Search

Gastrointestinal (GI) cancers are characterized by extensive tumor stroma that both promotes tumor progression and acts as a physical barrier for adjacent tumor cells, limiting the effect of current treatment modalities. Oncolytic virotherapy is currently investigated in clinical trials as a novel therapeutic agent for different malignancies of the GI tract, but it is largely unknown whether these viruses can also target the tumor stroma. Here, we investigated the tropism of two commonly studied OVs, adenovirus and reovirus, towards primary GI fibroblasts from human oesophageal, gastric, duodenal and pancreatic carcinomas (N = 36). GI fibroblasts were susceptible to type 3 Dearing (T3D) strain R124 and bioselected mutant reovirus (jin-3) infection but not oncolytic adenovirus (Ad5-Δ24). Efficient infection and apoptosis of human and mouse GI cancer-derived fibroblasts by these reoviruses was partially dependent on the expression of the reovirus entry receptor, Junctional Adhesion Molecule-A (JAM-A). Moreover, human GI cancer organoid-fibroblast co-cultures showed higher overall infectivity when containing JAM-A expressing fibroblasts as compared to JAM-A negative fibroblasts, indicating a potential role of JAM-A expressing fibroblasts for viral dissemination. We further show that JAM-A is not only necessary for efficient reovirus infection of fibroblasts but also partially mediates reovirus-induced apoptosis, dependent on signaling through the C-terminal PDZ-domain of JAM-A. Altogether, our data show the presence of JAM-A expressing fibroblasts in both human and murine GI cancers that are amenable to infection and induction of apoptosis by reovirus, extending the potential anti-cancer actions of reovirus with stromal targeting., (© 2022. The Author(s).)

The use of human adenoviruses (hAds) as oncolytic agents has demonstrated considerable potential. However, their efficacy in clinical studies is generally moderate and often varies between patients. This may, in part, be attributable to variable pre-existing neutralizing immunity in patients, which can impact the antitumor efficacy and lead to response heterogeneity. Our aim was to isolate new Ads for the development of oncolytic vectors with low prevalence of neutralizing immunity in the human population. To this end, we isolated a collection of new nonhuman primate (nhp) Ads from stool samples of four great ape species held captive. We elected 12 isolates comprising the broadest genetic variability for further characterization. For three new nhpAds, all classified as the human adenovirus B (HAdV-B) species, no neutralizing activity could be detected when exposed to a preparation of immunoglobulins isolated from a pool of >1,000 donors as a surrogate of population immunity. In addition, the nhpAds of the HAdV-B species showed enhanced oncolytic potency compared to nhpAds of the HAdV-C species as well as to human adenovirus type 5 (HAdV-C5) in vitro when tested in a panel of 29 human cancer cell lines. Next-generation sequencing of the viral genomes revealed higher sequence similarity between hAds and nhpAds of HAdV-B compared to HAdV-C, which might underlie the differences in oncolytic ability. As a proof-of-concept, the Rb-binding domain of the E1A protein of the gorilla-derived HAdV-B nhpAd-lumc007 was deleted, thereby creating a new oncolytic derivative, which demonstrated increased oncolytic potential compared to HAdV-C5. Collectively, our data demonstrate that nhpAds of the HAdV-B species can serve as an alternative for the development of potent oncolytic Ad vectors with limited pre-existing neutralizing immunity in humans.

The use of oncolytic viruses forms an appealing approach for cancer treatment. On the one hand the viruses replicate in, and kill, tumor cells, leading to their intra-tumoral amplification. On the other hand the viral infection will activate virus-directed immune responses, and may trigger immune responses directed against tumor cells and tumor antigens. To date, a wide variety of oncolytic viruses is being developed for use in cancer treatment. While the development of oncolytic viruses has often been initiated by researchers in academia and other public institutions, a large majority of the final product development and the testing of these products in clinical trials is industry led. As a consequence relatively few pre-clinical and clinical studies evaluated different oncolytic viruses in competitive side-by-side preclinical or clinical studies. In this review we will summarize the steps and considerations essential in the development and characterization of oncolytic viruses, and describe our multidisciplinary academic consortium, which involves a dozen departments in three different Dutch universities, collaborating in the development of oncolytic viruses. This consortium has the ambition to develop a small series of oncolytic viruses and to evaluate these in various cancers., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Reoviruses are non-enveloped viruses with a segmented double stranded RNA genome. In humans, they are not associated with serious disease. Human reoviruses exhibit an inherent preference to replicate in tumor cells, which makes them ideally suited for use in oncolytic virotherapies. Their use as anti-cancer agent has been evaluated in several clinical trials, which revealed that intra-tumoral and systemic delivery of reoviruses are well tolerated. Despite evidence of anti-tumor effects, the efficacy of reovirus in anti-cancer monotherapy needs to be further enhanced. The opportunity to treat both the primary tumor as well as metastases makes systemic delivery a preferred administration route. Several pre-clinical studies have been conducted to address the various hurdles connected to systemic delivery of reoviruses. The majority of those studies have been done in tumor-bearing immune-deficient murine models. This thwarts studies on the impact of the contribution of the immune system to the tumor cell eradication. This review focuses on key aspects of the reovirus/host-cell interactions and the methods that are available to modify the virus to alter these interactions. These aspects are discussed with a focus on improving the reovirus' antitumor efficacy.

A descriptive, correlational design was used to investigate the relationship of the longevity of the cancer experience and the presence of a relapse to the child's self-perception, cancer stressors, anxiety, and use of coping strategies. The 44 children included in this study were 6 1/2 to 13 1/2 years of age. Fifteen of the children had experienced a relapse of the disease either on or off therapy. The longevity of the cancer treatment and the presence of a relapse were negatively associated with the child's self-perception. Trait anxiety was positively associated with duration of the cancer experience and with the presence of a relapse. Longevity of the cancer experience and the presence of a relapse may be factors that signal the need for interventions designed to enhance the child's self-perception throughout treatment. Because children in this study who reported lower self-perception and higher trait anxiety levels also reported experiencing more cancer stressors, nursing efforts to develop innovative strategies designed to enhance patients' feelings of self-worth and decrease their anxiety may prove to be important contributions to the care of children receiving treatment for cancer.

Perceptions of cancer stressors and protective factors are predictors of stress experienced during treatment for childhood cancer were assessed in this study. Cancer stressors were the type of treatment received during two clinic visits and the child's perception of the cancer experience. Protective factors were self-perception, coping strategies, perceived social support, and family environment. The child's responses to stressors were assessed by epinephrine, norepinephrine, and cortisol levels of urine, and measures of state anxiety. Forty-four children between 6 1/2 and 13 1/2 years of age receiving treatment for cancer were evaluated during two clinic visits. Epinephrine was elevated for children during both clinic visits, while norepinephrine and cortisol remained normal. Stepwise multiple regression analyses revealed that the family environment and global self-worth were the best predictors of epinephrine levels, while social support from friends predicted norepinephrine levels. The family environment and social support from teachers predicted state anxiety.

This study investigated life change events and coping behaviors in families of children with cancer compared with those who have physically healthy children. The sample consisted of 21 families with a child with cancer and 17 families with physically healthy children. All the children in the study were 6 to 12 years of age. Parents from each group completed items from the Family Inventory of Life Events and Changes and the Family Crisis Oriented Evaluation Scales. These tools evaluate stressful life change events experienced by families within a 12-month period and coping behaviors used by families during difficult situations. Families with a child who has cancer experienced significantly more stressful life change events (t = 2.15, P = 0.04) than those with physically healthy children. There were no significant differences (t = 0.23, P = 0.82) in the coping behaviors that were used by the two groups. The results provided a clearer understanding of stressful life change events that impact families with a child with cancer.