Peptide-based anticancer vaccines: The making and unmaking of a T-cell graveyard

Abstract

Poorly biodegradable, incomplete Freund's adjuvant (IFA)-based anticancer vaccines primed CD8⁺ T cells that did not localize to the tumor site but to the persisting, antigen-rich vaccination site, which became a T-cell graveyard. Short-lived, water-based formulations and the provision of immunostimulatory molecules overcame this issue, resulting in tumor suppression. Here, we discuss the implications of these findings for the development of therapeutic anticancer vaccines.

Keywords: T-cell deletion; T-cell dysfunction; T-cell trafficking; antigen persistence; immunotherapy; sequestration; vaccine depot.

Figure 1. Proposed model of immune response after vaccination with peptide/IFA + covax vs. peptide/saline + covax. Vaccination with peptide in IFA + covax (top) results in a persistent, antigen-rich vaccine depot that primes T cells to become effector cells that enter the circulation. Effector T cells reaching vaccination sites encounter high densities of peptide antigen (high [Ag]), prompting high IFN-γ release, inflammation and chemokine production and stronger T-cell accumulation than comparatively low [Ag] tumors. Eventually, most T cells at vaccination sites are deleted while remaining T cells are dysfunctional and poorly control tumor growth. Vaccination with peptide in saline + covax (bottom) also primes T cells, but vaccine antigen is cleared rapidly, resulting in T-cell accumulation at the most antigen-dense remaining site (tumor). Remaining memory cells are functional to control recurrence and respond to booster vaccination.