Safety and Clinical Activity of MEDI0562, a Humanized OX40 Agonist Monoclonal Antibody, in Adult Patients with Advanced Solid Tumors

Glisson, Bonnie S.; Leidner, Rom S.; Ferris, Robert L.; Powderly, John D.; Rizvi, Naiyer A.; Keam, Bhumsuk; Schneider, Reva; Goel, Sanjay; Ohr, James; Burton, J. F.; Zheng, Yanan; Eck, Steven; Gribbin, Matthew; Streicher, Katie; Townsley, Danielle M.; Patel, Sandip Pravin

doi:10.1158/1078-0432.ccr-19-3070

Cited by 59 publications

(46 citation statements)

References 47 publications

(75 reference statements)

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“…Among them, activation of ICOS, 4-1BB, and GITR was shown to inhibit Treg suppressive function but stimulate effector T cells (57,58), leading to several clinical trials. Agonistic anti-OX40 mAb (59) is being tried as a monotherapy or a combination therapy with ICI on solid tumors (NCT02221960). GITR agonists are also being tested on solid tumors alone or in combinations with ICIs (NCT02583165 and NCT02628574) (60).…”

Section: Therapeutic Targets To Specifically Deplete Intratumoral Tregsmentioning

confidence: 99%

The Impact of Tregs on the Anticancer Immunity and the Efficacy of Immune Checkpoint Inhibitor Therapies

et al. 2021

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Although cancers arise from genetic mutations enabling cells to proliferate uncontrollably, they cannot thrive without failure of the anticancer immunity due in a large part to the tumor environment's influence on effector and regulatory T cells. The field of immune checkpoint inhibitor (ICI) therapy for cancer was born out of the fact that tumor environments paralyze the immune cells that are supposed to clear them by activating the immune checkpoint molecules such as PD-1. While various subsets of effector T cells work collaboratively to eliminate cancers, Tregs enriched in the tumor environment can suppress not only the native anticancer immunity but also diminish the efficacy of ICI therapies. Because of their essential role in suppressing autoimmunity, various attempts to specifically deplete tumor-associated Tregs are currently underway to boost the efficacy of ICI therapies without causing systemic autoimmune responses. A better understanding the roles of Tregs in the anti-cancer immunity and ICI therapies should provide more specific targets to deplete intratumoral Tregs. Here, we review the current understanding on how Tregs inhibit the anti-cancer immunity and ICI therapies as well as the advances in the targeted depletion of intratumoral Tregs.

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Section: Therapeutic Targets To Specifically Deplete Intratumoral Tregsmentioning

confidence: 99%

The Impact of Tregs on the Anticancer Immunity and the Efficacy of Immune Checkpoint Inhibitor Therapies

et al. 2021

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“…On ligand binding, T-cell survival, proliferation and effector function is enhanced (55). MEDI0562 is an agonistic, humanized IgG monoclonal antibody directed at OX40 that has undergone phase I evaluation with acceptable toxicity (56). It is anticipated that the combination of MEDI0562 with ICI may enhance the immunomodulatory effects.…”

Section: Mechanisms Of Ici Resistance In Hcc and Treatment Strategiesmentioning

confidence: 99%

Beyond First-Line Immune Checkpoint Inhibitor Therapy in Patients With Hepatocellular Carcinoma

Sharma

Aval

2021

Front. Immunol.

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Until recently, the treatment landscape for hepatocellular cancer (HCC) was dominated by tyrosine kinase inhibitors (TKIs) which offered an overall survival (OS) benefit when used both in the first-and second-line setting compared to best supportive care. However, the treatment landscape has changed with the introduction of immune checkpoint inhibitors (ICIs) for the treatment of HCC with significant improvement in OS and progression free survival reported with combination atezolizumab and bevacizumab compared to sorafenib in the first-line setting. Nonetheless, the response to ICIs is 20–30% and invariably patients will progress. What remains unclear is which therapeutics should be used following ICI exposure. Extrapolating from the evidence base in renal cell carcinoma, subsequent therapy with TKIs offers both a response and survival benefit and are recommended by European guidelines. However, there are a number of novel therapies emerging that target mechanisms of ICI resistance that hold promise both in combination with ICI or as subsequent therapy. This paper will discuss the evidence for ICIs in HCC, the position of second-line therapies following ICIs and research strategies moving forward.

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“…Co-stimulatory receptors are present on T cells and counter-act the negative regulation of inhibitory receptors such as PD-1 and CTLA-4 ( 51 ). Phase I studies of anti-OX40 agonists have yielded disappointing results, with a single partial response noted in the trial of MEDI0562 in advanced solid tumors, and best response of stable disease with GSK998 ( 52 , 53 ). When combined with pembrolizumab in a trial enrolling 96 patients, anti-OX40, gave 2 CRs and 7PRs ( 53 ).…”

Section: Alternative Checkpoint Receptor Pathwaysmentioning

confidence: 99%

Beyond PD-1: The Next Frontier for Immunotherapy in Melanoma

Rohatgi

Kirkwood

2021

Front. Oncol.

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The advent of first and second-generation immune checkpoint blockade (ICI) has resulted in improved survival of patients with metastatic melanoma over the past decade. However, the majority of patients ultimately progress despite these treatments, which has served as an impetus to consider a range of subsequent therapies. Many of the next generation of immunotherapeutic agents focus on modifying the immune system to overcome resistance to checkpoint blockade. ICI resistance can be understood as primary, or acquired—where the latter is the most common scenario. While there are several postulated mechanisms by which resistance, particularly acquired resistance, occurs, the predominant escape mechanisms include T cell exhaustion, upregulation of alternative inhibitory checkpoint receptors, and alteration of the tumor microenvironment (TME) into a more suppressive, anti-inflammatory state. Therapeutic agents in development are designed to work by combating one or more of these resistance mechanisms. These strategies face the added challenge of minimizing immune-related toxicities, while improving antitumor efficacy. This review focuses upon the following categories of novel therapeutics: 1) alternative inhibitory receptor pathways; 2) damage- or pathogen-associated molecular patterns (DAMPs/PAMPs); and 3) immune cell signaling mediators. We present the current state of these therapies, including preclinical and clinical data available for these targets under development.

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Safety and Clinical Activity of MEDI0562, a Humanized OX40 Agonist Monoclonal Antibody, in Adult Patients with Advanced Solid Tumors

Cited by 59 publications

References 47 publications

The Impact of Tregs on the Anticancer Immunity and the Efficacy of Immune Checkpoint Inhibitor Therapies

The Impact of Tregs on the Anticancer Immunity and the Efficacy of Immune Checkpoint Inhibitor Therapies

Beyond First-Line Immune Checkpoint Inhibitor Therapy in Patients With Hepatocellular Carcinoma

Beyond PD-1: The Next Frontier for Immunotherapy in Melanoma

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