Alphaviral vector-transduced dendritic cells are successful therapeutic vaccines against neu-overexpressing tumors in wild-type mice

Abstract

While dendritic cell (DC) vaccines can protect hosts from tumor challenge, their ability to effectively inhibit the growth of established tumors remains indeterminate. Previously, we have shown that human DCs transduced with Venezuelan equine encephalitis virus replicon particles (VRPs) were potent stimulators of antigen-specific T cells in vitro. Therefore, we investigated the ability of VRPtransduced DCs (VRP-DCs) to induce therapeutic immunity in vivo against tumors overexpressing the neu oncoprotein. Transduction of murine DCs with VRPs resulted in high-level transgene expression, DC maturation and secretion of proinflammatory cytokines. Vaccination with VRPtransduced DCs (VRP-DCs) expressing a truncated neu oncoprotein induced robust neu-specific CD8 + T cell and anti-neu IgG responses. Furthermore, a single vaccination with VRP-DCs induced the regression of large established tumors in wild-type mice. Interestingly, depletion of CD4 + , but not CD8 + , T cells completely abrogated inhibition of tumor growth following vaccination. Taken together, our results demonstrate that VRP-DC vaccines induce potent immunity against established tumors, and emphasize the importance of the generation of both CD4 + T cell and B cell responses for efficient tumor inhibition. These findings provide the rationale for future evaluation VRP-DC vaccines in the clinical setting.

An Alphavirus-Based Adjuvant Enhances Serum and Mucosal Antibodies, T Cells, and Protective Immunity to Influenza Virus in Neonatal Mice

“…Previous in vitro studies using VEE replicon particles (VRP) expressing GFP to infect adult human (38) and murine bone marrow-derived DCs (BMDCs) (37) showed an upregulation in costimulatory molecules CD40, CD80, and CD86. Additional studies using VRP-transduced human DCs showed DC maturation, secretion of proinflammatory cytokines, and significant expansion of antigen-specific T cells (38).…”

“…These infected immune cells then rapidly migrate to the draining lymphoid node(s) (DLN). Alternatively, GVI3000 particles can migrate directly to DLNs, where they preferentially target DCs (36,37). In both human-and mouse-derived DCs, in vitro studies have shown an upregulation of costimulatory molecules as well as secretion of proinflammatory cytokines, such as type I IFN, IL-6, and TNF after infection (37)(38)(39).…”

Treg depletion potentiates checkpoint inhibition in claudin-low breast cancer

“…Female mice (8 to 14 weeks) were used for all experiments. Rat Neu-expressing NT2 cells (HER2/Neu) and the 2250 (luminal A), 2225 (basal-like), and T11 (claudin-low) tumor models have been described (36)(37)(38). T12 cells were prepared by harvesting a T12 tumor from a tumor-bearing mouse, followed by manual digestion with razor blades and chemical digestion with Liberase TM (Roche) and DNase I (Sigma-Aldrich).…”

An alphavirus vector overcomes the presence of neutralizing antibodies and elevated numbers of Tregs to induce immune responses in humans with advanced cancer

“…Other advantages of VRP are their tropism for, and maturation of (5), DCs, which could result in enhanced T cell activation. A number of preclinical studies have reported that VRP induce potent immunity despite the presence of neutralizing antibodies (4)(5)(6)(7)(8)(9)(10)(11)(12).…”