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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.

SUBMITTER: Kleijn A

PROVIDER: S-EPMC4035348 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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The in vivo therapeutic efficacy of the oncolytic adenovirus Delta24-RGD is mediated by tumor-specific immunity.

Kleijn Anne A Kloezeman Jenneke J Treffers-Westerlaken Elike E Fulci Giulia G Leenstra Sieger S Dirven Clemens C Debets Reno R Lamfers Martine M

PloS one 20140527 5

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 trea ...[more]

PMID: 24866126

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Project description:Abstract Based on promising results of recent clinical trials using oncolytic viruses, virotherapy is evolving as an alternative to treat patients with malignant glioma. Our group developed the oncolytic adenovirus Delta-24-RGD (DNX-2401) that is being tested, alone or in combination with anti-PD1, in clinical trials for recurrent glioblastoma (NCT00805376; NCT01956734; NCT02798406). The results suggest that, besides the expected oncolytic effect, the injection of the pathogen initiated, in a subset of patients, an anti-tumoral immunity that led to 20% of long-term survivors (3.5–5 years). To further enhance this effect, we have armed Delta-24-RGD to express the co-stimulatory ligand GITRL, and generated Delta-24-GREAT. The intracranial injection of Delta-24-GREAT prolonged the survival of GL261 glioma-bearing immunocompetent mice when compared to Delta-24-RGD treatment (P=0.002, log-rank test). Delta-24-GREAT treatment resulted in enhanced frequency of tumor-infiltrating lymphocytes: T lymphocytes (CD45+/CD3+) and cytotoxic T lymphocytes (CD45+CD3+CD8+). Functional studies performed by culturing splenocytes from Delta-24-GREAT-treated mice with glioma cells and analyzing secretion of Th1 cytokines, such as IL2 and IFN-?, showed that lymphocytes recognized not only viral antigens but also tumoral antigens, suggesting the triggering of anti-tumoral immunity. Of interest, Delta-24-GREAT treatment resulted in an antigen-restricted anti-tumor memory effect and in the generation of central immune memory. Thus, rechallenging the survivor mice from the first experiment with a second implantation of glioma cells did not lead to tumor growth, and we detected an increased frequency of central memory CD8+ T cells (CD45+CD62L+). However, survivor mice developed lethal tumors when implanted intracranially with B16/F10 melanoma cells, strongly indicating that the developed immune response was specific for GL261 glioma antigens. This is a novel approach using an oncolytic adenovirus expressing GITRL to target cancer and to stimulate the immunity within the tumor. Our data strongly indicate that this type of strategy may be further developed to treat patients with malignant glioblastoma.

Project description:BackgroundSurvivin and octamer-binding transcription factor 4 (OCT4) are reportedly up-regulated in esophageal cancer (EC) and have been correlated with high tumor proliferative activity and poor prognosis. Oncolytic viruses encoding specific transgenes have been considered as therapeutic methods to increase therapeutic efficacy in a variety of solid tumors.MethodsIn this study, an oncolytic adenovirus carrying short hairpin RNA (shRNA) of survivin (shSRVN) and OCT4 (shOCT4) was constructed to achieve dual knockdown of survivin and OCT4 and to explore the potential effect of the oncolytic adenovirus in EC.ResultsThe oncolytic adenovirus replicated abundantly in human EC cells, with the replication multiplying by up to 192,085 and 620,055 times in esophageal carcinoma (Eca)-109 cells transfected with purified and completed recombinant adenoviruses called AdSProE1a-dual shRNA (shSRVN + shOCT4) and TE1 cells transfected with AdSProE1a-survivin shRNA (shSRVN) 96 hours after infection, respectively. The shRNAs targeting survivin and OCT4 significantly downregulated the expression levels of survivin and OCT4 in cells, thereby inhibiting the proliferative activity of cancer cells. Furthermore, E-cadherin and vimentin, which are both considered epithelial mesenchymal transition (EMT) markers, were found to be upregulated and downregulated, respectively, in cancer cells after exposure to the viral infection. The interference of survivin and OCT4 also contributed to cell cycle arrest and apoptosis, the half maximal inhibitory concentrations (IC50s) of oncolytic adenovirus loaded with AdSProE1a-shSRVN + shOCT4 in the Eca109 cells and the TE1 cells were 0.7271 and 0.1032 pfu/mL, respectively. Xenograft experiments in vivo showed that oncolytic adenovirus-mediated dual knockdown of survivin and OCT4 effectively inhibited the growth of xenografts and induced cancer cell apoptosis. We concluded that therapies targeting survivin and OCT4 have great potential for improving the therapeutic efficacy in EC.ConclusionsThe dual target design strategy ensured the efficacy and safety of the treatment system and provided a novel and effective adjuvant target therapy for EC.

Project description:Abstract Atypical teratoid/rhabdoid tumors (ATRTs) and primitive neuroectodermal tumors (PNETs) are two rare primary embryonal brain tumors, which are among the most frequent solid brain tumors in infants under one year old. The outcome for these children remains dismal, especially in ATRTs which have a 2-year overall survival below 20%. Therefore, we need to find out new efficient and safe therapeutic options for these children. Delta-24-RGD (DNX-2401 in the clinic) is an oncolytic adenovirus that has already been tested in Phase I/II clinical trials in patients affected by recurrent glioblastoma (NCT00805376; NCT01956734), demonstrating anti-tumor effect without any evidence of severe side effect associated with viral administration. Of interest for pediatric brain tumors, an ongoing Phase I trial using Delta-24-RGD for the treatment of diffuse intrinsic pontine gliomas (NCT03178032) has also demonstrated a safe profile in these children. For these reasons, we propose to evaluate the anti-tumor effect of Delta-24-RGD in preclinical models of ATRT and PNET. The virus was able to infect and replicate in tumor cell cultures (three models of ATRT and four of PNET), inducing a potent cytotoxic effect. In addition, this cytotoxicity resulted in the released the immunogenic cell death markers Hsp70, Hsp90, HMGB1 and ATP, as well as an increased calreticulin exposure in the outer cell surface. Although not conclusive, the presence of these markers suggest the triggering of an anti-tumor immune response. Intratumoral administration of the virus extended significantly the overall survival of mice bearing ATRT or PNET xenografts, leading to up to 40% of long-term survivors. We are currently setting up an intraventricular model of disseminated disease, since most of patients with ATRT actually die due to the presence of metastases. In conclusion, these results demonstrate that Delta-24-RGD could be a feasible therapeutic option for children with PNETs and AT/RTs.

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The in vivo therapeutic efficacy of the oncolytic adenovirus Delta24-RGD is mediated by tumor-specific immunity.

Publications

The in vivo therapeutic efficacy of the oncolytic adenovirus Delta24-RGD is mediated by tumor-specific immunity.

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