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The promise of oncolytic viral therapy for the treatment of peritoneal surface malignancies
Published in Wim P. Ceelen, Edward A. Levine, Intraperitoneal Cancer Therapy, 2015
John H. Stewart, Lauren Gillory
Several clinical trials of oncolytic adenovirus therapies have been reported [19,24,25]. The ONYX-015 (Pfizer Corp., Groton, CT) adenovirus was the first replication-selective oncolytic adenovirus used in clinical trials [26,27]. This oncolytic virus, which contains a deletion of the gene encoding the p53-inactivating protein E1B, specifically kills tumor cells with p53 mutations [28]. To date, more than 18 clinical trials have been conducted with ONYX-015 against a variety of cancers, including colorectal and ovarian carcinomas [19,29]. However, the antitumor efficacy of ONYX-015 as a single agent was disappointing in the majority of these trials [24,30].
Virus Wars
Published in Satya Prakash Gupta, Cancer-Causing Viruses and Their Inhibitors, 2014
Markus Vähä-Koskela, Fabrice Le Boeuf, Vincenzo Cerullo
As a modern day example, an oncolytic E1A Rb-binding defective adenovirus engineered to express HPV E2, a negative regulator of the HPV oncogenes E6 and E7, showed increased oncolytic activity against HPV-positive cancer cells compared to parental backbone virus (Wang et al. 2011). The E2-expressing adenovirus also conferred tumor cell sensitivity to ionizing radiation, which is a hallmark of HPV-associated cervical cancer, and it synergized with external beam irradiation in treating animals bearing HPV-positive xenografts. This strategy potentially also benefited from the capacity of HPV E6 protein to transactivate heterologous virus promoters, including the herpes simplex TK and adenovirus E2-promoter (Shirasawa et al. 1994). Moreover, HPV E7 protein counters the Rb-activating properties of HPV E2 protein, and constitutive E7 expression is required to maintain cell cycle in HPV-transformed cells (Psyrri et al. 2004). Therefore, oncolytic adenovirus in which the Rb-inactivating features have been removed could benefit from HPV-E7-mediated Rb silencing. Although not oncolytic, a replication-defective adenovirus vector expressing p53 homolog p73beta could overcome HPV E6-mediated loss of p53, inducing cell cycle arrest and apoptosis in HPV-infected tumor cells (Das et al. 2003). Overall, oncolytic adenovirus may be an excellent oncolytic candidate for treatment of HPV-induced cancer.
Molecular Imaging in Prostate Cancer
Published in Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman, Molecular Imaging in Oncology, 2008
Steve Y. Cho, Martin G. Pomper
One group that has expended great effort attempting to optimize gene therapy for PCa has been that at the Henry Ford Health System. They have performed studies in preclinical models, including canine dosimetry, using the sodium-iodide symporter (NIS) as the reporter gene and 99mTcO4 as the reporter probe (163,164). The strategy they employ is to use a replication-competent oncolytic adenovirus in combination with radiation therapy (165). The vector they use is conveniently outfitted with an imaging reporter (NIS). The vector, Ad5-yCD/mutTKSR39rep-hNIS, produces cytosine deaminase (for suicide gene therapy), a mutant form of the HSV1-TK, also for gene therapy—with ganciclovir—and the NIS for imaging. The HSV1-TK could also be used for imaging, with a suitably labeled TK substrate, such as 1-(2′-deoxy-2′fluoro-β-d-arabinofuranosyl)-5-[ 124I]iodouracil ([124I] FIAU) for PET, making this essentially a dual modality theranostic agent. The goals of clinical molecular-genetic imaging in PCa have been summarized by Freytag et al. as (i) to assess the quality of the adenovirus injection (although at more than one day after the injection), (ii)to determine the level and volume of therapeutic gene expression in the prostate, which can be correlated with clinical outcome, (iii) to optimize the deposition of adenovirus in the target organ, (iv) to determine the whole-body distribution of adenovirus, and (v) with serial imaging, to determine the persistence of therapeutic gene expression in the prostate, which can be correlated with clinical outcome. Kinetic studies such as that shown in Figure 10 have been performed, with changes in gene expression demonstrated long before any anatomic change in the tumor due to the oncolytic adenovirus are demonstrated. This study represents the first true molecular-genetic imaging study in PCa and is emblematic of the kinds of studies that will facilitate gene therapy for prostate and other cancers in the future.
Progress in the application of hydrogels in immunotherapy of gastrointestinal tumors
Published in Drug Delivery, 2023
Hao Zheng, Meng Li, Lili Wu, Wenshang Liu, Yu Liu, Jie Gao, Zhengmao Lu
In addition to systemic drug delivery, diverse effector cells and an oncolytic adenovirus expressing antitumor cytokines can be injected into tumors to exert an effective immunotherapy influence by oncolysis and transforming the tumor microenvironment. However, certain limitations were associated with this combination therapy. A large number of nontarget tissues can be infiltrated by effector cells and oncolytic viruses when the combination therapy is used at high concentrations. Moreover, because of the immunogenic nature of both treatments and their shorter bioactivity, multiple administrations were required to achieve a satisfactory curative effect. To overcome these barriers, Du et al. (Du et al., 2022) encapsulated a gelatin-based hydrogel capable of codelivery of an oncolytic adenovirus containing IL12, IL15 and CIK cells to enhance and prolong the antitumor effects of combined treatments after a single intratumoral injection in a colon cancer model. With an injectable, biodegradable hydrogel encapsulating high-dose oncolytic adenovirus, possible dispersion of the virus and CIK cells to the liver and nontarget tissues is reduced, and an effective antitumor immune response is continuously induced with only one single dosing ratio.
CXCL10-armed oncolytic adenovirus promotes tumor-infiltrating T-cell chemotaxis to enhance anti-PD-1 therapy
Published in OncoImmunology, 2022
Xiaofei Li, Mingjie Lu, Manman Yuan, Jing Ye, Wei Zhang, Lingyan Xu, Xiaohan Wu, Bingqing Hui, Yuchen Yang, Bin Wei, Ciliang Guo, Min Wei, Jie Dong, Xingxin Wu, Yanhong Gu
We found an increasing expression of PD-L1 on the MC38-CAR cells when they treated with oncolytic adenovirus. Also, we observed the same tendency during the oncolytic adenovirus therapy in vivo (Supplementary Figure S4). This suggested the treatment of oncolytic adenovirus enabled the TME to turn into a ‘hotter’ position, so we next wondered whether it could further enhance the anti-PD-1 effect in a colon cancer model. A brief experimental procedure is shown in Figure 4a. Consistent with our previous discovery, Adv-Ctrl- or Adv-CXCL10-treated mice showed a lower tumor volume than control mice. Surprisingly, Adv-CXCL10 strongly enhanced the therapeutic effect of the PD-1 antibody, and the tumor volume of the corresponding group even remained at a lower plateau for several days (Figure 4b-d). Notably, none of the interventions influenced the mouse’s body weight, indicating the safety of these treatments (Supplementary Figure S5). We further observed the survival rate of different groups and found that the mice in the Adv-CXCL10+ anti-PD-1 group lived longer than others (Figure 4e). H&E and TUNEL assays showed the best apoptosis-promoting effect in combination with Adv-CXCL10 and anti-PD-1 therapy (Figure 4f–i), and this combination also inhibited tumor proliferation compared with other regimens (Figure 4h,j).
Oncolytic adenovirus promotes vascular normalization and nonclassical tertiary lymphoid structure formation through STING-mediated DC activation
Published in OncoImmunology, 2022
Teng He, Zhixing Hao, Mingjie Lin, Zhongwei Xin, Yongyuan Chen, Wei Ouyang, Qi Yang, Xiaoke Chen, Hui Zhou, Wanying Zhang, Pin Wu, Feng Xu
We observed that the therapeutic effect of Ad-IL15 was different in the two mouse subcutaneous tumor models. In TME after Ad-IL15 treatment, the infiltrating T cells and NK cells were also inconsistent. This may be due to tumor heterogeneity. B16-F10 cells are tumor cells with low immunogenicity, while MC-38 cells are tumor cells with high immunogenicity.55 The main role of oncolytic adenovirus is to promote the transformation of “cold tumors” into “hot tumors”. Therefore, the chemotactic effects of Ad-IL15-treated B16-F10 and MC-38 on NK cells may be different. Interestingly, Ad-IL15 inhibited the growth of subcutaneous tumors compared with PBS treatment in the B16-F10 model of Rag-1−/− mice, which may be mediated by Ad-IL15-induced NK cell infiltration. Recently, an oncolytic vaccinia virus armed with IL15-Rα has demonstrated effective tumor growth inhibition in the intraperitoneal model of MC-38 colon cancer.56 The virus induced increased infiltration of immune cells, but depletion experiments showed that its antitumor effect was mainly dependent on CD8+T cells rather than NK cells. This may be due to the fact that the virus can inhibit NK cell functions in the TME through direct infection or the virus encodes multiple genes whose products are to inhibit NK cells via inhibition of the nuclear factor ĸB (NF- ĸB) pathway. This suggests that NK cells may play different roles in different types of viruses and tumor models.