Abstract LB181: Autologous glioblastoma tumor cells treated with an antisense oligonucleotide against insulin-like growth factor type 1 receptor protect mice against GL261 tumor challenge

Abstract

Abstract Background: Despite the current standard of care (SOC) established by Stupp et al (N Engl J Med. 2005:10;352:987-96), patients with glioblastoma continue to have a poor prognosis. IGV-001 is a novel immunotherapy that combines irradiated, patient-derived glioblastoma tumor cells and an antisense oligonucleotide against insulin-like growth factor type 1 receptor (IMV-001) in biodiffusion chambers (0.1-micron pore size). We recently evaluated IGV-001 in patients with newly diagnosed glioblastoma (Andrews et al. Clin Cancer Res. 2021; in press). In a subgroup of IGV-001-treated, Stupp-eligible patients with methylated O6-methylguanine-DNA methyl-transferase promoter, median progression free survival was 38.4 months (compared with 6.5 months in a historical SOC; P=0.0008). We sought to unravel the potential mechanism associated with the high degree of effectiveness of IGV-001 in patients using the GL261-luciferase (-Luc) glioblastoma orthotopic murine model. Methodology: Biodiffusion chambers (0.1- or 5-micron pore size for comparison) containing phosphate-buffered saline (PBS) alone or IGV-001 prepared with 1×106 GL261-Luc cells were implanted in the flanks of C57BL/6 albino female mice. The chambers were explanted after 48 hours (as done in the clinical protocol), followed by intracranial tumor challenge with GL261-Luc cells 26 days after chamber removal. Mice were monitored for survival and tumor growth. FluoroSpot assays were conducted to determine IFN-gamma production as a surrogate measure of antitumor Th1 cytotoxic lymphocyte (CTL) activity. Results: No mice died of disease in either IGV-001-treated group and continued to gain weight until the termination of the study, 28 days post-intracranial tumor challenge. In comparison, there was only one survivor in the PBS group at termination with a median survival time (MST) of 20 days (P<0.001). At the endpoint, 54% of all IGV-001-treated mice (0.1- and 5-micron chambers combined) presented with only a minimal GL-261-Luc bioluminescent signal (<1×108 photons/sec). FluoroSpot assays revealed that on day 29, post-chamber implantation, the number of IFN-gamma-producing cells in the peripheral blood was significantly greater (P<0.01) in IGV-001-treated versus PBS-treated mice, regardless of chamber size. Conclusions: These data support the antitumor activity of IGV-001 in newly diagnosed glioblastoma as demonstrated in the phase 1 study. The results suggest that IGV-001 effectiveness is at least in part associated with a systemic immunological effect, resulting in the generation of Th1 antitumor CTLs. Follow-up studies are aimed to determine the MST of mice receiving this immunotherapy and the factors triggering complete versus partial responses using phenotypic evaluation of T-cell activation/exhaustion markers and Th1/Th2 cytokine production. Citation Format: Jenny Zilberberg, Samantha Garcia, Amelia Zellander, David W. Andrews, Mark A. Exley. Autologous glioblastoma tumor cells treated with an antisense oligonucleotide against insulin-like growth factor type 1 receptor protect mice against GL261 tumor challenge [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB181.