Immunomodulation of murine brain tumors using Delta-24-RGDOX and IDO inhibitors induces durable and long-term survival
 
Teresa T. Nguyen^1,2, Yisel Rivera-Molina², Francisco W. Puerta-Martinez², Xuejun Fan², Amy Heimberger^2,3, Chantale Bernatchez^1,4, Joya Chandra^1,5, Scott Kopetz^1,6, Hong Jiang², Frederick Lang^2,3, Candelaria Gomez-Manzano^1,2, Juan Fueyo^1,2,3
University of Texas MD Anderson Cancer Center, Graduate School of Biomedical Sciences, Houston, TX¹, and the Departments of Neuro-Oncology², Neurosurgery³, Melanoma Medical Oncology⁴, Pediatrics⁵, and Gastrointestinal Medical Oncology⁶, MD Anderson Cancer Center, Houston, TX
 
Glioblastoma (GB) and metastatic melanoma (MM) can be characterized by an immunosuppressive tumor-microenvironment. Regulatory T-cells can cause immunosuppression by activating indolamine-2,3-dioxygenase (IDO). We have observed that the implantation of tumors in mice generates an immunosuppressive environment characterized by overrepresentation of CD4+ regulatory T-cells. The use of the oncolytic adenovirus, Delta-24-RGD, has been shown to induce complete responses in a subset of GB patients by immune mechanisms that activate anti-tumor cytotoxic properties of T-cells. The cytolytic effect can be enhanced by the addition of immune agonists, such as OX40L, a T-cell co-stimulator. We hypothesized that the combination of IDO inhibition (1MT or Indoximod) and Delta-24-RGD armed with the OX40 ligand (D24-RGDOX) will synergize and have a therapeutic effect in GB and MM.  In this study, an orthotopic glioma mouse model and a melanoma brain metastasis model were treated with D24-RGDOX and 1MT or Indoximod. In both models, D24-RGDOX treatment resulted in a significant survival benefit compared to the control groups (GB: mean survival, 46.5 vs. 38.5 days, p=0.02, MM: mean survival, 13 vs. 8 days, p=0.0003). Interestingly, the combination treatment of D24-RGDOX and the IDO inhibitor yielded a greater survival benefit compared to D24-RGDOX single treatment in both models, with the presence of long-term survivors (GB: mean survival, 46.5 vs. 108.5 days, p=0.03, MM: mean survival, 13 vs. 24 days, p=0.01). Moreover, when the long-term glioma survivors were re-challenged with the same cell line, 100% survival was observed compared to the control group (p=0.002), indicating the establishment of immune memory by D24-RGDOX and 1MT. These data support the use of IDO inhibitors with oncolytic adenoviruses as a potential treatment of GB and MM.