Localized Treatment with Oncolytic Adenovirus Delta-24-RGDOX Induces Systemic Immunity against Disseminated Subcutaneous and Intracranial Melanomas

Abstract

Purpose: Intratumoral injection of oncolytic adenovirus Delta-24-RGDOX induces efficacious antiglioma immunity in syngeneic glioma mouse models. We hypothesized that localized treatment with the virus is effective against disseminated melanomas.Experimental Design: We tested the therapeutic effect of injecting Delta-24-RGDOX into primary subcutaneous (s.c.) B16-Red-FLuc tumors in s.c./s.c. and s.c./intracranial (i.c.) melanoma models in C57BL/6 mice. Tumor growth and in vivo luciferase-expressing ovalbumin-specific (OT-I/Luc) T cells were monitored with bioluminescence imaging. Cells were profiled for surface markers with flow cytometry.Results: In both s.c./s.c. and s.c./i.c. models, 3 injections of Delta-24-RGDOX significantly inhibited the growth of both the virus-injected s.c. tumor and untreated distant s.c. and i.c. tumors, thereby prolonging survival. The surviving mice were protected from rechallenging with the same tumor cells. The virus treatment increased the presence of T cells and the frequency of effector T cells in the virus-injected tumor and mediated the same changes in T cells from peripheral blood, spleen, and brain hemispheres with untreated tumor. Moreover, Delta-24-RGDOX decreased the numbers of exhausted T cells and regulatory T cells in the virus-injected and untreated tumors. Consequently, the virus promoted the in situ expansion of tumor-specific T cells and their migration to tumors expressing the target antigen.Conclusions: Localized intratumoral injection of Delta-24-RGDOX induces an in situ antovaccination of the treated melanoma, the effect of which changes the immune landscape of the treated mice, resulting in systemic immunity against disseminated s.c. and i.c. tumors.

Stem cell programs in cancer initiation, progression, and therapy resistance

“…In addition to this primary effect, oncolytic viruses are also able to stimulate the immune system against cancer cells, in which the immune system is silenced by the TME 320 . The use of improved oncolytic adenovirus treatment regimens has demonstrated therapeutic activity in immunocompetent C57BL/6 mouse models by stimulating an influx of CD8 + T cells specific to tumor-associated antigens 321 , 322 . Moreover, in human patients, viral treatments have been shown to induce a tumor macrophage phenotypic shift 323 .…”

Oncolytic Adenoviruses for Cancer Therapy

“…OX40 is not constitutively expressed on resting naïve T-cells and plays a key role in the survival and homeostasis of effector and memory T-cells, and it regulates the differentiation and function of Foxp3+ Tregs [ 59 ]. H. Jiang et al have recently showed that OX40L-armed Onc.Ad (Delta-24-RGDOX) has a stronger anticancer efficacy compared to its predecessor Delta-24-RGD, triggering a greater tumor-specific lymphocyte activation and a proliferation of TAAs-specific CD8 + T-cells in two mouse glioma models [ 60 ]. In the same model, a synergistic therapeutic effect was observed by the intra-tumoral injection of Delta-24-RGDOX and an anti-PD-L1 antibody [ 61 ].…”

Viral Vectors as Gene Therapy Agents for Treatment of Glioblastoma

“…DNX-2440 (Delta-24-RGDOX) is an immunomodulatory recombinant selectively replication-competent serotype 5 strain Ad-encoding OX40 ligand (OX40L) driven by the cytomegalovirus (CMV) promoter. The protein is able to activate T cells via interaction with its receptor on the surface of T lymphocytes [ 28 , 29 ].…”