Search Results (8)

Immunotherapies, including checkpoint inhibitor antibodies, have precipitated significant improvements in clinical outcomes for melanoma. However, approximately half of patients do not benefit from approved treatments. Additionally, apart from Tebentafusp, which is approved for the treatment of uveal melanoma, there is a lack of immunotherapies directly focused on melanoma cells. This is partly due to few available targets, especially those expressed on the cancer cell surface. Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell surface molecule overexpressed in human melanoma, with restricted distribution and low expression in non-malignant tissues and involved in several cancer-promoting and dissemination pathways. Here, we summarize the current understanding of the expression and functional significance of CSPG4 in health and melanoma, and we outline immunotherapeutic strategies. These include monoclonal antibodies, antibody–drug conjugates (ADCs), chimeric-antigen receptor (CAR) T cells, and other strategies such as anti-idiotypic and mimotope vaccines to raise immune responses against CSPG4-expressing melanomas. Several showed promising functions in preclinical models of melanoma, yet few have reached clinical testing, and none are approved for therapeutic use. Obstacles preventing that progress include limited knowledge of CSPG4 function in human cancer and a lack of in vivo models that adequately represent patient immune responses and human melanoma biology. Despite several challenges, immunotherapy directed to CSPG4-expressing melanoma harbors significant potential to transform the treatment landscape. Full article

Despite comprising a very small proportion of circulating blood leukocytes, basophils are potent immune effector cells. The high-affinity receptor for IgE (FcɛRI) is expressed on the basophil cell surface and powerful inflammatory mediators such as histamine, granzyme B, and cytokines are stored in dense cytoplasmic granules, ready to be secreted in response to a range of immune stimuli. Basophils play key roles in eliciting potent effector functions in allergic diseases and type 1 hypersensitivity. Beyond allergies, basophils can be recruited to tissues in chronic and autoimmune inflammation, and in response to parasitic, bacterial, and viral infections. While their activation states and functions can be influenced by Th2-biased inflammatory signals, which are also known features of several tumor types, basophils have received little attention in cancer. Here, we discuss the presence and functional significance of basophils in the circulation of cancer patients and in the tumor microenvironment (TME). Interrogating publicly available datasets, we conduct gene expression analyses to explore basophil signatures and associations with clinical outcomes in several cancers. Furthermore, we assess how basophils can be harnessed to predict hypersensitivity to cancer treatments and to monitor the desensitization of patients to oncology drugs, using assays such as the basophil activation test (BAT). Full article

IgE, the predominant antibody class of the allergic response, is known for its roles in protecting against parasites; however, a growing body of evidence indicates a significant role for IgE and its associated effector cells in tumour immunosurveillance, highlighted by the field of AllergoOncology and the successes of the first-in-class IgE cancer therapeutic MOv18. Supporting this concept, substantial epidemiological data ascribe potential roles for IgE, allergy, and atopy in protecting against specific tumour types, with a corresponding increased cancer risk associated with IgE immunodeficiency. Here, we consider how epidemiological data in combination with functional data reveals a complex interplay of IgE and allergy with cancer, which cannot be explained solely by one of the existing conventional hypotheses. We furthermore discuss how, in turn, such data may be used to inform future therapeutic approaches, including the clinical management of different patient groups. With epidemiological findings highlighting several high-risk cancer types protected against by high IgE levels, it is possible that use of IgE-based therapeutics for a range of malignant indications may offer efficacy to complement that of established IgG-class antibodies. Full article

IgE contributes to host-protective functions in parasitic and bacterial infections, often by monocyte and macrophage recruitment. We previously reported that monocytes contribute to tumour antigen-specific IgE-mediated tumour growth restriction in rodent models. Here, we investigate the impact of IgE stimulation on monocyte response, cellular signalling, secretory and tumour killing functions. IgE cross-linking on human monocytes with polyclonal antibodies to mimic formation of immune complexes induced upregulation of co-stimulatory (CD40, CD80, CD86), and reduced expression of regulatory (CD163, CD206, MerTK) monocyte markers. Cross-linking and tumour antigen-specific IgE antibody-dependent cellular cytotoxicity (ADCC) of cancer cells by cancer patient-derived monocytes triggered release of pro-inflammatory mediators (TNFα, MCP-1, IL-10, CXCL-10, IL-1β, IL-6, IL-23). High intratumoural gene expression of these mediators was associated with favourable five-year overall survival in ovarian cancer. IgE cross-linking of trimeric FcεRI on monocytes stimulated the phosphorylation of intracellular protein kinases widely reported to be downstream of mast cell and basophil tetrameric FcεRI signalling. These included recently-identified FcεRI pathway kinases Fgr, STAT5, Yes and Lck, which we now associate with monocytes. Overall, anti-tumour IgE can potentiate pro-inflammatory signals, and prime tumour cell killing by human monocytes. These findings will inform the development of IgE monoclonal antibody therapies for cancer. Full article

Immunoglobulin E (IgE) antibodies are well known for their role in allergic diseases and for contributions to antiparasitic immune responses. Properties of this antibody class that mediate powerful effector functions may be redirected for the treatment of solid tumours. This has led to the rise of a new class of therapeutic antibodies to complement the armamentarium of approved tumour targeting antibodies, which to date are all IgG class. The perceived risk of type I hypersensitivity reactions following administration of IgE has necessitated particular consideration in the development of these therapeutic agents. Here, we bring together the properties of IgE antibodies pivotal to the hypothesis for superior antitumour activity compared to IgG, observations of in vitro and in vivo efficacy and mechanisms of action, and a focus on the safety considerations for this novel class of therapeutic agent. These include in vitro studies of potential hypersensitivity, selection of and observations from appropriate in vivo animal models and possible implications of the high degree of glycosylation of IgE. We also discuss the use of ex vivo predictive and monitoring clinical tools, as well as the risk mitigation steps employed in, and the preliminary outcomes from, the first-in-human clinical trial of a candidate anticancer IgE therapeutic. Full article

Birch pollen allergy is among the most prevalent pollen allergies in Northern and Central Europe. This IgE-mediated disease can be treated with allergen immunotherapy (AIT), which typically gives rise to IgG antibodies inducing tolerance. Although the main mechanisms of allergen immunotherapy (AIT) are known, questions regarding possible Fc-mediated effects of IgG antibodies remain unanswered. This can mainly be attributed to the unavailability of appropriate tools, i.e., well-characterised recombinant antibodies (rAbs). We hereby aimed at providing human rAbs of several classes for mechanistic studies and as possible candidates for passive immunotherapy. We engineered IgE, IgG₁, and IgG₄ sharing the same variable region against the major birch pollen allergen Bet v 1 using Polymerase Incomplete Primer Extension (PIPE) cloning. We tested IgE functionality and IgG blocking capabilities using appropriate model cell lines. In vitro studies showed IgE engagement with FcεRI and CD23 and Bet v 1-dependent degranulation. Overall, we hereby present fully functional, human IgE, IgG₁, and IgG₄ sharing the same variable region against Bet v 1 and showcase possible applications in first mechanistic studies. Furthermore, our IgG antibodies might be useful candidates for passive immunotherapy of birch pollen allergy. Full article

Basophils are involved in manifestations of hypersensitivity, however, the current understanding of their propensity for activation and their prognostic value in cancer patients remains unclear. As in healthy and atopic individuals, basophil populations were identified in blood from ovarian cancer patients (n = 53) with diverse tumor histologies and treatment histories. Ex vivo basophil activation was measured by CD63 expression using the basophil activation test (BAT). Irrespective of prior treatment, basophils could be activated by stimulation with IgE- (anti-FcεRI and anti-IgE) and non-IgE (fMLP) mediated triggers. Basophil activation was detected by ex vivo exposure to paclitaxel, but not to other anti-cancer therapies, in agreement with a clinical history of systemic hypersensitivity reactions to paclitaxel. Protein and gene expression analyses support the presence of basophils (CCR3, CD123, FcεRI) and activated basophils (CD63, CD203c, tryptase) in ovarian tumors. Greater numbers of circulating basophils, cells with greater capacity for ex vivo stimulation (n = 35), and gene signatures indicating the presence of activated basophils in tumors (n = 439) were each associated with improved survival in ovarian cancer. Circulating basophils in cancer patients respond to IgE- and non-IgE-mediated signals and could help identify hypersensitivity to therapeutic agents. Activated circulating and tumor-infiltrating basophils may be potential biomarkers in oncology. Full article

Immunoglobulin E (IgE) antibodies are well known for their role in mediating allergic reactions, and their powerful effector functions activated through binding to Fc receptors FcεRI and FcεRII/CD23. Structural studies of IgE-Fc alone, and when bound to these receptors, surprisingly revealed not only an acutely bent Fc conformation, but also subtle allosteric communication between the two distant receptor-binding sites. The ability of IgE-Fc to undergo more extreme conformational changes emerged from structures of complexes with anti-IgE antibodies, including omalizumab, in clinical use for allergic disease; flexibility is clearly critical for IgE function, but may also be exploited by allosteric interference to inhibit IgE activity for therapeutic benefit. In contrast, the power of IgE may be harnessed to target cancer. Efforts to improve the effector functions of therapeutic antibodies for cancer have almost exclusively focussed on IgG1 and IgG4 subclasses, but IgE offers an extremely high affinity for FcεRI receptors on immune effector cells known to infiltrate solid tumours. Furthermore, while tumour-resident inhibitory Fc receptors can modulate the effector functions of IgG antibodies, no inhibitory IgE Fc receptors are known to exist. The development of tumour antigen-specific IgE antibodies may therefore provide an improved immune functional profile and enhanced anti-cancer efficacy. We describe proof-of-concept studies of IgE immunotherapies against solid tumours, including a range of in vitro and in vivo evaluations of efficacy and mechanisms of action, as well as ex vivo and in vivo safety studies. The first anti-cancer IgE antibody, MOv18, the clinical translation of which we discuss herein, has now reached clinical testing, offering great potential to direct this novel therapeutic modality against many other tumour-specific antigens. This review highlights how our understanding of IgE structure and function underpins these exciting clinical developments. Full article