BRAF inhibitors and their immunological effects in malignant melanoma.

INTRODUCTION: The treatment of cutaneous melanoma has been revolutionized by the development of small-molecule inhibitors targeting the MAPK pathway, including inhibitors of BRAF (BRAFi) and MEK (MEKi), and immune checkpoint blockade antibodies, occurring in tandem. Despite these advances, the 5-year survival rate for patients with advanced melanoma remains only around 50%. Although not designed to alter immune responses within the tumor microenvironment (TME), MAPK pathway inhibitors (MAPKi) exert a range of effects on the host immune compartment that may offer opportunities for therapeutic interventions. AREAS COVERED: We review the effects of MAPKi, especially BRAFi, on the TME, focusing on alterations in inflammatory cytokine secretion, recruitment of immune cells and their functions, both during response to BRAFi treatment and as resistance develops. We outline potential combinations of MAPKi with established and experimental treatments. EXPERT OPINION: MAPKi in combination or in sequence with established treatments such as checkpoint inhibitors, anti-angiogenic agents, or new therapies such as adoptive cell therapies, may augment their immunological effects, reverse tumor-associated immune suppression, and offer the prospect of longer-lived clinical responses. Refining therapeutic tools at our disposal and embracing 'old friends' in the melanoma treatment arsenal, alongside new target identification, may improve the chances of therapeutic success.

Combined anti-PD-1 and anti-CTLA-4 checkpoint blockade: Treatment of melanoma and immune mechanisms of action.

Cytotoxic T-lymphocyte associated protein-4 (CTLA-4) and the Programmed Death Receptor 1 (PD-1) are immune checkpoint molecules that are well-established targets of antibody immunotherapies for the management of malignant melanoma. The monoclonal antibodies, Ipilimumab, Pembrolizumab, and Nivolumab, designed to interfere with T cell inhibitory signals to activate immune responses against tumors, were originally approved as monotherapy. Treatment with a combination of immune checkpoint inhibitors may improve outcomes compared to monotherapy in certain patient groups and these clinical benefits may be derived from unique immune mechanisms of action. However, treatment with checkpoint inhibitor combinations also present significant clinical challenges and increased rates of immune-related adverse events. In this review, we discuss the potential mechanisms attributed to single and combined checkpoint inhibitor immunotherapies and clinical experience with their use.

Cardiovascular Autonomic Dysfunction in Patients with Cancer.

PURPOSE OF REVIEW: Elucidating the mechanisms that contribute to adverse cardiovascular (CV) outcomes and reduce quality of life among patients with cancer is paramount. Cancer, certain cancer drugs, radiation therapy, cancer-associated lifestyle disturbances, and cancer-independent comorbidities combine to predispose oncology patients to autonomic dysfunction (AD). This review will explore the assessment, etiology, and clinical implications of AD in cancer patients and will speculate on therapeutic and research opportunities. RECENT FINDINGS: AD is particularly prevalent among patients with advanced cancer, but studies suggest increased prevalence across the entire continuum of cancer survivors compared to cancer-free controls. Data on cancer therapy-induced injury to the autonomic nervous system are limited to small studies. AD has been reported after cranial, neck, and mediastinal radiation therapy. Although AD has been shown to confer increased risk of adverse CV outcomes in cancer-free patients, the prognostic relevance of AD in oncology patients is less well investigated. Markers of AD including elevated resting heart rate (HR), reduced HR variability, and abnormal HR recovery have been associated with shorter survival times in various cancer cohorts. Furthermore, AD has been implicated in the etiology of cancer-related fatigue and exercise limitation. Multiple risk factors predispose oncology patients to AD, which is associated with adverse outcomes, including increased mortality, exercise limitation, and fatigue among this cohort. The contribution of AD to overall morbidity and mortality in cancer survivors has largely been overlooked to date. Further investigation is necessary to better understand cancer-treatment specific autonomic injury and to evaluate the role of various pharmacological and non-pharmacological interventions with potential to tackle the sympathovagal imbalance observed in cancer survivors.

Antibody structure and engineering considerations for the design and function of Antibody Drug Conjugates (ADCs).

Antibody-drug conjugates (ADCs) are emerging as effective tools in cancer therapy, combining the antibody's exquisite specificity for the target antigen-expressing cancer cell together with the cytotoxic potency of the payload. Much success stems from the rational design of "toxic warheads", chemically linked to antibodies, and from fine-tuning the intricate properties of chemical linkers. Here, we focus on the antibody moiety of ADCs, dissecting the impact of Fab, linkers, isotype and Fc structure on the anti-tumoral and immune-activating functions of ADCs. Novel design approaches informed by antibody structural attributes present opportunities that may contribute to the success of next generation ADCs.

Dispelling the nice or naughty myth: retrospective observational study of Santa Claus.

OBJECTIVE:  To determine which factors influence whether Santa Claus will visit children in hospital on Christmas Day. DESIGN:  Retrospective observational study. SETTING:  Paediatric wards in England, Northern Ireland, Scotland, and Wales. PARTICIPANTS:  186 members of staff who worked on the paediatric wards (n=186) during Christmas 2015. MAIN OUTCOME MEASURES:  Presence or absence of Santa Claus on the paediatric ward during Christmas 2015. This was correlated with rates of absenteeism from primary school, conviction rates in young people (aged 10-17 years), distance from hospital to North Pole (closest city or town to the hospital in kilometres, as the reindeer flies), and contextual socioeconomic deprivation (index of multiple deprivation). RESULTS:  Santa Claus visited most of the paediatric wards in all four countries: 89% in England, 100% in Northern Ireland, 93% in Scotland, and 92% in Wales. The odds of him not visiting, however, were significantly higher for paediatric wards in areas of higher socioeconomic deprivation in England (odds ratio 1.31 (95% confidence interval 1.04 to 1.71) in England, 1.23 (1.00 to 1.54) in the UK). In contrast, there was no correlation with school absenteeism, conviction rates, or distance to the North Pole. CONCLUSION:  The results of this study dispel the traditional belief that Santa Claus rewards children based on how nice or naughty they have been in the previous year. Santa Claus is less likely to visit children in hospitals in the most deprived areas. Potential solutions include a review of Santa's contract or employment of local Santas in poorly represented regions.