High grade gliomas (HGG) such as glioblastoma lack effective treatment with poor prognosis of median overall survival (OS) around 14-16 months with standard of care. Initiation of effective immune response against cancer requires functional dendritic cells, which are absent from the central nervous system, resulting in lack of anti-HGG immune responses. An effective anti-glioma immune response can be achieved by combining glioma cytotoxicity with HSV1-TK and valacyclovir, and recruitment of dendritic cells to the brain with Flt3L. This dual approach makes endogenous tumor antigens available to infiltrating dendritic cells in its microenvironment by causing: (i) dendritic cells' infiltration of gliomas, (ii) CD8+, CD4+ T cell immune cytotoxicity and memory, and (iii) the systemic immune system to recognize tumor neoantigens. We report the first in human phase I dose escalation trial of adenoviral vectors expressing HSV1-TK and Flt3L (NCT01811992). Injection of dose escalated HSV1-TK and Flt3L adenovectors (range 1x10^9 vp - 1x10^11 vp) to the tumor bed post-resection of newly diagnosed HGG was followed by two cycles of 14-day course of valacyclovir starting 1-3 days and 10-12 weeks post-op combined with standard of care upfront radiation, concurrent and adjuvant temozolomide. Key inclusion criteria were ages 18-75, KPS ≥70, and suspected newly diagnosed HGG amenable to gross total resection. Enrollment and vector injection occurred after frozen pathology confirmed HGG. Out of 18 patients, six are still alive. The primary endpoint of maximal tolerated dose was not reached and the experimental treatment was well tolerated without dose limiting toxicity. The secondary endpoint of OS is promising with median of 21.9 months (range 5.4-52.7). Five out of six patients (83%) who had re-resection at the time of suspected radiographic progression had treatment effect rather than true progression, and increase in markers for dendritic cells, CD4+ T cells, and macrophages were noted, indicating successful immunity recruitment consistent with pre-clinical findings. Updated survival data, as well as comparison to matched controls, and detailed toxicities will be presented at the time of the meeting. In conclusion, the use of dual adenoviral vectors expressing Flt3L and HSV1-TK is safe and well tolerated in newly diagnosed HGG patients. Our results indicate promising preliminary survival outcome and histological evidence of immune infiltration. Future studies to assess treatment efficacy is warranted.
Citation Format: Pedro Lowenstein, Daniel Orringer, Yoshie Umemura, Oren Sagher, Jason Heth, Shawn Hervey-Jumper, Aaron Mammoser, Denise Leung, Ted Lawrence, Mishell Kim, Daniel Wahl, Paul McKeever, Sandra Camelo-Piragua, Andrew Lieberman, Sriram Venneti, Kait Verbal, Karen Sagher, Patrick Dunn, Daniel Zamler, Andrea Comba, David Altshuler, Lili Zhao, Karin Muraszko, Larry Junck, Maria G. Castro. First in human phase I trial of adenoviral vectors expressing Flt3L and HSV1-TK to treat newly diagnosed high-grade glioma by reprogramming the brain immune system [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT105.