Let's talk about sex(ual) wellbeing! Staff perceptions of implementing a novel service for people with Multiple Sclerosis.

BACKGROUND: In people with multiple sclerosis (PwMS), a complex interplay of neurological dysfunction, polypharmacy and psychological issues, contrive to impair their sexual and reproductive wellbeing. Realising an unmet need, the Tayside MS service in collaboration with a sexual health clinician (LJ), established a 'Pelvic Health Clinic' to improve quality of life for PwMS. OBJECTIVE: To explore clinician's perceptions of implementing an MS Pelvic Health service with a view to establishing future outcomes for health care professionals about the utility in such a service. METHOD: In this small-scale qualitative case study, we explored clinician's perceptions of such a clinic adjunct. Semi-structured interviews were conducted, transcribed, and thematically analysed in a reflexive manner. RESULTS: Five participants consented. Ten sub-themes emerged, which were organised into three main themes: service tensions, patient needs and practitioner feelings. CONCLUSION: Clinicians highly valued the new MS 'pelvic health clinic'. Knowing that there was a service available empowered clinicians to ask patients about sexual health needs. Specific referral criteria may help further develop the service and improve patient care. Staff welcome training and support in this area or the option to signpost onwards; either mechanism lends itself to enhancing MS patient needs.

Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity.

mTOR inhibition can promote or inhibit immune responses in a context dependent manner, but whether this will represent a net benefit or be contraindicated in the context of immunooncology therapies is less understood. Here, we report that the mTORC1/2 dual kinase inhibitor vistusertib (AZD2014) potentiates anti-tumour immunity in combination with anti-CTLA-4 (αCTLA-4), αPD-1 or αPD-L1 immune checkpoint blockade. Combination of vistusertib and immune checkpoint blocking antibodies led to tumour growth inhibition and improved survival of MC-38 or CT-26 pre-clinical syngeneic tumour models, whereas monotherapies were less effective. Underlying these combinatorial effects, vistusertib/immune checkpoint combinations reduced the occurrence of exhausted phenotype tumour infiltrating lymphocytes (TILs), whilst increasing frequencies of activated Th1 polarized T-cells in tumours. Vistusertib alone was shown to promote a Th1 polarizing proinflammatory cytokine profile by innate primary immune cells. Moreover, vistusertib directly enhanced activation of effector T-cell and survival, an effect that was critically dependent on inhibitor dose. Therefore, these data highlight direct, tumour-relevant immune potentiating benefits of mTOR inhibition that complement immune checkpoint blockade. Together, these data provide a clear rationale to investigate such combinations in the clinic.

PI3Kα/δ inhibition promotes anti-tumor immunity through direct enhancement of effector CD8+ T-cell activity.

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.