM) progenitors, but chronic exposure to cancer neoantigens can lead to T-cell exhaustion and the inability to control tumor progression. Combining anti–PD-1 antibodies with neoantigen-based adenovector vaccines has been shown to promote eradication of established tumors; however, the mechanisms that drive this synergy are currently unknown. Therefore, D'Alise, Brasu, De Intinis, and colleagues used a gorilla adenovirus (GAd) vaccine that targets a panel of predicted immunogenic neoepitopes derived from point mutations specific to the murine colorectal adenocarcinoma cell line MC38 and showed that GAd combined with an anti–PD-1 antibody enhanced antitumor activity over anti–PD-1 monotherapy. Additionally, this combination significantly increased CD8+ T cells that were reactive to Adpgk, a peptide in the neoepitope panel, with lymph nodes and spleens being enriched in memory Adpgk-specific CD8+ T progenitors, while tumors had increased effector Adpgk-specific CD8+ T cells. Two distinct CD8+ T-cell lineage pathways were identified in response to combination therapy, and investigation of CD8+ T-cell clonotype dynamics demonstrated that combination therapy promotes greater clonotype expansion and diversification when compared to anti–PD-1 treatment alone. Furthermore, to determine translational relevance, a phase I clinical trial was conducted that combined anti–PD-1 treatment with Nous-209, a neoantigen-based vaccine encoding 209 frameshift peptides shared across 12 patients with mismatch repair–deficient tumors, which showed a durable neoepitope-specific T-cell response along with successful effector memory T-cell tumor infiltration and expanded and diverse T-cell receptor (TCR) clonotypes. In summary, these results show that neoantigen adenoviral vectors are a promising approach to increase the magnitude of the TSTEM precursor reservoir, expand the TCR repertoire, and promote T-cell tumor infiltration.
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