Progressive
tumor growth is associated with deficits in the immunity generated against
tumor antigens.
Vaccines targeting
tumor neoepitopes have the potential to address qualitative defects; however, additional mechanisms of immune failure may underlie
tumor progression. In such cases, patients would benefit from additional immune-oncology agents targeting potential mechanisms of immune failure. This study explores the identification of neoepitopes in the MC38 colon
carcinoma model by comparison of
tumor to normal
DNA and
tumor RNA sequencing technology, as well as neoepitope delivery by both
peptide- and adenovirus-based vaccination strategies. To improve antitumor efficacies, we combined the
vaccine with a group of rationally selected immune-oncology agents. We utilized an
IL15 superagonist to enhance the development of
antigen-specific immunity initiated by the neoepitope
vaccine, PD-L1 blockade to reduce
tumor immunosuppression, and a
tumor-targeted
IL12 molecule to facilitate T-cell function within the tumor microenvironment. Analysis of
tumor-infiltrating leukocytes demonstrated this multifaceted treatment regimen was required to promote the influx of CD8+ T cells and enhance the expression of transcripts relating to T-cell activation/effector function.
Tumor-targeted
IL12 resulted in a marked increase in clonality of T-cell repertoire infiltrating the
tumor, which when sculpted with the addition of either a
peptide or adenoviral neoepitope
vaccine promoted efficient
tumor clearance. In addition, the neoepitope
vaccine induced the spread of immunity to neoepitopes expressed by the
tumor but not contained within the
vaccine. These results demonstrate the importance of combining neoepitope-targeting
vaccines with a multifaceted treatment regimen to generate effective antitumor immunity.