Activating Systemic T-Cell Immunity Against Self Tumor Antigens to Support Oncolytic Virotherapy with Vesicular Stomatitis Virus
- 1 November 2011
- journal article
- research article
- Published by Mary Ann Liebert Inc in Human Gene Therapy
- Vol. 22 (11), 1343-1353
- https://doi.org/10.1089/hum.2010.216
Abstract
We have shown that the antitumor activity of vesicular stomatitis virus (VSV) against B16ova tumors in C57BL/6 mice is predominantly due to innate antiviral immune effectors. We have also shown that the innate immune-activating properties of VSV can be harnessed to prime adaptive T-cell responses against a tumor-associated antigen (TAA) if the virus is engineered to express the cDNA of the antigen. Here, we show that the combination of VSV expressing OVA as a model tumor antigen, along with adoptive T-cell therapy targeted against the same antigen, is superior to either treatment alone and induces systemic antitumor activity. In addition, we extend our findings with the OVA model to the therapeutic use of VSV expressing hgp100, a self TAA against which tolerance is well established in C57BL/6 mice. In contrast to VSV-ova, T-cell responses raised by VSV-hgp100 were insufficient to improve therapy against B16ova tumors compared with VSV-GFP alone. However, in combination with adoptive transfer of gp100-specific pmel T cells, intratumoral VSV-hgp100 cured significantly more mice than either virus or T cells alone. Even in an aggressive model of metastatic disease, antitumor therapy was generated at levels similar to those observed in the VSV-ova/OT-I model in which a potently immunogenic, nonself TAA was targeted. Therefore, individual poorly effective virotherapies and T-cell therapies that target self TAA of low immunogenicity, which reflects the situation in patients, can be combined to generate very effective antitumor therapy. Wongthida and colleagues demonstrate that a combination of vesicular stomatitis virus expressing a tumor-associated antigen (TAA), along with adoptive T-cell therapy targeted against the same antigen, is superior to either treatment alone and induces systemic antitumor activity in a mouse model. In addition, they show that the therapeutic use of combination oncolytic virotherapy with adoptive T-cell therapy to target a self-TAA, against which tolerance is well established in C57BL/6 mice, is effective in the context of an aggressive model of metastatic disease.Keywords
This publication has 51 references indexed in Scilit:
- VSV Oncolytic Virotherapy in the B16 Model Depends Upon Intact MyD88 SignalingMolecular Therapy, 2011
- Potentiating Cancer Immunotherapy Using an Oncolytic VirusMolecular Therapy, 2010
- Synergistic Interaction Between Oncolytic Viruses Augments Tumor KillingMolecular Therapy, 2010
- Enhancing the Therapeutic Effect Against Ovarian Cancer Through a Combination of Viral Oncolysis and Antigen-specific ImmunotherapyMolecular Therapy, 2010
- Oncolytic herpes simplex virus armed with xenogeneic homologue of prostatic acid phosphatase enhances antitumor efficacy in prostate cancerGene Therapy, 2010
- Recombinant Newcastle Disease Virus as a Vaccine Vector for Cancer TherapyMolecular Therapy, 2008
- Adoptive cell transfer: a clinical path to effective cancer immunotherapyNature Reviews Cancer, 2008
- Loading of oncolytic vesicular stomatitis virus onto antigen-specific T cells enhances the efficacy of adoptive T-cell therapy of tumorsGene Therapy, 2008
- Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patientsCancer Immunology, Immunotherapy, 2006
- Cyclophosphamide enhances glioma virotherapy by inhibiting innate immune responsesProceedings of the National Academy of Sciences of the United States of America, 2006