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The effects of radiation on antitumor efficacy of an oncolytic adenovirus vector in the Syrian hamster model.

ABSTRACT: We report that radiation enhances the antitumor efficacy of the oncolytic adenovirus vector VRX-007 in Syrian hamster tumors. We used tumor-specific irradiation of subcutaneous tumors and compared treatment options of radiation alone or combined with VRX-007 and cyclophosphamide (CP). Radiation therapy further augmented the VRX-007-mediated inhibition of tumor growth, in both CP-treated and non-CP-treated hamsters, even though radiation did not lead to increased viral replication in tumors when compared with those treated with VRX-007 alone. Moreover, tumor growth inhibition was similar in tumors irradiated either 1 week before or after injection with VRX-007, which suggests that radiation exerts its antitumor effect independently from vector therapy. Thus, our results demonstrate that these two therapies do not have to be provided simultaneously to enhance their combined effectiveness against subcutaneous hamster tumors.

SUBMITTER: Young BA

PROVIDER: S-EPMC3778061 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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The effects of radiation on antitumor efficacy of an oncolytic adenovirus vector in the Syrian hamster model.

Young B A BA Spencer J F JF Ying B B Toth K K Wold W S M WS

Cancer gene therapy 20130809 9

We report that radiation enhances the antitumor efficacy of the oncolytic adenovirus vector VRX-007 in Syrian hamster tumors. We used tumor-specific irradiation of subcutaneous tumors and compared treatment options of radiation alone or combined with VRX-007 and cyclophosphamide (CP). Radiation therapy further augmented the VRX-007-mediated inhibition of tumor growth, in both CP-treated and non-CP-treated hamsters, even though radiation did not lead to increased viral replication in tumors when ...[more]

PMID: 23928730

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Immunosuppression enhances oncolytic adenovirus replication and antitumor efficacy in the Syrian hamster model.

Project description:We recently described an immunocompetent Syrian hamster model for oncolytic adenoviruses (Ads) that permits virus replication in tumor cells as well as some normal tissues. This model allows exploration of interactions between the virus, tumor, normal organs, and host immune system that could not be examined in the immunodeficient or nonpermissive animal models previously used in the oncolytic Ad field. Here we asked whether the immune response to oncolytic Ad enhances or limits antitumor efficacy. We first determined that cyclophosphamide (CP) is a potent immunosuppressive agent in the Syrian hamster and that CP alone had no effect on tumor growth. Importantly, we found that the antitumor efficacy of oncolytic Ads was significantly enhanced in immunosuppressed animals. In animals that received virus therapy plus immunosuppression, significant differences were observed in tumor histology, and in many cases little viable tumor remained. Notably, we also determined that immunosuppression allowed intratumoral virus levels to remain elevated for prolonged periods. Although favorable tumor responses can be achieved in immunocompetent animals, the rate of virus clearance from the tumor may lead to varied antitumor efficacy. Immunosuppression, therefore, allows sustained Ad replication and oncolysis, which leads to substantially improved suppression of tumor growth.

| S-EPMC3437752 | biostudies-other

The role of cyclophosphamide in enhancing antitumor efficacy of an adenovirus oncolytic vector in subcutaneous Syrian hamster tumors.

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| S-EPMC3778155 | biostudies-literature

Pre-existing immunity and passive immunity to adenovirus 5 prevents toxicity caused by an oncolytic adenovirus vector in the Syrian hamster model.

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Effect of preexisting immunity on oncolytic adenovirus vector INGN 007 antitumor efficacy in immunocompetent and immunosuppressed Syrian hamsters.

Project description:Immune responses against adenovirus (Ad) vectors pose a possible concern for the outcome of treatment efficacy. To address the role of preexisting immunity in oncolytic Ad vector antitumor efficacy following intratumoral injection of vector as well as tumor-to-tissue spread of the vector, we employed the Syrian hamster model. These animals are immunocompetent, and their tumors and tissues are permissive for replication of Ad type 5 (Ad5). We used the adenovirus death protein-overexpressing Ad5-based vector INGN 007. Subcutaneous tumors were established in groups of hamsters that were or were not immunized with Ad5. Half of the hamsters in these groups were immunosuppressed with cyclophosphamide. For all groups, tumors injected with INGN 007 grew significantly more slowly than those injected with buffer. Under immunocompetent conditions, there was no significant effect of preexisting immunity on vector antitumor efficacy. Soon after the tumors in naïve animals were injected with vector, the hamsters developed neutralizing antibody (NAb) and the difference in NAb titers between the naïve and immunized groups diminished. Under immunosuppressed conditions, preexisting NAb did significantly reduce vector efficacy. Thus, NAb do reduce vector efficacy to some extent, but immunosuppression is required to observe the effect. Regarding vector toxicity, there was spillover of vector from the tumor to the liver and lungs in naïve immunocompetent hamsters, and this was nearly eliminated in the immunized hamsters. Thus, preexisting immunity to Ad5 does not affect INGN 007 antitumor efficacy following intratumoral injection, but immunity prevents vector spillover from the tumor to the liver and lungs.

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Bifidobacterium affects antitumor efficacy of oncolytic adenovirus in a mouse model of melanoma.

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Oncolytic adenovirus coexpressing interleukin-12 and shVEGF restores antitumor immune function and enhances antitumor efficacy.

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| S-EPMC5356712 | biostudies-literature

INGN 007, an oncolytic adenovirus vector, replicates in Syrian hamsters but not mice: comparison of biodistribution studies.

Project description:Preclinical biodistribution studies with INGN 007, an oncolytic adenovirus (Ad) vector, supporting an early stage clinical trial were conducted in Syrian hamsters, which are permissive for Ad replication, and mice, which are a standard model for assessing toxicity and biodistribution of replication-defective (RD) Ad vectors. Vector dissemination and pharmacokinetics following intravenous administration were examined by real-time PCR in nine tissues and blood at five time points spanning 1 year. Select organs were also examined for the presence of infectious vector/virus. INGN 007 (VRX-007), wild-type Ad5 and AdCMVpA (an RD vector) were compared in the hamster model, whereas only INGN 007 was examined in mice. DNA of all vectors was widely disseminated early after injection, but decayed rapidly in most organs. In the hamster model, DNA of INGN 007 and Ad5 was more abundant than that of the RD vector AdCMVpA at early times after injection, but similar levels were seen later. An increased level of INGN 007 and Ad5 DNA but not AdCMVpA DNA in certain organs early after injection, and the presence of infectious INGN 007 and Ad5 in lung and liver samples at early times after injection, strongly suggests that replication of INGN 007 and Ad5 occurred in several Syrian hamster organs. There was no evidence of INGN 007 replication in mice. In addition to providing important information about INGN 007, the results underscore the utility of the Syrian hamster as a permissive immunocompetent model for Ad5 pathogenesis and oncolytic Ad vectors.

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Antitumor Effects of Oncolytic Adenovirus-Carrying siRNA Targeting Potential Oncogene EphA3.

Project description:Conditionally replicating adenoviruses (CRAds) armed with antitumor transgenes hold promise for cancer treatment. In previous studies, we showed that the 1504-siRNA targeting potential oncogene EphA3 was an efficient therapeutic transgene and that the telomerase reverse transcriptase promoter (TERTp) driving the CRAd was a more advanced generation of CRAd. Therefore, we combined Ad-TERTp-E1A-1504 by inserting 1504-siRNA into the CRAd to study its antitumor effects and mechanism of action, using Ad-TERTp-E1A-NC and nonreplicating adenovirus carrying 1504-siRNA as controls. Cell viability assays and ED50 studies of growth inhibition confirmed that Ad-TERTp-E1A-1504 has 3.5- and 1,400-fold greater ability to kill EphA3- and TERT-expressing tumor cells compared to Ad-TERTp-E1A-NC and Ad-ΔE1A-1504, respectively. Also, Ad-TERTp-E1A-1504 had little effect on cells that modestly expressed EphA3 and TERT such as 2BS. The antitumor efficacy of Ad-TERTp-E1A-1504 was also validated in vivo. Furthermore, the virus yield of Ad-TERTp-E1A-1504 in C4-2B was ~1,000 times greater than that in 2BS. No obvious differences were observed between Ad-TERTp-E1A-1504 and Ad-TERTp-E1A-NC. Both acridine orange staining and Beclin1 protein measurements indicated that autophagy with Ad-TERTp-E1A-1504 at 5 and 10 MOI was higher than that of Ad-TERTp-E1A-NC. Finally, the classical negatively regulated autophagy signaling pathway, PI3K/AKT/mTOR, was suppressed (reduced phosphorylated form) in contrast to NC, and that this was mediated by 1504-siRNA. Thus, Ad- TERTp-E1A-1504 does not harm normal cells but has dual inhibiting and killing effects on TERT- and EphA3-positive tumor cells, and this effect is mediated by the AKT/mTOR signaling pathway via induction of autophagy. These data may offer a foundation for novel antitumor therapies targeting this mechanism.

| S-EPMC4433270 | biostudies-literature

Syngeneic syrian hamster tumors feature tumor-infiltrating lymphocytes allowing adoptive cell therapy enhanced by oncolytic adenovirus in a replication permissive setting.

Project description:Adoptive transfer of tumor-infiltrating lymphocytes (TIL) has shown promising yet sometimes suboptimal results in clinical trials for advanced cancer, underscoring the need for approaches improving efficacy and safety. Six implantable syngeneic tumor cell lines of the Syrian hamster were used to initiate TIL cultures. TIL generated from tumor fragments cultured in human interleukin-2 (IL-2) for 10 d were adoptively transferred into tumor-bearing hamsters with concomitant intratumoral injections of oncolytic adenovirus (Ad5-D24) for the assessment of antitumor efficacy. Pancreatic cancer (HapT1) and melanoma (RPMI 1846) TIL exhibited potent and tumor-specific cytotoxicity in effector-to-target (E/T) assays. MHC Class I blocking abrogated the cell killing of RPMI 1846 TIL, indicating cytotoxic CD8(+) T-cell activity. When TIL were combined with Ad5-D24 in vitro, HapT1 tumor cell killing was significantly enhanced over single agents. In vivo, the intratumoral administration of HapT1 TIL and Ad5-D24 resulted in improved tumor growth control compared with either treatment alone. Additionally, splenocytes derived from animals treated with the combination of Ad5-D24 and TIL killed autologous tumor cells more efficiently than monotherapy-derived splenocytes, suggesting that systemic antitumor immunity was induced. For the first time, TIL of the Syrian hamster have been cultured, characterized and used therapeutically together with oncolytic adenovirus for enhancing the efficacy of TIL therapy. Our results support human translation of oncolytic adenovirus as an enabling technology for adoptive T-cell therapy of solid tumors.

| S-EPMC4910707 | biostudies-literature

Strong antitumor efficacy of a pancreatic tumor-targeting oncolytic adenovirus for neuroendocrine tumors.

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| S-EPMC5633550 | biostudies-literature

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