Cancer immunotherapy has shown impressive results, but most patients do not respond. We hypothesized that the effector response in the tumour could be visualized as a complex network of interacting gene products and that by mapping this network we could predict effective pharmacological interventions. Here, we provide proof of concept for the validity of this approach in a murine mesothelioma model, which displays a dichotomous response to anti-CTLA4 immune checkpoint blockade. Network analysis of gene expression profiling data from responding versus non-responding tumours was employed to identify modules associated with response. Targeting the modules via selective modulation of hub genes or alternatively by using repurposed pharmaceuticals selected on the basis of their expression perturbation signatures dramatically enhanced the efficacy of CTLA4 blockade in this model. Our approach provides a powerful platform to repurpose drugs, and define contextually relevant novel therapeutic targets.

We describe an approach to inhibit chemotherapy-induced myelosuppression. We found that short-term exposure of mice to the FLT3 inhibitor quizartinib induced the transient quiescence of multipotent progenitors (MPPs). This property of quizartinib conferred marked protection to MPPs in mice receiving fluorouracil or gemcitabine. The protection resulted in the rapid recovery of bone marrow and blood cellularity, thus preventing otherwise lethal myelosuppression. A treatment strategy involving quizartinib priming that protected wild-type bone marrow progenitors, but not leukemic cells, from fluorouracil provided a more effective treatment than conventional induction therapy in mouse models of acute myeloid leukemia. This strategy has the potential to be extended for use in other cancers where FLT3 inhibition does not adversely affect the effectiveness of chemotherapy. Thus, the addition of quizartinib to cancer treatment regimens could markedly improve cancer patient survival and quality of life.

In the event of a novel influenza A virus pandemic, prophylaxis mediated by antibodies provides an adjunct control option to vaccines and antivirals. This strategy is particularly pertinent to unvaccinated populations at risk during the lag time to produce and distribute an effective vaccine. Therefore, development of effective prophylactic therapies is of high importance. Although previous approaches have used systemic delivery of monoclonal antibodies or convalescent sera, available supply is a serious limitation. Here, we have investigated intranasal delivery of influenza-specific ovine polyclonal IgG antibodies for their efficacy against homologous influenza virus challenge in a mouse model. Both influenza-specific IgG and F(ab’)2 reduced clinical scores, body weight loss and lung viral loads in mice treated 1 hour before virus exposure. Full protection from disease was also observed when antibody was delivered up to 3 days prior to virus infection. Furthermore, effective prophylaxis was independent of a strong innate immune response. This strategy presents a further option for prophylactic intervention against influenza A virus using ruminants to generate a bulk supply that could potentially be used in a pandemic setting, to slow virus transmission and reduce morbidity associated with a high cytokine phenotype.