Abstract
Toca 511 (vocimagene amiretrorepvec) is a gamma retroviral replicating vector that selectively infects cancer cells in vivo and encodes cytosine deaminase. In combination with the prodrug, 5-fluorocytosine (5-FC), Toca 511 produces 5-fluorouracil (5-FU) locally in the tumor microenvironment. This work aimed to determine if the addition of a checkpoint inhibitor, αCTLA-4 would provide therapeutic benefit to Toca 511 and 5-FC in a mouse model of glioma. Initially, we noted that Toca 511 and 5-FC was highly efficacious and that it provided little room for improvement and therefore combination with αCTLA-4 was not able to show additive benefit against the primary cancer. Further examination revealed that tumor associated Regulatory T cells were significantly reduced with αCTLA-4 treatment and long term memory was shown to be significantly improved with the combination. Adoptive transfer of immune cells from animals that cleared their primary tumor through Toca 511, 5-FC, and αCTLA-4 showed 100% survival benefit to animals bearing orthotopic gliomas; significantly greater than the ~50% survival seen with transfer from animals that cleared primary tumor through Toca 511 and 5-FC alone. Further, αCTLA-4 treatment during clearance of primary tumors resulted in a marked reduction of memory T regulatory cells in secondary tumors. Finally, we wanted to determine if αCTLA-4 in combination with Toca 511 and 5-FC significantly reduced tumor burden in a model using a submaximal infection level of Toca 511. Specifically, restricting Toca 511 infection to only 2% of tumor cells limited the activity of 5-FC in a subcutaneous setting and the loss of efficacy with 2% infection was rescued when 5-FC treatment was combined with αCTLA-4. These data suggest that αCTLA-4, and other compounds that target T regulatory cells, should be evaluated in patients receiving Toca 511 and Toca FC to determine if the combination confers additional clinical benefits.