Ben Coumbe - Academia.edu (original) (raw)

Papers by Ben Coumbe

OncoImmunology, Nov 20, 2017

Expert Review of Clinical Immunology, 2022

ABSTRACT Introduction The treatment of cutaneous melanoma has been revolutionized by the developm... more ABSTRACT 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.

European Journal of Immunology, 2021

Cytotoxic T‐lymphocyte associated protein‐4 (CTLA‐4) and the Programmed Death Receptor 1 (PD‐1) a... more 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.

Oncoimmunology, 2018

Antibody-drug conjugates (ADCs) are emerging as effective tools in cancer therapy, combining the ... more 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.

Rheumatology, 2021

Background/Aims Systemic sclerosis (SSc) is a rare and progressive connective tissue disease tha... more Background/Aims Systemic sclerosis (SSc) is a rare and progressive connective tissue disease that is more common in women in the third to fifth decades of life and is rare in children. Calcinosis cutis, the deposition of calcium deposits within the subcutaneous tissue, remains a challenging non-lethal complication of SSc. The development of calcinosis cutis is a poorly understood area and there are no functional mouse models or laboratory models for calcinosis in SSc. In this study we present clinical database analysis plus two potential in vitro models for examining calcinosis in the setting of SSc. Methods Clinical modelling through database analysis of n = 79 SSc patients with and without calcinosis was attempted. In tissue culture studies, the first model system utilised adipose-derived mesencyhmal stem cells (MSCs) stimulated with interstitial fluid from healthy controls or SSc patients (both n = 4). In a second model, macrophages from patients with SSc (n = 4 lines) were use...

Annals of the Rheumatic Diseases, 2021

Background:Ophthalmic conditions are common manifestations in patients with rheumatic diseases (R... more Background:Ophthalmic conditions are common manifestations in patients with rheumatic diseases (RDs), orbital myositis (OM) remain rare. Only 1 case each for scleroderma and undifferentiated connective tissue disease (UCTD) reported.Objectives:Report frequency of Rheumatic Diseases with OM (RDs-OM), diagnosis and treatments.Methods:Patients database were obtained from trust electronic record and literature review of case reports were performed.Results:4 out of 7 patients in our clinic with RDs-OM. Both Scleroderma-myositis (SCM) patients were positive for anti-PM/SCL antibody. All received glucocorticosteroid (GCS) and Mycophenolate as steroid-sparing or rescue therapy with good tolerance and outcome. One idiopathic OM has residual muscle paresis.Table 1.Case series of patients with Orbital MyositisIdiopathicOM(n=3)Rheumatology Diseases(n=4)p-valueAge (years)48 (27-72)42.75 (21-60)P= 0.8571Gender – Female (Male)2 (1)4(0)Median Period Of Follow Up (months)24.60 (7-37)47.25(1-120)Unde...

The therapeutic armamentarium available for treatment of rheumatoid arthritis (RA) has changed si... more The therapeutic armamentarium available for treatment of rheumatoid arthritis (RA) has changed significantly over the past 30 years, transforming the therapeutic landscape and prognosis for a substantial proportion of patients with RA. Combination therapies represent an important therapeutic paradigm for management of rheumatoid arthritis. The rationale for combination therapies is clear and demonstrated to bring treatment benefit to patients achieving lower disease activity scores and reduced radiologic progression according to ‘treat-to-target’ principles. A rigorous evidence-based debate is required involving not only parameters related to disease activity scores and radiologic progression, but related to the cost-effectiveness analysis of using many of these newer agents compared to older csDMARDs. This chapter addresses the evidence related to the utilization of combination strategies for the management of RA as compared to monotherapy.