Tumors are complex ecosystems composed of networks of interacting 'normal' and malignant cells. It is well recognized that cytokine-mediated cross-talk between normal stromal cells, including cancer-associated fibroblasts (CAFs), vascular endothelial cells, immune cells, and cancer cells, influences all aspects of tumor biology. Here we demonstrate that the cross-talk between CAFs and cancer cells leads to enhanced growth of oncolytic virus (OV)-based therapeutics. Transforming growth factor-β (TGF-β) produced by tumor cells reprogrammed CAFs, dampened their steady-state level of antiviral transcripts and rendered them sensitive to virus infection. In turn, CAFs produced high levels of fibroblast growth factor 2 (FGF2), initiating a signaling cascade in cancer cells that reduced retinoic acid-inducible gene I (RIG-I) expression and impeded the ability of malignant cells to detect and respond to virus. In xenografts derived from individuals with pancreatic cancer, the expression of FGF2 correlated with the susceptibility of the cancer cells to OV infection, and local application of FGF2 to resistant tumor samples sensitized them to virotherapy both in vitro and in vivo. An OV engineered to express FGF2 was safe in tumor-bearing mice, showed improved therapeutic efficacy compared to parental virus and merits consideration for clinical testing.

Oncolytic viruses (OVs) have shown promising clinical activity when administered by direct intratumoral injection. However, natural barriers in the blood, including antibodies and complement, are likely to limit the ability to repeatedly administer OVs by the intravenous route. We demonstrate here that for a prototype of the clinical vaccinia virus based product Pexa-Vec, the neutralizing activity of antibodies elicited by smallpox vaccination, as well as the anamnestic response in hyperimmune virus treated cancer patients, is strictly dependent on the activation of complement. In immunized rats, complement depletion stabilized vaccinia virus in the blood and led to improved delivery to tumors. Complement depletion also enhanced tumor infection when virus was directly injected into tumors in immunized animals. The feasibility and safety of using a complement inhibitor, CP40, in combination with vaccinia virus was tested in cynomolgus macaques. CP40 pretreatment elicited an average 10-fold increase in infectious titer in the blood early after the infusion and prolonged the time during which infectious virus was detectable in the blood of animals with preexisting immunity. Capitalizing on the complement dependence of antivaccinia antibody with adjunct complement inhibitors may increase the infectious dose of oncolytic vaccinia virus delivered to tumors in virus in immune hosts.

Introduction: Ovarian cancer impacts approximately 1 in 75 women. Sexual health is receiving increasing attention as a critical aspect of gynecologic cancer treatment and a component of quality of life. Therefore, investigating how women with ovarian cancer experience and express sexuality is an important area of inquiry. Aims: To evaluate how women with ovarian cancer experience and express sexuality, a major determinant of quality of life, in the context of their illness. Methods: In a mixed-methods approach, 6 validated self-report questionnaires (n ¼ 64) and an in-depth focus group (n ¼ 3) were used to gather data. Results: The quantitative phase of the study showed that women with ovarian cancer have a poorer quality of life and higher rates of sexual dysfunction and sexual distress compared with published norms from the general population. They also have lower levels of relationship satisfaction and increased rates of depression. The qualitative phase of the study revealed 6 themes: (i) changes to relationship satisfaction; (ii) sexual difficulties; (iii) challenges with body image; (iv) gaps in communication with healthcare providers; (v) feelings of guilt, grief, resentment, anxiety, and fear; and (vi) strategies used for coping. Conclusions: Ovarian cancer impacts women's lives beyond mere survival, including their sexual function and quality of life. Healthcare providers are urged to prepare women with ovarian cancer for these challenges and offer information and resources to help improve their quality of life and sexuality.