Loading of oncolytic vesicular stomatitis virus onto antigen-specific T cells enhances the efficacy of adoptive T-cell therapy of tumors

Gene Ther. 2008 Apr;15(8):604-16. doi: 10.1038/sj.gt.3303098. Epub 2008 Feb 28.

Abstract

Although adoptive T-cell therapy has shown clinical success, efficacy is limited by low levels of T-cell trafficking to, and survival in, the immunosuppressive environment of an established tumor. Oncolytic virotherapy has recently emerged as a promising approach to induce both direct tumor cell killing and local proinflammatory environments within tumors. However, inefficient systemic delivery of oncolytic viruses remains a barrier to use of these agents against metastatic disease that is not directly accessible to the end of a needle. Here we show that the ability of antigen-specific T cells to circulate freely, and to localize to tumors, can be exploited to achieve the systemic delivery of replication-competent, oncolytic vesicular stomatitis virus (VSV). Thus, VSV loaded onto OT-I T cells, specific for the SIINFEKL epitope of the ovalbumin antigen, was efficiently delivered to established B16ova tumors in the lungs of fully immune-competent C57Bl/6 mice leading to significant increases in therapy compared to the use of virus, or T cells, alone. Although OT-I T-cell-mediated delivery of VSV led to viral replication within tumors and direct viral oncolysis, therapy was also dependent upon an intact host immune system. Moreover, VSV loading onto the T cells increased both T-cell activation in vitro and T-cell trafficking in vivo. The combination of adoptive T-cell transfer of antigen-specific T cells, along with oncolytic virotherapy, can, therefore, increase the therapeutic utility of both approaches through multiple mechanisms and should be of direct translational value.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer / methods*
  • Animals
  • Antigens, Neoplasm / immunology*
  • Cell Movement
  • Combined Modality Therapy
  • Genetic Therapy / methods
  • Lung Neoplasms / secondary
  • Lung Neoplasms / therapy
  • Lymphocyte Activation
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Lymphocytes, Tumor-Infiltrating / virology
  • Melanoma, Experimental
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Neoplasm Metastasis / therapy
  • Neoplasm Transplantation
  • Neoplasms / therapy*
  • Oncolytic Virotherapy / methods*
  • Vesiculovirus / genetics*
  • Virus Replication

Substances

  • Antigens, Neoplasm