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Ruxolitinib is a selective, Janus kinase (JAK)1 and JAK2 inhibitor, which is effective in management of chronic graft-versus-host disease (cGvHD). However, the ensuing immunosuppressive effects can give rise to aggressive cutaneous tumours, including Merkel cell carcinoma. We present this case to highlight the development of cutaneous tumours with ruxolitinib, an increasingly used therapy, and the challenge of managing such tumours in the context of refractory cGvHD. Click here for the corresponding questions to this CME article., (© 2022 British Association of Dermatologists.)

Background: Inflammation can modulate tumour growth and progression, and influence clinical response to treatment. We investigated the potential of circulating inflammatory proteins for response stratification of immune checkpoint inhibitor (ICI) therapy for advanced melanoma., Methods: Study subjects were 87 patients with unresectable stage III or IV cutaneous melanoma from the multiple centres across the United Kingdom (UK) and the Netherlands (NL) who received ipilimumab, nivolumab, or pembrolizumab, or a combination of ipilimumab and nivolumab. Serum samples were collected before and during ICI therapy at follow-up visits scheduled every third week over a 12-week period. We performed targeted quantification of 92 proteins involved in inflammation and tested for association of their pre-treatment and on-treatment levels, as well as longitudinal changes, with overall response rate, progression-free survival, and overall survival., Findings: We observed consistently higher pre-treatment levels of interleukin-6 (IL-6), hepatocyte growth factor (HGF), and monocyte chemotactic protein 2 (MCP-2), in non-responders compared to responders (meta-analysis p=3.31 × 10 -4 , 2.29 × 10 -4 , and 1.02 × 10 -3 , respectively). Patients' stratification according to the median value of IL-6, HGF, and MCP-2 highlighted a cumulative negative effect of pre-treatment levels of the three proteins on response (p=1.13 × 10 -2 ), with overall response rate among patients presenting with combined elevated IL-6, HGF, and MCP-2 levels being three-fold lower (26.7%) compared to patients with none of the three proteins elevated (80.0%, p=9.22 × 10 -3 ). Longitudinal data analysis showed that on-treatment changes in circulating inflammatory proteins are not correlated with response., Interpretation: Our findings are in line with an increasing body of evidence that the pro-inflammatory cytokine IL-6 can influence response to ICI in advanced melanoma, and further support a role of circulating HGF and MCP-2 levels as prognostic biomarkers as suggested by previous smaller studies. Inflammatory proteins may serve as predictive biomarkers of ICI response and valuable targets for combination therapy., Funding: This work was supported by the Seerave Foundation and Dutch Cancer Society., Competing Interests: Declaration of interests RKW acted as a consultant for Takeda, received unrestricted research grants from Takeda, Johnson & Johnson, Tramedico, and Ferring, and received speaker fees from MSD, Abbvie and Janssen Pharmaceuticals. TDS is a co-founder of Zoe Global. EGEdV reports an advisory role at Daiichi Sankyo, NSABP and Sanofi (paid to University Medical Center Groningen), and research funding from Amgen, AstraZeneca, Bayer, Crescendo, Chugai Pharma, CytomX Therapeutics, G1 Therapeutics, Genentech, Nordic Nanovector, Radius Health, Regeneron, Roche, Servier and Synthon (paid to University Medical Center Groningen). SP received speaker fees from Almirall, BMS, ISDIN, La Roche Posay, Leo Pharma, Regeneron, Roche, Sanofi, and acted as an advisory board for Almirall, ISDIN, La Roche Posay, Pfizer, Roche, Regeneron, Sanofi, Sunpharma and research funding from Abbie, AMGEN, ISDIN, La Roche Posay, Leo Pharma, Novartis. SP is also an employee of Enara Bio. RB has received honoraria from, and sits on advisory boards of, Novartis, BMS and MSD. PN has received honoraria in the last 2 years for advisory board membership for AztraZeneca, Esai, BMS, Immunocore, Ipsen, Merck, MSD, Novartis, Pfizer, 4SC. HS has received honoraria for consulting/advisory board membership and speaker's bureau from Novartis, BMS, Sanofi and MSD, along with honoraria for consulting/advisory board membership from Immunocore, Idera, Iovance, Genmab, Genzyme/Regeneron, Macrogenics and Roche. JS received a grant to his institution to fund investigator led research from Immunocore, along with personal fees and institution fees for advisory roles and presentations at meetings from Immunocore. JS also declares a grant for an investigator sponsored trial, personal fees for advisory board attendance and support in attending conferences along with institutional support to run BMS sponsored trials from BMS. JS has received a grant to fund investigator sponsored trials from AstraZeneca, funding from Replimune to his institution to fund Replimune sponsored research and honoraria from Pierre-Fabre. JS has received fees from MSD for advisory board/conference attendance as well as his institution receiving funding to run MSD clinical trials. PL has received personal fees from BMS, Merck, Novartis, GSK, Amgen, Chugai, Pierre-Fabre, NeraCare, Roche and Oncology Education Canada. LT reports research funding from a Sanofi iAward. GH received a research grant from BMS, along with consultancy/advisory relationships with Amgen, Bristol-Myers Squibb, Roche, MSD, Pfizer, Novartis, Sanofi and Pierre Fabre., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

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.

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., (© 2021 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)