Oncolytic Adenovirus and Tumor-Targeting Immune Modulatory Therapy Improve Autologous Cancer Vaccination

Abstract

Oncolytic viruses selectively lyse tumor cells, disrupt immunosuppression within the tumor and reactivate anti-tumor immunity, but they have yet to live up to their therapeutic potential. Immune checkpoint modulation has been efficacious in a variety of cancer with an immunogenic microenvironment, but is associated with toxicity due to nonspecific T-cell activation. Therefore, combining these two strategies would likely result in both effective and specific cancer therapy. To test the hypothesis, we first constructed oncolytic adenovirus Delta-24-RGDOX expressing the immune co-stimulator OX40 ligand (OX40L). Like its predecessor Delta-24-RGD, Delta-24-RGDOX induced immunogenic cell death and recruit lymphocytes to the tumor site. Compared to Delta-24-RGD, Delta-24-RGDOX exhibited superior tumor-specific activation of lymphocytes and proliferation of CD8+ T cells specific to tumor-associated antigens, resulting in cancer-specific immunity. Delta-24-RGDOX mediated more potent anti-glioma activity in immune-competent C57BL/6 but not immune-deficient athymic mice, leading to specific immune memory against the tumor. In order to further overcome the immune suppression mediated by programmed death-ligand 1 (PD-L1) expression on cancer cells accompanied with virotherapy, intratumoral injection of Delta-24-RGDOX and an anti-PD-L1 antibody showed synergistic inhibition of gliomas and significantly increased survival in mice. Our data demonstrate that combining an oncolytic virus with tumor-targeting immune checkpoint modulators elicits potent in situ autologous cancer vaccination, resulting in an efficacious, tumor-specific and long-lasting therapeutic effect.

Glioblastoma stem cells: lessons from the tumor hierarchy in a lethal cancer

“…Oncolytic viral therapy represents a new therapeutic modality with increasing promise. Improved oncolytic adenovirus treatment regimens have demonstrated efficacy in mouse models through stimulating an influx of T cells (Jiang et al 2017) and in human patients through altering the composition of TAMs (van den Bossche et al 2018). Modified herpes simplex viruses combined with immune checkpoint inhibition increase CD8 + killer T-cell infiltration and transition to a more inflammatory antitumor macrophage phenotype (Saha et al 2017).…”

A Flow Cytometry-Based Method to Determine the Titer of Adenoviruses Expressing an Extraneous Gene

“…[22][23][24][25] In recent times, different types of recombinant oncolytic viruses have been developed, which enhance the functioning of the immune system against cancer, by attenuating the PD-1/PD-L1 axis and/or enhancing cancer immune system. [26][27][28] The high precision of expression titers like a GFP 50 titer helps accurate determination of the viral titer and transgene expression level, which, in turn, contributes to the quality control regimen for pharmaceutical products. Expression levels of transgene products can be measured by immunofluorescent staining using specific antibodies, instead of using reporter genes, including GFP.…”

Delivery and Biosafety of Oncolytic Virotherapy

“…The elevated expression of PD-L1 in the tumor microenvironment inhibits the infiltration of immune cells, which results in an immunosuppressed tumor microenvironment, which restricts the antitumor effect of oncolytic viruses. The combined approach of an oncolytic virus and a PD-1 or PD-L1 blockade can enhance antitumor immunity and the oncolytic effect (25)(26)(27)(28). Additionally, the combination of oncolytic virotherapy and CAR-T immunotherapy produces a synergistic effect in cancer patients.…”