The In Vivo Therapeutic Efficacy of the Oncolytic Adenovirus Delta24-RGD Is Mediated by Tumor-Specific Immunity

Abstract

The oncolytic adenovirus Delta24-RGD represents a new promising therapeutic agent for patients with a malignant glioma and is currently under investigation in clinical phase I/II trials. Earlier preclinical studies showed that Delta24-RGD is able to effectively lyse tumor cells, yielding promising results in various immune-deficient glioma models. However, the role of the immune response in oncolytic adenovirus therapy for glioma has never been explored. To this end, we assessed Delta24-RGD treatment in an immune-competent orthotopic mouse model for glioma and evaluated immune responses against tumor and virus. Delta24-RGD treatment led to long-term survival in 50% of mice and this effect was completely lost upon administration of the immunosuppressive agent dexamethasone. Delta24-RGD enhanced intra-tumoral infiltration of F4/80+ macrophages, CD4+ and CD8+ T-cells, and increased the local production of pro-inflammatory cytokines and chemokines. In treated mice, T cell responses were directed to the virus as well as to the tumor cells, which was reflected in the presence of protective immunological memory in mice that underwent tumor rechallenge. Together, these data provide evidence that the immune system plays a vital role in the therapeutic efficacy of oncolytic adenovirus therapy of glioma, and may provide angles to future improvements on Delta24-RGD therapy.

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

“…56,57 Although different immune-stimulatory agents were investigated, the discrepancies between these results may be due to the timing of dexamethasone treatment relative to tumor implantation. Whereas treatment was postponed until tumor establishment, other studies gave dexamethasone either before or immediately following tumor implantation.…”

Adenovirus Improves the Efficacy of Adoptive T-cell Therapy by Recruiting Immune Cells to and Promoting Their Activity at the Tumor

“…Adenovirus infection of tumors results in chemokine secretion, release of tumor-associated antigens (TAA) from infected dying tumor cells, and activation of APCs, which recognize the multiple pathogen-associated molecular patterns (PAMP) of the virus (9). Importantly, infection also results in changes in immune cell composition of the tumor, supporting the argument that local immunosuppression can be overcome (11). As the efficacy of adoptive antitumor immunotherapy may depend on support by innate immune responses (12), combination with oncolytic virus therapy appears an attractive approach that warrants testing.…”

Immune Checkpoint Blockade, Immunogenic Chemotherapy or IFN-α Blockade Boost the Local and Abscopal Effects of Oncolytic Virotherapy

“…In the majority of cases, the most effective OV treatments combine potent viral oncolysis with induction of a specific immune response against tumor antigens, as shown in several clinical and preclinical studies (9)(10)(11)(12). The mechanisms how OV therapies elicit antitumor immune responses are not clearly understood yet, but likely involve the capture of released tumor antigens by bystander antigen-presenting cells (APC) following tumor cell lysis (13).…”