TY - JOUR
T1 - Loading of oncolytic vesicular stomatitis virus onto antigen-specific T cells enhances the efficacy of adoptive T-cell therapy of tumors
AU - Qiao, J.
AU - Wang, H.
AU - Kottke, T.
AU - Diaz, R. M.
AU - Willmon, C.
AU - Hudacek, A.
AU - Thompson, J.
AU - Parato, K.
AU - Bell, J.
AU - Naik, J.
AU - Chester, J.
AU - Selby, P.
AU - Harrington, K.
AU - Melcher, A.
AU - Vile, R. G.
N1 - Funding Information:
We thank Toni L Higgins for expert secretarial assistance. This work was supported by the Mayo Foundation
Funding Information:
and by NIH Grant CA RO1107082-02. JQ is supported by a grant from the Susan G Komen Breast Cancer Foundation.
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
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U2 - 10.1038/sj.gt.3303098
DO - 10.1038/sj.gt.3303098
M3 - Article
C2 - 18305577
AN - SCOPUS:43049176729
SN - 0969-7128
VL - 15
SP - 604
EP - 616
JO - Gene Therapy
JF - Gene Therapy
IS - 8
ER -