Combining Oncolytic Vaccinia Virus with GD2.CAR-modified Vaccinia Virus-specific T-cells for the Treatment of Relapsed Neuroblastoma and Sarcoma
Our aim is to develop potent immune-based therapies for high-risk neuroblastoma that produce complete tumor responses without toxicity and without compromising quality of life.
We have already demonstrated that T-cells genetically modified to recognize the GD2 protein expressed on neuroblastoma cells can safely eliminate local relapsed neuroblastoma, but complete responses of bulky or metastatic tumors were not obtained, likely because tumor-specific T-cells travel poorly to tumor sites and because neuroblastomas are immunosuppressive.
To overcome these problems we will combine tumor-specific T-cells with an oncolytic vaccinia virus (OVV) that selectively infects and kills tumor cells, including neuroblastoma. Because vaccinia virus (VV) induces potent anti-viral immunity, we hypothesized that VV-specific T-cells (VVSTs) expressing the GD2 receptor (GD2-CAR-VVSTs) would be attracted to the tumor site by the OVV-induced inflammation and there be activated by vaccinia proteins to expand massively, kill tumor cells not eliminated by the OVV and travel to distant tumor sites to eliminate metastatic tumor cells.
We have proved this hypothesis in a mouse model in which OVV increased the numbers of murine CD19-CAR-VVSTs that were then able to eliminate CD19-expressing murine melanomas.
We have developed protocols for expansion of human VVSTs in culture and shown that VVSTs increase in numbers in patients with liver cancer or neuroblastoma who had received OVV (JX-594) on clinical trials. We now plan to optimize the specificity and function of human GD2-CAR-VVSTs in a mouse model of human neuroblastoma and prepare a clinical trial for combining OVV with GD2-CAR-VVSTs in patients with relapsed, high-risk neuroblastoma.