Taking advantage of the antigen (Ag)-specific T cell induction of a protein vaccine (containing a cell-penetrating peptide, Ag, and a peptide TLR4 agonist) and the powerful innate-adaptive stimulation by a VSV oncolytic virus (OV) carrying the same Ag, Das and Belnoue et al. demonstrated that s.c. protein vaccine priming followed by i.v. OV boosting led to the optimal Ag-specific CD8+ T cell responses (number and quality), resulting in significant TME remodeling and tumor control in multiple models. Resistance to complete tumor control was associated with the presence of early exhausted T cells, and addition of anti-PD-1 axis therapy led to more CRs.
Contributed by Ed Fritsch
ABSTRACT: Functional tumor-specific cytotoxic T cells elicited by therapeutic cancer vaccination in combination with oncolytic viruses offer opportunities to address resistance to checkpoint blockade therapy. Two cancer vaccines, the self-adjuvanting protein vaccine KISIMA, and the recombinant oncolytic vesicular stomatitis virus pseudotyped with LCMV-GP expressing tumor-associated antigens, termed VSV-GP-TAA, both show promise as a single agent. Here we find that, when given in a heterologous prime-boost regimen with an optimized schedule and route of administration, combining KISIMA and VSV-GP-TAA vaccinations induces better cancer immunity than individually. Using several mouse tumor models with varying degrees of susceptibility for viral replication, we find that priming with KISIMA-TAA followed by VSV-GP-TAA boost causes profound changes in the tumor microenvironment, and induces a large pool of poly-functional and persistent antigen-specific cytotoxic T cells in the periphery. Combining this heterologous vaccination with checkpoint blockade further improves therapeutic efficacy with long-term survival in the spectrum. Overall, heterologous vaccination with KISIMA and VSV-GP-TAA could sensitize non-inflamed tumors to checkpoint blockade therapy.
