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Superior infectivity of the fiber chimeric oncolytic adenoviruses Ad5/35 and Ad5/3 over Ad5-delta-24-RGD in primary glioma cultures.

ABSTRACT: Ad5-delta-24-RGD is currently the most clinically advanced recombinant adenovirus (rAd) for glioma therapy. We constructed a panel of fiber-modified rAds (Ad5RGD, Ad5/3, Ad5/35, Ad5/3RGD, and Ad5/35RGD, all harboring the delta-24 modification) and compared their infectivity, replication, reproduction, and cytolytic efficacy in human and rodent glioma cell lines and short-term cultures from primary gliomas. In human cells, both Ad5/35-delta-24 and Ad5/3-delta-24 displayed superior infectivity and cytolytic efficacy over Ad5-delta-24-RGD, while Ad5/3-delta-24-RGD and Ad5/35-delta-24-RGD did not show further improvements in efficacy. The expression of the adenoviral receptors/coreceptors CAR, DSG2, and CD46 and the integrins αVβ3/αVβ5 did not predict the relative cytolytic efficacy of the fiber-modified rAds. The cytotoxicity of the fiber-modified rAds in human primary normal cultures of different origins and in primary glioma cultures was comparable, indicating that the delta-24 modification did not confer tumor cell selectivity. We also revealed that CT-2A and GL261 glioma cells might be used as murine cell models for the fiber chimeric rAds in vitro and in vivo. In GL261 tumor-bearing mice, Ad5/35-delta-24, armed with the immune costimulator OX40L as the E2A/DBP-p2A-mOX40L fusion, produced long-term survivors, which were able to reject tumor cells upon rechallenge. Our data underscore the potential of local Ad5/35-delta-24-based immunovirotherapy for glioblastoma treatment.

SUBMITTER: Stepanenko AA

PROVIDER: S-EPMC8761956 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Abstract As part of a phase 1, dose-escalation, biological-endpoint clinical study (NCT00805376) of DNX-2401 (Delta-24-RGD), a Rb-targeted, tumor-selective, replication-competent oncolytic adenovirus, conducted in 37 patients with recurrent malignant glioma, 12 patients received an intratumoral injection through an implanted catheter, followed 14-days later by en bloc resection and DNX-2401 injections into the post-resection tumor bed. 10 surgical post-treatment specimens and 5 pre-treated tumors were examined for markers of immune response. From all selected cases, formalin fixed, paraffin embedded tissue blocks were selected. IHC was performed using a Leica Bond Max automated stainer as previously described. The slides were scanned in an Aperio AT2 scanner (Leica Biosystems). The IHC scores for CD3, CD4, CD8, CD45Ro, FOXP3, TIM3, LAG-3, VISTA, CD20, CD57, CD68, and OX40 were expressed as cell density in the inflammatory cell population (number of positive cells per mm square of tumor area), except PD-L1, PD-L2, B7-H3, B7-H4, IDO-1, which were expressed using percentage of positive tumor cells, and also as H-Score of the tumor cells. Correlations between immunostaining marker values and survival and dose level were assessed using Spearman rank correlation analysis. Differences in immunostaining marker values before and after treatment were assessed. These analyses demonstrated that all the target proteins are expressed in gliomas in different patterns and tumor regions. Although, we did not observe significant treatment-related changes in the expression of PD-1 in lymphocytes and PD-L1 in glioma cells, TIM3, a marker for T cell exhaustion, was downregulated after DNX-2401 treatment. In addition, expression of B7-H3, a marker of poor prognosis in other tumors, correlated with poorer survival. Because PD-1 and TIM3 cooperate to maintain T-cell exhaustion our data provide a rationale for the combination of DNX-2401 and anti-PD-1 antibodies for the treatment of malignant gliomas. A multicenter clinical trial (NCT02798406) to test this strategy is ongoing.

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Superior infectivity of the fiber chimeric oncolytic adenoviruses Ad5/35 and Ad5/3 over Ad5-delta-24-RGD in primary glioma cultures.

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