The immune system employs several checkpoint pathways to regulate responses, maintain homeostasis and prevent self-reactivity and autoimmunity. Tumor cells can hijack these protective mechanisms to enable immune escape, cancer survival and proliferation. Blocking antibodies, designed to interfere with checkpoint molecules CTLA-4 and PD-1/PD-L1 and counteract these immune suppressive mechanisms, have shown significant success in promoting immune responses against cancer and can result in tumor regression in many patients. While inhibitors to CTLA-4 and the PD-1/PD-L1 axis are well-established for the clinical management of melanoma, many patients do not respond or develop resistance to these interventions. Concerted efforts have focused on combinations of approved therapies aiming to further augment positive outcomes and survival. While CTLA-4 and PD-1 are the most-extensively researched targets, results from pre-clinical studies and clinical trials indicate that novel agents, specific for checkpoints such as A2AR, LAG-3, IDO and others, may further contribute to the improvement of patient outcomes, most likely in combinations with anti-CTLA-4 or anti-PD-1 blockade. This review discusses the rationale for, and results to date of, the development of inhibitory immune checkpoint blockade combination therapies in melanoma. The clinical potential of new pipeline therapeutics, and possible future therapy design and directions that hold promise to significantly improve clinical prognosis compared with monotherapy, are discussed.
IgE antibodies are key mediators of antiparasitic immune responses, but their potential for cancer treatment via antibodydependent cell-mediated cytotoxicity (ADCC) has been little studied. Recently, tumor antigen-specific IgEs were reported to restrict cancer cell growth by engaging high-affinity Fc receptors on monocytes and macrophages; however, the underlying therapeutic mechanisms were undefined and in vivo proof of concept was limited. Here, an immunocompetent rat model was designed to recapitulate the human IgE-Fce receptor system for cancer studies. We also generated rat IgE and IgG mAbs specific for the folate receptor (FRa), which is expressed widely on human ovarian tumors, along with a syngeneic rat tumor model expressing human FRa. Compared with IgG, anti-FRa IgE reduced lung metastases. This effect was associated with increased intratumoral infiltration by TNFa þ and CD80
Identification of mutations in the gene encoding the serine/threonine-protein kinase, BRAF, and constitutive activation of the mitogen-activated protein kinase (MAPK) pathway in around 50% of malignant melanomas have led to the development and regulatory approval of targeted pathway inhibitor drugs. A proportion of patients are intrinsically resistant to BRAF inhibitors, and most patients who initially respond, acquire resistance within months. In this review, we discuss pathway inhibitors and their mechanisms of resistance, and we focus on numerous efforts to improve clinical benefits through combining agents with disparate modes of action, including combinations with checkpoint inhibitor antibodies. We discuss the merits of combination strategies based on enhancing immune responses or overcoming tumor-associated immune escape mechanisms. Emerging insights into mechanisms of action, resistance pathways and their impact on host-tumor relationships will inform the design of optimal combinations therapies to improve outcomes for patients who currently do not benefit from recent treatment breakthroughs.
Overexpression of the chondroitin sulfate proteoglycan 4 (CSPG4) has been associated with the pathology of multiple types of such as melanoma, breast cancer, squamous cell carcinoma, mesothelioma, neuroblastoma, adult and pediatric sarcomas, and some hematological cancers. CSPG4 has been reported to exhibit a role in the growth and survival as well as in the spreading and metastasis of tumor cells. CSPG4 is overexpressed in several malignant diseases, while it is thought to have restricted and low expression in normal tissues. Thus, CSPG4 has become the target of numerous anticancer treatment approaches, including monoclonal antibody-based therapies. This study reviews key potential anti-CSPG4 antibody and immune-based therapies and examines their direct antiproliferative/metastatic and immune activating 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.
Our findings indicate safety of MOv18 IgE, in conjunction with efficacy and immune activation, supporting the translation of this therapeutic approach to the clinical arena.
Background: All antibodies approved for the treatment of cancer are monoclonal IgGs, and no IgE therapy has yet been tested in humans. The biology of IgE, compared with IgG, offers potential for enhanced immune surveillance and superior effector cell potency against tumor cells. IgE antibodies in preclinical cancer models are not associated with allergic toxicity even in immunocompetent animals, and in vivo efficacy compares favorably with equivalent IgGs. Methods: We conducted a first-in-human first-in-class trial of MOv18, a chimeric monoclonal IgE, in patients with solid tumors expressing folate receptor-alpha, the antigen recognized by this antibody. Antigen expression was deemed positive in the presence of >5% membrane staining of any intensity using the mouse clone BN3.2. Intravenous treatment was administered weekly for 6 weeks, then two-weekly. The trial incorporated pre-treatment skin prick testing with MOv18 IgE, and an ex vivo basophil activation test (BAT) using patient whole blood, with the aim of predicting systemic allergic toxicity and excluding patients at potential risk. Safety, efficacy, markers of immune response, and pharmacokinetics have been evaluated in 24 patients to date, at total doses ranging from 0.07 to 3.0mg. Results: Treatment was well tolerated in almost all patients. The most common toxicity was readily manageable urticaria, without systemic symptoms, signs or tryptase elevation. One patient treated at the 0.5mg dose experienced anaphylaxis, with tryptase elevation, despite a negative pre-dose skin prick test. This was the only patient in the trial with baseline circulating basophils that could be activated by ex vivo exposure to MOv18 IgE. This BAT assay was subsequently used to ensure no further patient with reactive basophils was exposed. Maximum tolerated dose has not yet been reached. Dose-dependent increases in Cmax were observed, and plasma concentrations of 70-100ng/mL achieved at the 1.5mg dose are comparable to typical levels of endogenous IgE. No consistent anti-drug antibody response has been detected. Preliminary evidence of anti-tumor activity was seen in a patient with ovarian cancer at a total MOv18 IgE dose of 0.7mg. Shrinkage of peritoneal metastases was accompanied by a tumor marker reduction meeting Gynecologic Cancer InterGroup criteria for response. Conclusions: These results support for the first time the safety of IgE as a treatment for cancer, and provide preliminary evidence for anti-tumor efficacy of this new therapeutic class. The mechanism of cutaneous toxicity is being investigated. Clinical testing of class-switched IgE versions of approved IgG-based therapeutic antibodies is warranted. Citation Format: James Spicer, Bristi Basu, Ana Montes, Udai Banerji, Rebecca Kristeleit, Gareth J. Veal, Christopher Corrigan, Stephen Till, George Nintos, Timothy Brier, Ionut G. Funingana, Joo Ern Ang, Kam Zaki, Annie Griffin, Claire Barton, Paul Jones, Sarah Mellor, Susan Brook, Katie Stoddart, Christopher Selkirk, Simon Carroll, Heike Lentfer, Natalie Woodman, Amy Pope, Giulia Pellizzari, Mano Nakamura, Kristina M. Ilieva, Atousa Khiabany, Chara Stavraka, Hannah Gould, Jitesh Chauhan, Heather Bax, Sarah Pinder, Debra Josephs, Sophia Karagiannis. Phase 1 trial of MOv18, a first-in-class IgE antibody therapy for cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT141.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.