Theiler's Murine Encephalomyelitis Virus as a Vaccine Candidate for Immunotherapy

Abstract

The induction of sterilizing T-cell responses to tumors is a major goal in the development of T-cell vaccines for treating cancer. Although specific components of anti-viral CD8+ immunity are well characterized, we still lack the ability to mimic viral CD8+ T-cell responses in therapeutic settings for treating cancers. Infection with the picornavirus Theiler's murine encephalomyelitis virus (TMEV) induces a strong sterilizing CD8+ T-cell response. In the absence of sterilizing immunity, the virus causes a persistent infection. We capitalized on the ability of TMEV to induce strong cellular immunity even under conditions of immune deficiency by modifying the virus to evaluate its potential as a T-cell vaccine. The introduction of defined CD8+ T-cell epitopes into the leader sequence of the TMEV genome generates an attenuated vaccine strain that can efficiently drive CD8+ T-cell responses to the targeted antigen. This virus activates T-cells in a manner that is capable of inducing targeted tissue damage and glucose dysregulation in an adoptive T-cell transfer model of diabetes mellitus. As a therapeutic vaccine for the treatment of established melanoma, epitope-modified TMEV can induce strong cytotoxic T-cell responses and promote infiltration of the T-cells into established tumors, ultimately leading to a delay in tumor growth and improved survival of vaccinated animals. We propose that epitope-modified TMEV is an excellent candidate for further development as a human T-cell vaccine for use in immunotherapy.

Enhancing the Tumor Selectivity of a Picornavirus Virotherapy Promotes Tumor Regression and the Accumulation of Infiltrating CD8+ T Cells

“…The implantation of B16, B16-OVA and TUBO tumors into the flank of B6 and Balb/c mice was performed as described previously (15, 16). Mice were monitored daily and tumor size was measured every second or third day after virus treatment.…”

“…We have developed TMEV as an immunotherapy vector that drives strong T-cell responses to tumor antigens embedded within its genome (15, 16). Our vector was designed using the genetic backbone of the TO subgroup member Daniel's strain (DA), a strain that is most often readily cleared from intracranially infected mice after the development of an immunodominant CD8+ T-cell response (17).…”

“…These studies identified a strategy for driving cytotoxic T-cell responses that subsequently target tumors and inhibit their outgrowth. This strategy has been shown to effectively inhibit melanoma, breast cancer and glioblastoma outgrowth when delivered systemically (15, 16, 18). Although our studies focused on the immune potential of this vector, it is unclear whether direct infection of tumors with TMEV could provide further therapeutic benefit for the treatment of cancers.…”

Picornavirus Infection Leading to Immunosuppression

“…A number of picornaviruses are currently being trialed as oncolytic agents: coxsackievirus (CAVATAK), poliovirus (PVS-RIPO) and Seneca Valley virus (NTX-010; oncolytic virotherapy is reviewed in [48]). Furthermore, an epitope modifed TMEV has been proposed as a candidate T-cell vaccine for use as an immunotherapeutic against tumors [49]. We are not aware of any trials currently using viruses to combat autoimmune diseases.…”

Modulatory effects of perforin gene dosage on pathogen-associated blood-brain barrier (BBB) disruption

“…RT-PCR was performed as previously described [36]. In brief, whole brain suspension was mixed with TRIzol LS Reagent (Life Technologies) and chloroform.…”