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BackgroundThe ability to modulate immune-inhibitory pathways using checkpoint blockade antibodies such as αPD-1, αPD-L1, and αCTLA-4 represents a significant breakthrough in cancer therapy in recent years. This has driven interest in identifying small-molecule-immunotherapy combinations to increase the proportion of responses. Murine syngeneic models, which have a functional immune system, represent an essential tool for pre-clinical evaluation of new immunotherapies. However, immune response varies widely between models and the translational relevance of each model is not fully understood, making selection of an appropriate pre-clinical model for drug target validation challenging.MethodsUsing flow cytometry, O-link protein analysis, RT-PCR, and RNAseq we have characterized kinetic changes in immune-cell populations over the course of tumor development in commonly used syngeneic models.ResultsThis longitudinal profiling of syngeneic models enables pharmacodynamic time point selection within each model, dependent on the immune population of interest. Additionally, we have characterized the changes in immune populations in each of these models after treatment with the combination of α-PD-L1 and α-CTLA-4 antibodies, enabling benchmarking to known immune modulating treatments within each model.ConclusionsTaken together, this dataset will provide a framework for characterization and enable the selection of the optimal models for immunotherapy combinations and generate potential biomarkers for clinical evaluation in identifying responders and non-responders to immunotherapy combinations.

The Ataxia telangiectasia and Rad3-related (ATR) inhibitor ceralasertib in combination with the PD-L1 antibody durvalumab demonstrated encouraging clinical benefit in melanoma and lung cancer patients who progressed on immunotherapy. Here we show that modelling of intermittent ceralasertib treatment in mouse tumor models reveals CD8 + T-cell dependent antitumor activity, which is separate from the effects on tumor cells. Ceralasertib suppresses proliferating CD8 + T-cells on treatment which is rapidly reversed off-treatment. Ceralasertib causes up-regulation of type I interferon (IFNI) pathway in cancer patients and in tumor-bearing mice. IFNI is experimentally found to be a major mediator of antitumor activity of ceralasertib in combination with PD-L1 antibody. Improvement of T-cell function after ceralasertib treatment is linked to changes in myeloid cells in the tumor microenvironment. IFNI also promotes anti-proliferative effects of ceralasertib on tumor cells. Here, we report that broad immunomodulatory changes following intermittent ATR inhibition underpins the clinical therapeutic benefit and indicates its wider impact on antitumor immunity. The ATR inhibitor ceralasertib has shown clinical activity in combination with immune-checkpoint inhibitors in several cancer types. Here the authors report the anti-tumor activity and the immunomodulatory changes, dependent on up-regulation of type I interferon pathway, following intermittent ATR inhibition in preclinical cancer models.

Malaria remains a global health burden. Elimination of the hypnozoite is required in patients infected with P. vivax to prevent relapse. In this report, the safety of a single dose of tafenoquine was similar to that of a 14-day course of primaquine in patients with normal G6PD activity.

Clearing of the dormant liver stage (the hypnozoite) of P. vivax malaria is important to prevent the relapse of infection. In this randomized clinical trial, a single dose of tafenoquine is shown to have significant activity against the hypnozoite form of P. vivax .

PI3K inhibitors with differential selectivity to distinct PI3K isoforms have been tested extensively in clinical trials, largely to target tumor epithelial cells. PI3K signaling also regulates the immune system and inhibition of PI3Kδ modulate the tumor immune microenvironment of pre-clinical mouse tumor models by relieving T-regs-mediated immunosuppression. PI3K inhibitors as a class and PI3Kδ specifically are associated with immune-related side effects. However, the impact of mixed PI3K inhibitors in tumor immunology is under-explored. Here we examine the differential effects of AZD8835, a dual PI3Kα/δ inhibitor, specifically on the tumor immune microenvironment using syngeneic models. Continuous suppression of PI3Kα/δ was not required for anti-tumor activity, as tumor growth inhibition was potentiated by an intermittent dosing/schedule in vivo. Moreover, PI3Kα/δ inhibition delivered strong single agent anti-tumor activity, which was associated with dynamic suppression of T-regs, improved CD8 + T-cell activation and memory in mouse syngeneic tumor models. Strikingly, AZD8835 promoted robust CD8 + T-cell activation dissociated from its effect on T-regs. This was associated with enhancing effector cell viability/function. Together these data reveal novel mechanisms by which PI3Kα/δ inhibitors interact with the immune system and validate the clinical compound AZD8835 as a novel immunoncology drug, independent of effects on tumor cells. These data support further clinical investigation of PI3K pathway inhibitors as immuno-oncology agents.

Rural health services, and the workforces that provide those services, are under unprecedented pressure due to insufficient health workforce numbers and distribution of health workforce weighted to urban areas. This creates health service access issues in rural areas, compounding existing health inequalities between rural and urban people. Many approaches to date have aimed to rectify these issues, with moderate success. In this article we present a call to action to pursue a complementary approach: supporting the capability of the rural health workforce. We hypothesise that further exploring what it means to be a 'capable' rural health professional and what processes or conditions support or erode capability may additionally bolster efforts toward strong rural and remote health systems. The Capability Approach is a theory proposed by Amartya Sen, who was awarded the Nobel Memorial Prize in Economic Sciences in 1998 for this work. Although the Capability Approach inspired, for instance, the UN's Human Development Index, it has not been deeply explored in the context of rural health workforce. While still untested, a focus on capability may assist us in taking a broader view, which encompasses functioning and the freedom to pursue different functioning combinations. The feasible freedom and opportunities are paramount to the concept of capability. We posit that competence is static and the responsibility of the practitioner (and their education), but that capability is fluid and multidimensional and the responsibility of the practitioner, community and system. Therefore, we hypothesise that a focus on a Capability Approach, which modulates the relation between the contextual factors and outcomes, may provide us with greater understanding and avenues for action when we aim to improve outcomes such as rural health service sustainability. Developing a list of appropriate capabilities and setting strategies to support capability and its more nuanced domains may present unique opportunities for influence, and these may have positive effects on the rural health workforce. Of course it will need to be determined if improving rural primary health professionals' capability has positive impacts upon quality and access to care, and whether supporting capability is sustainable and worthy of investment.